All Databases | PubMed | Nucleotide | Protein | Genome | Structure | PMC | Taxonomy | OMIM
Search for Save Search
|  | Limits |  |  |  | Preview/Index |  |  |  | History |  |  |  | Clipboard |  |  |  | Details |  |  |

Entrez OMIM Search OMIM Search Gene Map Search Morbid Map Help OMIM Help How to Link FAQ Numbering System Symbols How to Print Citing OMIM Download OMIM Facts Statistics Update Log Restrictions on Use Allied Resources Genetic Alliance Databases HGMD Locus-Specific Model Organisms MitoMap Phenotype Davis Human/Mouse Homology Maps Coriell The Jackson Laboratory Human Gene Nomenclature Human Genome Resources Genes and Disease LocusLink Map Viewer Sequencing Progress |  |
Display Show
| All: 55 |  |
Items 1 - 20 of 55 |
| of 3 |  | Next
1: | *607585 | GeneTests, Links
| ATAXIA-TELANGIECTASIA MUTATED GENE; ATM
### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE STRUCTURE MAPPING GENE FUNCTION MOLECULAR GENETICS ANIMAL MODEL ALLELIC VARIANTS View List SEE ALSO REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 11q22.3 ### TEXT #### DESCRIPTION The ATM protein is a member of the phosphatidylinositol-3 kinase (601232) family of proteins that respond to DNA damage by phosphorylating key substrates involved in DNA repair and/or cell cycle control. #### CLONING Kapp et al. (1992) reported the cloning of a putative gene responsible for ataxia-telangiectasia (AT; 208900) that mapped to the region between THY1 and D11S83 on chromosome 11q23 previously shown to contain the AT locus. They rescued the integrated cosmid sequences that partially restored resistance to ionizing radiation in an ataxia-telangiectasia cell line of complementation group D. Southern blot analysis indicated that the gene, which they called ATDC, is present in single copy in the human genome. However, RNA blot analysis showed mRNA of several sizes (1.8, 2.6, 3.0, 4.7, and 5.7 kb), varying among different cell lines. Because no large rearrangements were detected by Southern or RNA blot analysis in the group D cell line, abnormality in the gene must involve a point mutation or a small rearrangement. By the strategy of positional cloning, Savitsky et al. (1995) identified a gene that they designated ATM (for 'AT mutated'). A partial ATM cDNA clone of 5.9 kb identified a 12-kb band on Northern blot. In order to clone ATM, Savitsky et al. (1995) constructed a YAC contig and cosmid contigs spanning the interval between D11S384 and D11S1818. Two complementary methods were used for identification of transcribed sequences: hybrid selection based on direct hybridization of genomic DNA with cDNAs, and exon amplification to identify putative exons in genomic DNA by their splicing capacity. One cDNA clone had an open reading frame that predicted a protein of 1,708 amino acids corresponding to the C-terminal half of the ATM protein. Savitsky et al. (1995) reported the sequence of a cDNA contig spanning the entire open reading frame of the ATM gene. The predicted 3,056-amino acid protein has a molecular mass of 350.6 kD and shows significant sequence similarities to several yeast, Drosophila, and mammalian phosphatidylinositol 3-prime (PI-3) kinases (e.g., 171833, 171834) that are involved in mitogenic signal transduction, meiotic recombination, detection of DNA damage, and cell cycle control. Mutations in these genes confer a variety of phenotypes with features similar to those observed in human AT cells. Savitsky et al. (1995) speculated that the discovery of ATM may allow the identification of AT heterozygotes who are at increased risk of cancer. Byrd et al. (1996) reported the 1,348-amino acid sequence of the N-terminal half of the ATM gene product. No homology with other genes was found within the N-terminal half of the AT protein. Kastan (1995) reviewed the implications of the cloning of the ATM gene. Pecker et al. (1996) showed that the mouse Atm gene encodes a deduced 3,066-amino acid protein with 84% identity to the human sequence. Northern blot analysis detected expression of a 13-kb transcript in brain, skeletal muscle, and testis, with lower expression in other tissues. A 10.5-kb band was also seen in testis mRNA. #### GENE STRUCTURE Uziel et al. (1996) determined the genomic organization of the ATM gene, using long distance PCR between exons. The gene contains 66 exons spanning approximately 150 kb of genomic DNA. The first 2 exons, 1a and 1b, are used differentially in alternative transcripts; the initiation codon lies within exon 4; and the final, 3.8-kb exon has about 3.6 kb of 3-prime untranslated sequence. #### MAPPING Linkage analysis of ataxia-telangiectasia led to mapping of the ATM gene to chromosome 11q22.3 (39,41:Gatti et al., 1988, 1993). Matsuda et al. (1996) determined the chromosomal locations of the Atm and Acat1 (203750) genes in mouse, rat, and Syrian hamster by direct R-banding fluorescence in situ hybridization. The 2 genes colocalized to mouse 9C-D, the proximal end of rat 8q24.1, and 12qa4-qa5 of Syrian hamster. The regions in the mouse and rat are homologous to human chromosome 11q. In the study of interspecific backcross mice, no recombinants were found among Atm, Npat (601448), and Acat1. By interspecific backcross analysis, Xia et al. (1996) also mapped the mouse Atm gene to chromosome 9. By FISH, Pecker et al. (1996) refined the location of the mouse Atm gene to band 9C. #### GENE FUNCTION For early functional studies in yeast and Drosophila, see below. Using an antiserum developed to a peptide corresponding to the deduced amino acid sequence of ATM, Brown et al. (1997) showed that the ATM protein is a single, high molecular weight protein predominantly confined to the nucleus of human fibroblasts, although it is present in both nuclear and microsomal fractions from human lymphoblast cells and peripheral blood lymphocytes. ATM protein levels and localization remain constant throughout all stages of the cell cycle. Truncated ATM protein was not detected in lymphoblasts from AT patients homozygous for mutations leading to premature protein termination. Exposure of normal human cells to gamma-irradiation and the radiomimetic drug neocarzinostatin had no effect on ATM protein levels, in contrast to a noted rise in p53 (TP53; 191170) levels over the same time interval. The findings of constitutive expression and nuclear localization of the ATM protein were consistent with its potential role in choreographing appropriate cellular responses to genomic damage. Brzoska et al. (1995) found that the ATDC protein physically interacts with the intermediate-filament protein vimentin (193060), which is a protein kinase C (176960) substrate and colocalizing protein, and with an inhibitor of protein kinase C, PKCI1 (601314). Indirect immunofluorescence analysis of cultured cells transfected with a plasmid encoding an epitope-tagged ATDC protein localized the protein to vimentin filaments. Brzoska et al. (1995) suggested that the ATDC and PKCI1 proteins may be components of a single transduction pathway that is induced by ionizing radiation and mediated by protein kinase C. The fact that the ATM gene encodes a protein with a putative phosphatidylinositol 3-kinase domain and functions as a lipid-mediated signaling molecule is consistent with a model in which ATDC and PKC function downstream from ATM in this pathway. Hawley and Friend (1996) commented on the state of ATM research and concluded that ATM must play crucial roles in normally developing or undamaged cells, as well as the studied role in irradiated cells, in order to explain the neurologic, immune, and reproductive problems observed in AT patients. They also proposed that ATM may be intimately associated with both p53 and the molecular machinery required for chromosomal exchange, perhaps as components of the recombination nodules. Zhang et al. (1997) discussed the cloning of a full-length cDNA encoding ATM and correction of multiple aspects of the radiosensitive phenotype of AT cells by transfection with this cDNA. Overexpression of ATM cDNA in AT cells enhanced their survival after radiation exposure, decreased radiation-induced chromosome aberrations, reduced radioresistant DNA synthesis, and partially corrected defective cell cycle checkpoints and induction of stress-activated protein kinase. This correction of the defects of AT cells provided further evidence of the multiplicity of effector functions of the ATM protein and suggested possible approaches to gene therapy. Banin et al. (1998) and Canman et al. (1998) observed enhanced phosphorylation of p53 by ATM in response to DNA damage. Both found that ATM had intrinsic protein kinase activity and phosphorylated p53 on serine-15 in a manganese-dependent manner. Ionizing radiation, but not ultraviolet radiation, rapidly enhanced the p53-directed kinase activity of endogenous ATM. Phosphorylation of p53 on serine-15 in response to ionizing radiation was reduced in ataxia-telangiectasia cells. Khanna et al. (1998) reported direct interaction between ATM and p53 involving 2 regions in ATM, one at the N terminus and the other at the C terminus, corresponding to the PI-3 kinase domain. Recombinant ATM protein phosphorylated p53 on serine 15 near the N terminus. Ectopic expression of ATM in AT cells restored normal ionizing radiation-induced phosphorylation of p53, whereas expression of ATM antisense RNA in control cells abrogated the rapid IR-induced phosphorylation of p53 on serine 15. The results demonstrated that ATM can bind p53 directly and is responsible for its serine 15 phosphorylation, thereby contributing to the activation and stabilization of p53 during the IR-induced DNA damage response. Using the yeast 2-hybrid system, Lim et al. (1998) demonstrated that the ATM protein binds to beta-adaptin (600157), one of the components of the AP-2 adaptor complex, which is involved in clathrin-mediated endocytosis of receptors. The interaction between ATM and beta-adaptin was confirmed in vitro, and coimmunoprecipitation and colocalization studies showed that the proteins also associate in vivo. The ATM protein also interacted in vitro with beta-NAP (602166), a neuronal beta-adaptin homolog that had been identified as an autoantigen in a patient with cerebellar degeneration. The finding of an association of ATM with beta-adaptin in vesicles indicated that ATM may play a role in intracellular vesicle and/or protein transport mechanisms. The interaction may help explain how mutations in the ATM gene cause the pleiotropic nature of the ataxia-telangiectasia phenotype. The large size of the ATM protein and its multiple subcellular localization suggest that ATM may have more than one function. Cortez et al. (1999) demonstrated that the checkpoint protein kinase ATM is required for phosphorylation of Brca1 (113705) in response to ionizing radiation. ATM resides in a complex with Brca1 and phosphorylated Brca1 in vivo and in vitro, in a region that contains clusters of serine-glutamine residues. Cortez et al. (1999) used tandem mass spectrometry to demonstrate the 4 serines (S1189, S1457, S1524, S1542) in this region of Brca1 that are phosphorylated in vivo. A mutated Brca1 protein lacking 2 phosphorylation sites (serines 1423 and 1524) failed to rescue the radiation hypersensitivity of a Brca1-deficient cell line. Cortez et al. (1999) concluded that phosphorylation of Brca1 by ATM may be critical for proper response to DNA double-strand breaks and may provide a molecular explanation for the role of ATM in breast cancer. Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM, BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. By coimmunoprecipitation and in vitro pull-down assays, Beamish et al. (2002) verified direct interaction between ATM and BLM. By mutation analysis, they mapped the BLM-binding domain of ATM to residues 82 through 89, amino acids that are also involved in ATM binding of p53 and BRCA1. The ATM-binding region of BLM mapped to residues 636 to 1,074. Beamish et al. (2002) determined that the mitosis-associated hyperphosphorylation of BLM was partially dependent upon ATM phosphorylating thr99 and thr122 in the N-terminal region of BLM. Radiation-induced phosphorylation of BLM at thr99 was dose-dependent in normal cells and was defective in AT cells. Because of the similarities between ataxia-telangiectasia and Nijmegen breakage syndrome (251260), Lim et al. (2000) evaluated the functional interactions between the ATM and nibrin (NBS1; 602667) genes. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that NBS1 may not be required for signaling to ATM after ionizing radiation. However, NBS1 was phosphorylated on serine-343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. An NBS1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations linked ATM and NBS1 in a common signaling pathway and provided an explanation for the phenotypic similarities between the 2 disorders. Gatei et al. (2000) demonstrated that NBS1 is phosphorylated within 1 hour of treatment of cells with ionizing radiation. This response was abrogated in AT cells that either do not express ATM protein or express near full-length mutant protein. Gatei et al. (2000) also showed that ATM physically interacts with and phosphorylates NBS1 on serine-343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of NBS1 does not affect NBS1-MRE11-RAD50 (604040) association, as revealed by radiation-induced foci formation. Gatei et al. (2000) concluded that their data provide a biochemical explanation for the similarity in phenotype between AT and NBS. Zhao et al. (2000) demonstrated that catalytically active ATM is required for phosphorylation of NBS1, induced by ionizing radiation. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. Zhao et al. (2000) identified 2 residues of NBS1, serine-278 and serine-343, that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci, and rescue of hypersensitivity to ionizing radiation. Zhao et al. (2000) concluded that together, these results demonstrated a biochemical link between cell cycle checkpoints activated by DNA damage and DNA repair in 2 genetic diseases with overlapping phenotypes. Wu et al. (2000) reported that phosphorylation of NBS1 mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, NBS1 was phosphorylated on many serine residues, of which serine-343, serine-397, and serine-615 were phosphorylated by ATM in vitro. At least 2 of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated ATM-dependent phosphorylation. Reconstituting NBS1 cells with a mutant form of NBS1 that cannot be phosphorylated at selected ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Wu et al. (2000) concluded that phosphorylation of NBS1 by ATM is critical for certain responses of human cells to DNA damage. When exposed to ionizing radiation, eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the ionizing radiation-induced S-phase checkpoint cause 'radioresistant DNA synthesis,' a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia. The CDC25A phosphatase (116947) activates the cyclin-dependent kinase 2 (CDK2; 116953) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Falck et al. (2001) reported a functional link between ATM, checkpoint signaling kinase CHK2 (604373), and CDC25A, and implicated this mechanism in controlling the S-phase checkpoint. Falck et al. (2001) showed that ionizing radiation-induced destruction of CDC25A requires both ATM and the CHK2-mediated phosphorylation of CDC25A on serine-123. An ionizing radiation-induced loss of CDC25A protein prevents dephosphorylation of CDK2 and leads to a transient blockade of DNA replication. Falck et al. (2001) also showed that tumor-associated CHK2 alleles cannot bind or phosphorylate CDC25A, and that cells expressing these CHK2 alleles, elevated CDC25A, or a CDK2 mutant unable to undergo inhibitory phosphorylation (CDK2AF) fail to inhibit DNA synthesis when irradiated. Falck et al. (2001) concluded that their results support CHK2 as a candidate tumor suppressor, and identify the ATM--CHK2--CDC25A--CDK2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis. Falck et al. (2002) demonstrated that experimental blockade of either the NBS1-MRE11 function or the CHK2-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A-CDK2 pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication. Lee and Paull (2005) showed that the MRE11-RAD50-NBS1 (MRN) complex acts as a double-strand break sensor for ATM and recruits ATM to broken DNA molecules. Inactive ATM dimers were activated in vitro with DNA in the presence of MRN, leading to phosporylation of the downstream cellular targets p53 and CHK2. ATM autophosphorylation was not required for monomerization of ATM by MRN. The unwinding of DNA ends by MRN was essential for ATM stimulation, which is consistent with the central role of single-stranded DNA as an evolutionarily conserved signal for DNA damage. Bao et al. (2001) demonstrated a direct regulatory linkage between RAD17 and the checkpoint kinases ATM and ATR (601215). Treatment of human cells with genotoxic agents induced ATM/ATR-dependent phosphorylation of RAD17 at serine-635 and serine-645. Overexpression of a RAD17 mutant bearing alanine substitutions at both phosphorylation sites abrogated the DNA damage-induced G2 checkpoint and sensitized human fibroblasts to genotoxic stress. In contrast to wildtype RAD17, the RAD17 mutant showed no ionizing radiation-inducible association with RAD1 (603153), a component of the RAD1-RAD9 (603761)-HUS1 (603760) checkpoint complex. These findings demonstrated that ATR/ATM-dependent phosphorylation of RAD17 is a critical early event during checkpoint signaling in DNA-damaged cells. Taniguchi et al. (2002) identified FANCD2 (227646) as a link between the FA (607139) and ATM damage response pathways. ATM phosphorylated FANCD2 on ser222 in vitro. This site was also phosphorylated in vivo in an ATM-dependent manner following ionizing radiation. Phosphorylation of FANCD2 was required for activation of an S-phase checkpoint. The authors determined that the ATM-dependent phosphorylation of FANCD2 on ser222 and the FA pathway-dependent monoubiquitination of FANCD2 on lys561 are independent posttranslational modifications regulating discrete cellular signaling pathways. Biallelic disruption of FANCD2 resulted in both mitomycin C and ionizing radiation hypersensitivity. Bakkenist and Kastan (2003) demonstrated that ATM is dormant in unirradiated cells as a dimer or higher-order multimer, with the kinase domain bound to a region surrounding serine-1981 that is contained within the previously described FAT domain. Cellular irradiation induced intermolecular autophosphorylation of serine-1981 that caused dimer dissociation and initiated cellular ATM kinase activity. Most ATM molecules in the cell were rapidly phosphorylated on this site after doses of radiation as low as 0.5 Gy, and binding of a phosphospecific antibody was detectable after the introduction of only a few DNA double-strand breaks in the cell. Activation of the ATM kinase seems to be an initiating event in cellular responses to irradiation. Bakkenist and Kastan (2003) concluded that ATM activation is not dependent on direct binding to DNA strand breaks, but may result from changes in the structure of chromatin. #### Early Functional Studies in Yeast and Drosophila Mutants of the mei-41 gene in Drosophila melanogaster, which is homologous to the human ATM gene, were first identified on the basis of a defect in meiotic recombination and subsequently by their mutagen sensitivity to a wide range of mutagens, including ionizing radiation, ultraviolet radiation, methyl methanesulfonate, and hydroxyurea (Banga et al., 1986; Baker et al., 1976). Indeed, there is no overlap between the x-ray dose-kill curves for wildtype and for mei-41 mutants, and females heterozygous for mei-41 mutations display an intermediate level of mutagen sensitivity (Boyd et al., 1976; Nguyen et al., 1979). Hari et al. (1995) noted that mutations in the mei-41 gene also cause high levels of chromosome breakage and instability in mitotic cells and in the male germline. A number of gaps and breaks are enhanced following treatment with x-rays to the extent that after 220 R of irradiation, virtually all of the subsequent metaphases possess at least 1 break or rearrangement. They commented that the observation of chromatid breaks and gaps in the metaphase chromosomes of both mutagenized and unmutagenized mei-41 cells is surprising, because many organisms possess cell cycle checkpoint controls that prevent cells with damaged DNA from exiting G2 and entering the M phase. Hari et al. (1995) demonstrated that mei-41 has a similar if not identical effect on G2/M progression of x-irradiated neuroblasts in Drosophila as is observed in ataxia-telangiectasia: cells irradiated in G2 fail to display an initial block in cell cycle progression that is characteristic of normal cells. Hari et al. (1995) also showed that the Drosophila mei-41 and the human ATM gene are homologous at the level of predicted amino acid sequence. Like the ATM protein, the mei-41 protein belongs to a family of phosphatidylinositol 3-kinase (PI3K)-like proteins that include the yeast rad3 and Mec1p proteins. Hari et al. (1995) concluded that the mei-41 gene of Drosophila is a functional homolog of the human ATM gene. Greenwell et al. (1995) showed that the ATM gene has strong homology to 2 known yeast genes, ESR1/MEC1 of Saccharomyces cerevisiae and rad3 of Schizosaccharomyces pombe, and to a yeast open reading frame, YBLO88. Greenwell et al. (1995) showed that YBLO88 encodes TEL1, a gene required for maintaining wildtype telomere length. Yeast chromosomes terminate in tracts of simple repetitive DNA, poly-G1-3-T. Mutations in the TEL1 gene result in shortened telomeres. Sequence analysis of TEL1 indicated that it encodes a very large protein (322 kD) with amino acid motifs found in phosphatidylinositol/protein kinases. The authors found that the closest homolog to TEL1 is the human ATM gene. Morrow et al. (1995) presented data indicating that TEL1 and the checkpoint gene MEC1 in S. cerevisiae are functionally related and that functions of the human ATM gene are apparently divided between at least 2 S. cerevisiae homologs. Paulovich and Hartwell (1995) likewise identified MEC1 as a yeast homolog of ATM. Zakian (1995) provided a dendrogram indicating the relationship between ATM and the various ATM-like genes. She pointed out that 'whether or not these ATM-like genes are ATM homologs, continued inquiry in genetically tractable model organisms like yeast and Drosophila will surely provide valuable insight into the functions of this family of proteins.' Telomeres are essential for stable maintenance of linear chromosomes in eukaryotes. As indicated earlier, the ATM family of genes, including TEL1 of budding yeast, rad3+ of fission yeast, and human ATM itself, appear to be involved in telomere length regulation. Naito et al. (1998) cloned another fission yeast ATM homolog, tel1+, and found that a tel1rad3 double mutant lost all telomeric DNA sequences. Thus, the ATM homologs are essential in telomere maintenance. The mutant grew poorly and formed irregular-shaped colonies, probably due to chromosome instability; however, during prolonged culture of double mutants, cells forming normal round-shaped colonies arose at a relatively high frequency. All 3 chromosomes in these derivative cells were circular and lacked telomeric sequences. This appeared to be the first report of eukaryotic cells whose chromosomes were all circular. Upon meiosis, these derivative cells produced few viable spores. Therefore, the exclusively circular genome lacking telomeric sequences is proficient for mitotic growth, but does not permit meiosis. Ito et al. (2004) showed that ATM has an essential role in the reconstitutive capacity of hematopoietic stem cells but is not as important for the proliferation or differentiation of progenitors, in a telomere-independent manner. Atm-null mice older than 24 weeks showed progressive bone marrow failure resulting from a defect in the hematopoietic stem cell function that was associated with elevated reactive oxygen species. Treatment with antioxidative agents restored the reconstitutive capacity of Atm-null hematopoietic stem cells, resulting in the prevention of bone marrow failure. Activation of the p16(INK4a) (600160)-retinoblastoma (RB; 180200) gene product pathway in response to elevated reactive oxygen species led to the failure of Atm-null hematopoietic stem cells. Ito et al. (2004) concluded that the self-renewal capacity of hematopoietic stem cells depends on ATM-mediated inhibition of oxidative stress. #### MOLECULAR GENETICS Savitsky et al. (1995) found that ATM was mutated in ataxia-telangiectasia (AT; 208900) patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. In affected members of an extended Palestinian-Arab AT family that had not been assigned to a complementation group (Ziv et al., 1992), Savitsky et al. (1995) identified a homozygous deletion in the ATM gene that included almost the entire genomic region spanned by the original cDNA clone. This finding led to a systematic search for mutations in additional AT patients. The restriction endonuclease fingerprinting (REF) method was applied to DNA products of RT-PCR-amplified RNA derived from AT cell lines. When an abnormal REF pattern was found, the relevant portion of the transcript was directly sequenced. Most of the mutations identified in 14 patients, including 3 sib pairs, were predicted to lead to premature truncation of the protein product. Three mutations were predicted to create in-frame deletions of 1, 2, or 3 amino acid residues; see 607585.0001, 607585.0002, and 607585.0003. Byrd et al. (1996) identified 6 mutations affecting the N-terminal half of the ATM protein. One of these mutations was found to be associated with a haplotype that is common to 4 apparently unrelated families of Irish descent. All the patients so far examined for both AT alleles had been shown to be compound heterozygotes. None of these mutations affected the putative promoter region which made direct divergent transcription of both the ATM gene and a novel gene, E14 (601448). All of the mutations identified by Byrd et al. (1996) were deletions except for 1 insertion. Gilad et al. (1996) performed mutation analysis in 55 families with AT, using RT-PCR of total RNA from cultured fibroblasts or lymphoblasts, followed by restriction endonuclease fingerprinting of PCR products. Of the 44 AT mutations identified, 39 (89%) were expected to inactivate the ATM protein by truncating it, abolishing correct initiation or termination of translation, or deleting large segments. Additional mutations included 4 smaller in-frame deletions and insertions, and 1 substitution of a highly conserved amino acid at the PI-3 kinase domain. Wright et al. (1996) assayed 38 cell lines, including 36 from unrelated AT patients and 2 control cell lines, for ATM gene mutations. They detected 30 mutations. Twenty-five of these were distinct, and most of the patients were compound heterozygotes. The mutations included nucleotide substitutions (2 cases), insertions (1 case), and deletions of 2 to 298 nucleotides (27 cases). The most frequent variant (detected in 3 unrelated patients) was a 9-bp deletion at codon 2546 in exon 54 (607585.0007). This mutation had previously been reported in 5 different patients and constituted 8% of the reported mutations at that time. Twenty-two of the observed alterations would be predicted to lead to protein alterations. Wright et al. (1996) discussed the practicality of population screening in light of their results. Concannon and Gatti (1997) pointed out that although in vitro cell fusion studies had suggested that AT is genetically heterogeneous, all AT patients studied to that time had been found to harbor mutations in the ATM gene. More than 100 ATM mutations had been documented; these were broadly distributed throughout the gene. Except for patients from families with known consanguinity, most AT patients were compound heterozygotes. More than 70% of the mutations were predicted to lead to protein truncation. Many of the reported mutations affected mRNA splicing with at least half of the coding exons (32/62) having been found to undergo exon skipping. The large size of the ATM gene (66 exons spanning approximately 150 kb of genomic DNA), together with the diversity and broad distribution of mutations in AT patients, limited direct mutation screening as a diagnostic tool, or method of carrier identification, except where founder effect mutations are involved. Teraoka et al. (1999) found that mutations resulting in defective splicing constituted a significant proportion (30 of 62, or 48%) of a new series of mutations in the ATM gene that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA in patients with ataxia-telangiectasia. Fewer than half of the splicing mutations involved the canonical AG splice acceptor site or GT splice donor site. A higher proportion of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice acceptor or splice donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by Western blotting in any AT cell line in which splicing mutations were identified. Teraoka et al. (1999) also observed several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations. By PCR amplification from genomic DNA and automated sequencing of the entire coding region (66 exons) and splice junctions of the ATM gene, Li and Swift (2000) detected 77 mutations in 90 AT chromosomes (85%). Heteroduplex analysis detected another 42 mutations at the AT locus. Of a total of 71 unique mutations, 50 were found only in a single family, and 51 had not been reported previously. Most (58/71, 82%) mutations were frameshift and nonsense mutations that were predicted to cause truncation of the AT protein; less common mutation types were missense (9/71, 13%), splicing (3/71, 4%), and 1 in-frame deletion of 3 bp beginning at nucleotide 2546. The mean survival and height distribution of 134 AT patients correlated significantly with the specific mutations present in the patients. Patients homozygous for a single truncating mutation, typically near the N-terminal end of the gene, or heterozygous for the in-frame deletion, were shorter and had significantly shorter survival than those heterozygous for a splice site or missense mutation, or heterozygous for 2 truncating mutations. (See also POPULATION GENETICS in 208900 for characterization of mutations in selected ethnic groups.) Tchirkov and Lansdorp (2003) monitored the changes in telomere length in A-T homozygous, heterozygous, and control fibroblasts cultured in vitro under various conditions of oxidative stress using quantitative fluorescent in situ hybridization. Compared with normal cells, the rate of telomere shortening was 1.5-fold increased under 'normal' levels of oxidative stress in A-T heterozygous cells and 2.4- to 3.2-fold in A-T homozygous cells. Mild chronic oxidative stress induced by hydrogen peroxide increased the rate of telomere shortening in A-T cells but not in normal fibroblasts, and the telomere shortening rate decreased in both normal and A-T fibroblasts if cultures were supplemented with the antioxidant phenyl-butyl-nitrone. Increased telomere shortening upon oxidative stress in A-T cells was associated with a significant increase in the number of extrachromosomal fragments of telomeric DNA and chromosome ends without detectable telomere repeats. The authors proposed that the ATM (A-T mutated) protein may have a role in the prevention or repair of oxidative damage to telomeric DNA, and that enhanced sensitivity of telomeric DNA to oxidative damage in A-T cells may result in accelerated telomere shortening and chromosomal instability. Eng et al. (2004) described 9 examples of nonclassic splicing mutations in 12 ataxia-telangiectasia patients and compared cDNA changes to estimates of splice junction strengths based on maximum entropy modeling. These mutations fell into 3 categories: pseudoexon insertions (type II), single-nucleotide changes within the exon (type III), and intronic changes that disrupt the conserved 3-prime splice sequence and lead to partial exon deletion (type IV). Four patients with a previously reported type II (pseudoexon) mutation (Pagani et al., 2002) all shared a common founder haplotype. Three patients with apparent missense or silent mutations actually had type III aberrant splicing and partial deletion of an exon. Five patients had type IV mutations that could have been misinterpreted as classic splicing mutations; instead, their mutations disrupted a splice site and used another AG splice site located nearby within the exon and led to partial deletions at the beginning of exons. The nonclassic splicing mutations created frameshifts that resulted in premature termination codons. Without screening of cDNA or using accurate models of splice site strength, the consequences of these genomic mutations cannot be reliably predicted, possibly leading to further misinterpretation of genotype-phenotype correlations and subsequently impacting upon gene-based therapy. #### Malignancy By analyzing tumor DNA from patients with sporadic T-cell prolymphocytic leukemia (TPLL), a rare clonal malignancy with similarities to a mature T-cell leukemia seen in ataxia-telangiectasia, Vorechovsky et al. (1997) demonstrated a high frequency of ATM mutations in TPLL. In marked contrast to the ATM mutation pattern in AT, the most frequent nucleotide changes in this leukemia were missense mutations (e.g.; 607585.0009). These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast, and Drosophila. The resulting amino acid substitutions were predicted to interfere with ATP binding or substrate recognition. Two of 17 mutated TPLL samples had a previously reported AT allele. One of these, a 9-bp deletion causing loss of a string of 3 amino acids (607585.0007), was the most frequent ATM allele reported in AT patients. The other, val2424 to gly (607585.0005), had been observed in a patient with atypically mild ataxia-telangiectasia. In neither of these 2 cases was any wildtype allele detectable. Vorechovsky et al. (1997) also studied B-cell non-Hodgkin lymphomas (BNHL) for ATM mutations and detected 3 missense mutations (e.g.; 607585.0010). In mantle cell lymphoma (MCL), the translocation t(11;14) is considered the cytogenetic hallmark of the disease. Stilgenbauer et al. (1999) identified a commonly deleted region of 11q22-q23, smaller than 1 Mb in size, that includes the ATM locus in cases of MCL. Schaffner et al. (2000) performed mutation analysis of ATM in 12 sporadic cases of MCL, 7 of whom had a deletion of 1 ATM gene copy. In all 7 cases containing a deletion of 1 ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, truncation, or alteration of the protein. In addition, biallelic ATM mutations were identified in 2 MCLs that did not contain 11q deletions. In 3 cases analyzed, the ATM mutations detected in the tumor cells were not present in nonmalignant cells, demonstrating their somatic rather than germline origin. The inactivation of both alleles of the ATM gene by deletion and deleterious point mutation in the majority of cases analyzed indicated that ATM plays a role in the initiation and/or progression of MCL. Deletion in chromosome bands 11q22-q23 is one of the most frequent chromosomal aberrations in B-CLL. It is associated with extensive lymph node involvement and poor survival. The ATM gene falls within the minimal consensus deletion segment. To investigate the potential pathogenic role of ATM in B-cell tumorigenesis, Schaffner et al. (1999) performed mutation analysis of ATM in 29 malignant lymphomas of B-cell origin (27 cases of B-CLL and 2 cases of mantle cell lymphoma). Twenty-three of the 29 patients carried an 11q22-q23 deletion. In 5 B-CLLs and 1 mantle cell lymphoma with deletion of 1 ATM allele, a point mutation in the remaining allele was detected, which resulted in aberrant transcript splicing, alteration, or truncation of the protein. In addition, mutation analysis identified point mutations in 3 cases without 11q deletion: 2 B-CLLs with 1 altered allele and 1 mantle cell lymphoma with both alleles mutated. In 4 cases analyzed, the ATM alterations were not present in the germline, indicating a somatic origin of the mutations. The study demonstrated somatic disruption of both alleles at the ATM locus by deletion of point mutation and thus its pathogenic role in sporadic B-cell lineage tumors. Mutations have been described in the ATM gene in small numbers of cases of lymphoid neoplasia. Surveys of the ATM mutation status in lymphoma have been limited due to the large size (62 exons) and complex mutational spectrum of this gene. Fang et al. (2003) used microarray-based assays with 250,000 oligonucleotides to screen lymphomas from 120 patients for all possible ATM coding and splice junction mutations. The subtypes included 6 varieties. They found the highest percentage of ATM mutations within the mantle cell (MCL) subtype: 12 of 28 cases (43%). In 6 MCL cases examined, 4 ATM variants were due to somatic mutation in the tumor cells, whereas 2 others seemed to be germline in origin. There was no difference in p53 mutation status in the ATM mutant and wildtype groups of MCL. There was no statistically significant difference in the median overall survival of patients with wildtype versus mutated ATM in MCL. Li et al. (2000) demonstrated that the BRCA1-associated protein CTIP (604124) becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase ATM. ATM phosphorylates CTIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CTIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. Li et al. (2000) concluded that ATM, by phosphorylating CTIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer. Epidemiologic data support an increased risk for breast and other cancers in AT heterozygotes. However, screening breast cancer cases for truncating mutations in the ATM gene has failed largely to reveal an increased incidence in these patients. Though some evidence supports the implication of ATM missense mutations in breast cancer, the presence of a large variety of rare missense variants in addition to common polymorphisms in ATM has made it difficult to establish such a relationship by association studies. To investigate the functional significance of these changes, Scott et al. (2002) introduced missense substitutions that had been identified in either AT or breast cancer patients into ATM cDNA before establishing stable cell lines to determine their effect on ATM function. Pathogenic missense mutations and neutral missense variants were distinguished initially by their capacity to correct the radiosensitive phenotype in AT cells. Furthermore, missense mutations abolished the radiation-induced kinase activity of ATM in normal control cells, caused chromosome instability, and reduced cell viability in irradiated control cells, whereas neutral variants failed to do so. Mutant ATM was expressed at the same level as endogenous protein, and interference with normal ATM function seemed to be by multimerization. The approach of Scott et al. (2002) represented a means of identifying genuine ATM mutations and addressing the significance of missense changes in the ATM gene in a variety of cancers, including breast cancer. (See also HETEROZYGOTES in 208900). Medulloblastoma occurs with increased frequency in ataxia-telangiectasia (Gatti et al., 1991); however, Liberzon et al. (2003) did not identify mutations in 13 childhood medulloblastomas. #### ANIMAL MODEL Barlow et al. (1996) created a murine model of ataxia-telangiectasia by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. Most of the animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulated the ataxia-telangiectasia phenotype in humans. The authors noted that humans also show incomplete sexual maturation in ATM (Boder, 1975). Elson et al. (1996) generated a mouse model for ataxia-telangiectasia using gene targeting to generate mice that did not express the Atm protein. Atm-deficient mice were retarded in growth, did not produce mature sperm, and exhibited severe defects in T-cell maturation while going on to develop thymomas. Atm-deficient fibroblasts grew poorly in culture and displayed a high level of double-stranded chromosome breaks. Atm-deficient thymocytes underwent spontaneous apoptosis in vitro significantly more often than controls. Atm-deficient mice then exhibited many of the same symptoms found in ataxia-telangiectasia patients and in cells derived from them. Furthermore, Elson et al. (1996) demonstrated that the Atm protein exists as 2 discrete molecular species, and that loss of 1 or both of these can lead to the development of the disease. Xu and Baltimore (1996) disrupted the mouse ATM gene by homologous recombination. Xu et al. (1996) reported that Atm -/- mice are viable, growth-retarded, and infertile. The infertility results from meiotic failure, as meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. The cerebella of Atm -/- mice appear normal by histologic examination, and the mice have no gross behavioral abnormalities. Atm -/- mice exhibit multiple immune defects similar to those of AT patients, and most develop thymic lymphomas at 3 to 4 months of age and die of the tumors by 4 months. Xu and Baltimore (1996) showed that mouse Atm -/- cells are hypersensitive to gamma irradiation and defective in cell cycle arrest following radiation, and Atm -/- thymocytes are more resistant to apoptosis induced by gamma radiation than normal thymocytes. They also provide direct evidence that ATM acts as an upregulator of p53. Atm-null mice, as well as those null for p53, develop mainly T-cell lymphomas, supporting the view that these genes have similar roles in thymocyte development. To study the interactions of these 2 genes on an organismal level, Westphal et al. (1997) bred mice heterozygous for null alleles of both atm and p53 to produce all genotypic combinations. Mice doubly null for atm and p53 exhibited a dramatic acceleration of tumor formation relative to singly null mice, suggesting that the 2 genes collaborate to prevent tumorigenesis. With respect to their roles in apoptosis, loss of atm rendered thymocytes only partly resistant to irradiation-induced apoptosis, whereas additional loss of p53 engendered complete resistance. This implied that the irradiation-induced atm and p53 apoptotic pathways are not completely congruent. Furthermore, Westphal et al. (1997) found that atm and p53 do not appear to interact in acute radiation toxicity, suggesting a separate atm effector pathway for this DNA damage response and having implications for the prognosis and treatment of human tumors. To study the role of p21 (116899) in ATM-mediated signal transduction pathways, Wang et al. (1997) examined the combined effects of the genetic loss of ATM and p21 on growth control, radiation sensitivity, and tumorigenesis. They found that p21 modifies the in vitro senescent response seen in AT fibroblasts. Wang et al. (1997) found that p21 is a downstream effector of ATM-mediated growth control. However, loss of p21 in the context of an Atm-deficient mouse leads to delay in thymic lymphomagenesis and an increase in acute radiation sensitivity in vivo (the latter principally because of effects on the gut epithelium). Modification of these 2 crucial aspects of the ATM phenotype can be related to an apparent increase in spontaneous apoptosis seen in tumor cells and in the irradiated intestinal epithelium of mice doubly null for Atm and p21. Thus, loss of p21 seems to contribute to tumor suppression by a mechanism that operates via a sensitized apoptotic response. Ataxia-telangiectasia is characterized by markedly increased sensitivity to ionizing radiation. Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS). Barlow et al. (1999) therefore hypothesized that AT is due to oxidative damage resulting from loss of function of the ATM gene product. To assess this hypothesis, they employed an animal model of AT, i.e., the mouse with a disrupted Atm gene. They showed that organs that develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected. They suggested that these observations provide a mechanistic basis for the AT phenotype and lay a rational foundation for therapeutic intervention. Barlow et al. (1999) exposed Atm +/+ and Atm +/- littermates to a sublethal dose, 4 Gy (400 Rad) of ionizing radiation. The Atm +/- mice had premature graying and decreased life expectancy (median survival 99 weeks vs 71 weeks in wildtype and heterozygous mice, respectively, P = 0.0042). Tumors and infections of similar type were found in all autopsied animals, regardless of genotype. The central nervous system (CNS) of Atm null mice shows a pronounced defect in apoptosis induced by genotoxic stress, suggesting that ATM functions to eliminate neurons with excessive genomic damage. Chong et al. (2000) reported that the death effector Bax (600040) is required for a large proportion of Atm-dependent apoptosis in the developing CNS after IR. Although many of the same regions of the CNS in both Bax -/- and Atm -/- mice were radioresistant, mice nullizygous for both Bax and Atm showed additional reduction in IR-induced apoptosis in the CNS. Therefore, although the major IR-induced apoptotic pathway in the CNS requires Atm and Bax, a p53-dependent collateral pathway exists that has both Atm- and Bax-independent branches. Furthermore, Atm- and Bax-dependent apoptosis in the CNS also required caspase-3 (600636) activation. These data implicated Bax and caspase-3 as death effectors in neurodegenerative pathways. Through gene targeting, Borghesani et al. (2000) generated a line of Atm mutant mice. In contrast to other Atm mutant mice, their Atm y/y mice showed a lower incidence of thymic lymphoma and survived beyond a few months of age. They exhibited deficits in motor learning indicative of cerebellar dysfunction. Even though they found no gross cerebellar degeneration in older Atm y/y animals, ectopic and abnormally differentiated Purkinje cells were apparent in mutant mice of all ages. These findings established that some neuropathologic abnormalities seen in ataxia telangiectasia patients also are present in Atm mutant mice. In addition, they found a previously unrecognized effect of Atm deficiency on development or maintenance of CD4+8+ thymocytes. Hande et al. (2001) examined the length of individual telomeres in cells from Atm -/- mice by fluorescence in situ hybridization. Telomeres were extensively shortened in multiple tissues of Atm -/- mice. More than the expected number of telomere signals was observed in interphase nuclei of Atm -/- mouse fibroblasts. Signals corresponding to 5 to 25 kb of telomeric DNA that were not associated with chromosomes were also noticed in Atm -/- metaphase spreads. Extrachromosomal telomeric DNA was also detected in fibroblasts from AT patients. The authors proposed a role for ATM in telomere maintenance and replication, which may explain in part the poor growth of Atm -/- cells and increased tumor incidence in both AT patients and Atm -/- mice. Spring et al. (2002) provided evidence in mice that human AT carriers have a cancer predisposition. Although no tumors had been observed in heterozygous Atm-knockout mice (Atm +/-), the authors demonstrated that Atm 'knock-in' heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation (607585.0007) showed an increased susceptibility to developing tumors. In parallel, Spring et al. (2002) reported the appearance of tumors in 6 humans, from 12 families, who were heterozygous for the 7636del9 mutation. Expression of ATM cDNA containing the 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. The inhibited ATM kinase activity reduced the survival of control cells after radiation exposure and enhanced the level of radiation-induced chromosomal aberrations. Spring et al. (2002) concluded that their results showed for the first time that mouse carriers of the mutated Atm that are capable of expressing Atm have a higher risk of cancer. Stern et al. (2002) found that Atm null mice accumulated DNA breaks in neuronal tissue. These animals showed depleted pyridine nucleotide levels, including NAD(+) required for DNA repair, and increased mitochondrial respiration rate. The cerebellum was prominent among the neural tissues effected. Allen et al. (2001) studied proliferation and differentiation of neural cells of the dentate gyrus in wildtype and Atm -/- mice. They found that Atm is abundant in wildtype dividing neural progenitor cells and is downregulated in differentiated cells. Atm -/- neural progenitor cells showed abnormally high rates of proliferation and genomic instability. Atm -/- cells in vivo and in cell culture showed blunted responses to environmental stimuli that normally promote neuronal progenitor cell proliferation, survival, and differentiation. Wong et al. (2003) examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and Terc. These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multiorgan system compromise, accelerated aging, and premature death. Wong et al. (2003) showed that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of ataxia-telangiectasia pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves. ### ALLELIC VARIANTS (selected examples) #### .0001 ATAXIA-TELANGIECTASIA, COMPLEMENTATION GROUP A [ATM, 3-BP DEL, SER1512DEL] In a Dutch family in which ataxia-telangiectasia of complementation group A was observed (208900) (AT3NG), Savitsky et al. (1995) found compound heterozygosity for mutations in the ATM gene. One allele showed deletion of 3 bp, resulting in loss of serine-1512. #### .0002 ATAXIA-TELANGIECTASIA, COMPLEMENTATION GROUP E [ATM, 9-BP DEL, CODONS 1198-1200] In an Australian family of Irish/British ethnic extraction, Savitsky et al. (1995) found that 2 sibs with ataxia-telangiectasia of complementation group E (208900) were homozygous for deletion of 9 bp, resulting in a loss of amino acids 1198-1200 in the gene product. The typing of these patients (AT1ABR and AT2ABR) was performed by Chen et al. (1984). #### .0003 ATAXIA-TELANGIECTASIA, COMPLEMENTATION GROUP D [ATM, 6-BP DEL, CODONS 1079-1080] In 2 sibs of Indian/English ancestry, Savitsky et al. (1995) found that their ataxia-telangiectasia complementation group D (208900) was a result of compound heterozygosity for mutations in the ATM gene. One allele showed deletion of 6 bp, resulting in deletion of 2 amino acids (1079 and 1080) in the gene product. #### .0004 ATAXIA-TELANGIECTASIA VARIANT [ATM, 137-BP INS, NT5762] McConville et al. (1996) identified 14 families with AT (208900) in which the ATM gene mutation was associated with a less severe clinical and cellular phenotype ('variant' AT). This form of AT constituted 10 to 15% of AT families in the UK and was characterized by a later mean age of onset and a slower rate of neurological deterioration. In 10 of these families all homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice donor site. The second allele of ATM had a different mutation in each patient. In 2 brothers with exceptionally mild adult-onset ataxia telangiectasia, Sutton et al. (2004) identified homozygosity for a 5762A-G transition in the ATM gene, resulting in the 5762ins137 mutation. Protein expression studies showed that the ATM protein was expressed from both the wildtype and mutant alleles, yielding approximately 11% of normal levels. In vitro functional analysis of the 5762ins137 mutant protein showed that it retains inducible residual kinase activity. Age at onset was 17 years in one brother and 22 years in the other, with mild ataxia, ocular movement abnormalities, and identification of ocular telangiectasia. #### .0005 ATAXIA-TELANGIECTASIA VARIANT [ATM, VAL2424GLY ] T-CELL PROLYMPHOCYTIC LEUKEMIA, SOMATIC McConville et al. (1996) reported a 7271T-G point mutation in the ATM gene in patients from 2 families with a mild form of AT ('variant') (208900). The transversion results in a val2424-to-gly substitution. They also reported another point mutation (607585.0006). The authors noted that point mutations are uncommon in AT. In a sporadic case of T-cell prolymphocytic leukemia (TPLL), Vorechovsky et al. (1997) observed this same mutation in tumor tissue. No wildtype allele was demonstrable in tumor DNA. Material was not available to permit determination of whether the mutation was present in the germline. Stankovic et al. (1998) observed 2 families in which members affected with a milder clinical and cellular phenotype of AT shared a 7271T-G transversion in the ATM gene and a common haplotype. The 7271T-G mutation was predicted to produce a change in codon 2424, with replacement of valine by glycine. One family, in which the mutation was present in homozygous state, contained the oldest patients in the British Isles with demonstrable AT, including 1 patient in his seventh decade, possibly the oldest AT patient reported. Furthermore, 1 affected female, 50 years old at the time of report, had an unaffected son. Three members of a sibship of 4 had long-standing ataxia. Their parents were first cousins and originated from Orkney, in the north of Scotland. The proband, her older sister with AT, and her mother had breast cancer. The affected individuals had minimal telangiectasia and no obvious increased tendency toward infections, except for recurrent urinary tract infections in the brother of the proband. The second family had the 7271T-G transversion in compound heterozygous state with a 3910del7nt mutation. The mutation was predicted to cause premature termination of the ATM protein, but no truncated ATM protein was detected. There were 2 affected brothers, aged 16 and 28 years, whose age at onset of ataxia was 8 and 4 years, respectively. Two of 3 paternal aunts had breast cancer, one at age 50 years and the other at age 55 years. #### .0006 ATAXIA-TELANGIECTASIA VARIANT [ATM, PHE2827CYS ] McConville et al. (1996) reported this 8480T-G point mutation in patients from 2 families with a mild form of AT ('variant') (208900). The transversion results in a phe2827-to-cys substitution in ATM. They also reported another point mutation (607585.0005). The authors noted that point mutations are uncommon in AT. #### .0007 ATAXIA-TELANGIECTASIA [ATM, 9-BP DEL, CODONS 2546-2548] T-CELL PROLYMPHOCYTIC LEUKEMIA, SOMATIC, INCLUDED The most frequent variant of the ATM gene detected out of 30 AT (208900) mutant lines studied by Wright et al. (1996) was a 9-bp deletion at codon 2546 in exon 54. The deletion was detected by them in 3 unrelated patients and had been previously reported in 5 different patients, corresponding to 8% of the mutations reported at that time. This same mutation was identified by Vorechovsky et al. (1997) in tumor tissue from a sporadic case of T-cell prolymphocytic leukemia (TPLL), a rare clonal malignancy with similarities to a mature T-cell leukemia seen in ataxia-telangiectasia. This mutation was identified in heterozygous form in a female breast cancer patient with a family history of multiple malignancies (Vorechovsky et al., 1996). The deleted sequence is 5-prime-TCTAGAATT-3-prime. Spring et al. (2002) demonstrated the appearance of tumors in 6 humans, from 12 families, who were heterozygous for the 7636del9 mutation. In parallel, they showed that 'knock-in' heterozygous mice harboring an in-frame deletion corresponding to the human 7636del9 mutation showed increased susceptibility to tumors. The 7636del9 mutation had a dominant-negative effect in control cells, inhibiting radiation-induced ATM kinase activity in vivo and in vitro. #### .0008 ATAXIA-TELANGIECTASIA [ATM, ARG35TER] Gilad et al. (1996) reported that a single AT (208900) mutation was observed in 32 of 33 defective ATM alleles in Jewish AT families of North African origin, coming from various regions of Morocco and Tunisia. This mutation, a 103C-T transition, results in a stop codon at position 35 of the ATM protein. No ATM protein could be detected in cells from patients with this mutation. Gilad et al. (1996) developed a rapid carrier detection assay for this mutation suitable for population-based screening. #### .0009 T-CELL PROLYMPHOCYTIC LEUKEMIA, SOMATIC [ATM, ASP1682HIS ] One of the TPLL mutations identified by Vorechovsky et al. (1997) was a G-to-C transversion at nucleotide 5044, predicted to produce an asp1682-to-his (D1682H) amino acid change. The wildtype allele was absent from tumor tissue. Because of the way in which the study was done it was impossible to determine whether any of these mutations were in the germline. #### .0010 B-CELL NON-HODGKIN LYMPHOMA, SOMATIC [ATM, MET1040VAL] Vorechovsky et al. (1997) found ATM mutations in sporadic T-cell prolymphocytic leukemia, a rare clonal malignancy with similarities to a mature T-cell leukemia seen in AT (607585.0009). In addition to the increased risk of neoplasia of T-cell origin, AT homozygotes also show elevated risk of developing B-cell malignancies, especially B-cell non-Hodgkin lymphomas (BNHL). In a study of tumor DNAs from 32 patients with BNHL and 5 BNHL cell lines, analyzed by SSCP, 3 missense mutations of the ATM gene were found. One was an A-to-G transition of nucleotide 3118 predicted to lead to a met1040-to-val (M1040V) amino acid substitution in the ATM protein. The wildtype allele could not be demonstrated in tumor DNA. The tumor in this case was a high-grade diffuse large cell BNHL. #### .0011 ATAXIA-TELANGIECTASIA WITHOUT IMMUNODEFICIENCY [ATM, LEU2656PRO] Toyoshima et al. (1998) reported the case of a 24-year-old Japanese male with ataxia-telangiectasia (208900) without immunodeficiency. He had developed ataxic gait at 6 years of age and telangiectases at 9 years. There was no susceptibility to infections. His height and weight were 165 cm and 35.2 kg, respectively. Truncal ataxia, intention tremor, nystagmus, oculomotor apraxia, dysarthria, and ocular telangiectasia were observed. Deep tendon reflexes were decreased. He also had dystonic movements of the trunk and limbs, and mild mental retardation. Laboratory findings included elevated alpha-fetoprotein and increased sensitivity to DNA-damaging chemicals. Mutation analysis demonstrated compound heterozygosity for a missense mutation leading to a leu2656-to-pro amino acid substitution and a nonsense mutation leading to truncation at codon 3047 (607585.0012). The latter mutation was within the phosphatidylinositol 3-kinase-like domain and the former was outside but close to that domain. #### .0012 ATAXIA-TELANGIECTASIA WITHOUT IMMUNODEFICIENCY [ATM, ARG3047TER ] See 607585.0011 and Toyoshima et al. (1998). #### .0013 ATAXIA-TELANGIECTASIA [ATM, ASP2625GLU AND ASP2626PRO ] In a Dutch family, van Belzen et al. (1998) demonstrated that affected members with ataxia-telangiectasia (208900) were homozygous for 2 consecutive base substitutions in exon 55 of the ATM gene: a T-to-G transversion at position 7875 of the ATM cDNA and a G-to-C transversion at position 7876. The double base substitution resulted in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 and of an alanine to a proline at codon 2626 of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. The change in secondary structure of the ATM protein carrying the D2625E/A2626P mutation, as predicted by the method of Chou and Fasman (1978) and of Garnier et al. (1978), suggested that the double base substitution is a disease-causing mutation. #### .0014 ATAXIA-TELANGIECTASIA, FRESNO VARIANT [ATM, IVS33, T-C, +2] In identical twin girls, Curry et al. (1989) identified a classic AT phenotype (208900) combined with features of the Nijmegen breakage syndrome (251260). Gilad et al. (1998) derived a fibroblast cell line from 1 of the sisters originally described by Curry et al. (1989) and found that it was as radiosensitive as a typical AT cell line. Using an anti-ATM antibody, Gilad et al. (1998) identified no immunoreactive material in this cell line. Screening the ATM transcript in this cell line revealed homozygosity for a typical AT mutation, which abolished a splice site at intron 33 of the ATM gene and led to skipping of exon 32. A deletion of 165 nucleotides beginning with nucleotide 4612 led to in-frame deletion of 55 amino acids beginning at codon 1538. The large deletion in the protein probably severely destabilized the ATM molecule. #### .0015 ATAXIA-TELANGIECTASIA [ATM, 5-BP DEL, NT7884 ] Ejima and Sasaki (1998) found deletion of 5 nucleotides following nucleotide 7883 to be 1 of 2 common mutations in the population of 8 unrelated Japanese families with ataxia-telangiectasia (208900). The other common mutation was a 4612del165 (607585.0014). Forty-four percent of the mutant alleles in these 8 families had 1 of these 2 mutations. #### .0016 ATAXIA-TELANGIECTASIA [ATM, 3245ATC-TGAT] In 11 Norwegian AT (208900) families, Laake et al. (1998) found that 12 of 22 ATM alleles carried a mutation affecting nucleotides 3245-3247 and codon 1082 of the gene, changing the sequence from ATC to TGAT. The result was the introduction of a stop codon downstream at codon 1095, leading to truncation of the ATM protein. Haplotype analyses using 8 microsatellite markers, within and flanking the ATM gene, demonstrated that all carriers of this mutation had the same haplotype of the 5 closest CA-repeat microsatellite markers. Genealogic investigations identified a common ancestor for 3 of the families: a women born in 1684 in the area from which these families originated. The prevalence of this mutation in Norwegian patients allowed a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cancer risk can be evaluated. In the study of ATM mutations in Nordic families, Laake et al. (2000) included 15 Norwegian families; 17 of the 30 mutant alleles (57%) carried the insdel mutation, indicating founder effect. #### .0017 ATAXIA-TELANGIECTASIA [ATM, 3-BP DEL, VAL2662DEL] In a 7-year-old girl with AT (208900) who developed ataxia by the age of 3 years, Sandoval et al. (1999) observed a 3-bp deletion (7983-7991) in exon 56 of the ATM gene, leading to deletion of val2662, 1 of 3 consecutive valines in exon 56. The patient remained free of recurrent infections despite laboratory evidence of absent IgA and lowered IgG3 levels. Chromosome instability was shown by increased bleomycin-induced chromosome breakage rates. Cell lines from this patient with the val2662del mutation exhibited detectable ATM levels, which varied from culture to culture and ranged between apparently normal and 20% of the normal level. The protein was thought to be unstable, possibly in certain tissues, and therefore to fluctuate according to physiologic conditions. #### .0018 ATAXIA-TELANGIECTASIA [ATM, 3576G-A ] In 3 unrelated patients with AT (208900), 1 Italian, 1 Turkish, and 1 Georgian, Sandoval et al. (1999) found a G-to-A transition at nucleotide 3576 in exon 26, which caused aberrant splicing of the ATM message. The mutation was present in homozygous form in 2 of the patients and heterozygous in 1 patient. Because of the origin of the patients, Sandoval et al. (1999) suggested that this splicing mutation may be more common in southeast Europe than in Germany, where the study was performed. The mutation resulted in skipping of exon 26. #### .0019 ATAXIA-TELANGIECTASIA [ATM, ARG2443TER ] Telatar et al. (1998) found an arg2443-to-ter mutation as the cause of AT (208900) in African-Americans. Sandoval et al. (1999) found the same mutation in 2 unrelated patients in Germany. The mutations may have arisen by independent mutation events, as the underlying nucleotide substitution affects the CpG dinucleotide, a known hotspot of mutations in general (Cooper and Youssoufian, 1988). The truncating mutation was caused by a C-to-T transition at nucleotide 7327 in exon 52. #### .0020 BREAST CANCER, FAMILIAL [ATM, IVS61DS, 2-BP INS, +2TA ] KIDNEY CANCER, INCLUDED In a family with multiple cancers, Bay et al. (1999) found heterozygosity for an insertion of TA at position +2 of intron 61 of the ATM gene, which caused skipping of exon 61 in the mRNA. The mutation was associated with a previously undescribed polymorphism in intron 61, a C-to-T transition abolishing a Taq1 restriction site at position +104. The mutation was inherited by 2 sisters, one of whom developed breast cancer (114480) at age 39 years and the second at age 44 years, from their mother, who developed kidney cancer at age 67 years. Studies of irradiated lymphocytes from both sisters revealed elevated numbers of chromatid breaks, typical of AT heterozygotes. In the breast tumor of the older sister, loss of heterozygosity (LOH) was found in the ATM region of 11q23.1, indicating that the normal ATM allele was lost in the breast tumor. LOH was not seen at the BRCA1 (113705) or BRCA2 (600185) loci. BRCA2 was considered an unlikely cancer-predisposing gene in this family because each sister inherited different chromosomes 13 from each parent. The findings suggested that haploinsufficiency at ATM may promote tumorigenesis, even though LOH at the ATM locus supported a more classic 2-hit tumor suppressor gene model. #### .0021 BREAST CANCER, SUSCEPTIBILITY TO [ATM, IVS10AS, T-G, -6 ] ATAXIA TELANGIECTASIA, INCLUDED In a series of 82 Dutch patients who had developed breast cancer (114480) under the age of 45 years and had survived 5 years or more, Broeks et al. (2000) identified 3 who carried a splice site mutation of the ATM gene, a T-to-G transversion at position -6 of the 3-prime splice acceptor site of intron 10. They stated that this mutation had not been detected in a small series of Dutch patients with ataxia-telangiectasia (AT) (Broeks et al., 1998). However, they pointed to a German patient with AT (208900) who was homozygous for this mutation. Broeks et al. (2003) genotyped a number of polymorphic markers in and around the ATM locus in 18 samples from different populations carrying the IVS10-6T-G mutation: 17 unrelated breast cancer patients who were heterozygous for the mutation and a single ataxia-telangiectasia patient who was homozygous. The same markers were also genotyped among 39 unrelated healthy individuals without this mutation. Haplotype analyses revealed one common ancestor in all mutation carriers. By means of a maximum likelihood method, they estimated the age of this mutation to be approximately 2,000 generations. They concluded that the mutation occurred only once during human evolution, at least 50,000 years ago. They predicted that this mutation could be widely distributed across Europe and probably the Middle East and Western Asia. #### .0022 MANTLE CELL LYMPHOMA [ATM, GLU2423GLY] Schaffner et al. (2000) found biallelic ATM mutations in 2 mantle cell lymphomas that contained no 11q deletions. One of these cases had a 7268A-G transition in exon 51 resulting in a glu2423-to-gly amino acid substitution in the gene product; and, in the other allele, an insertion of 3 bp, GAA, in exon 51 resulting in insertion of a lysine residue between codons 2418 and 2419. #### .0023 MANTLE CELL LYMPHOMA [ATM, 3-BP INS, 7253GAA] See 607585.0022 and Schaffner et al. (2000). #### .0024 MANTLE CELL LYMPHOMA, SOMATIC [ATM, GLN1361TER ] In a patient with mantle cell lymphoma and deletion of 11q22-q23 on 1 chromosome, Schaffner et al. (2000) found a 4081C-T transition in exon 29 resulting in a gln1361-to-ter truncating mutation. This mutation was not found in leukopheresis cells obtained from the patient in remission, demonstrating the somatic rather than germline origin. #### .0025 T-CELL PROLYMPHOCYTIC LEUKEMIA, SOMATIC [ATM, SER1770TER] Given the marked predisposition of AT patients to develop neoplasms of the T-cell lineage, Stilgenbauer et al. (1997) analyzed a series of T-cell leukemias (T-cell prolymphocytic leukemia, or T-PLL) in non-AT patients in a search for genomic changes associated with development of this disease. Deletion of 11q was very frequent. A small commonly deleted segment at 11q22.3-q23.1 was defined in 15 of 24 T-PLLs studied. Since this critical region contained ATM, they further analyzed the remaining copy of the gene in 6 cases showing deletions affecting 1 ATM allele. In all 6 cases, mutations of the second ATM allele were identified, leading to the absence, premature truncation, or alteration of the ATM gene product. Thus, the study demonstrated disruption of both ATM alleles by deletion or point mutation in T-PLL, suggesting that ATM functions as a tumor suppressor gene in tumors of non-AT individuals. One of the mutations was a ser1770-to-ter substitution caused by a 5309C-G transversion in exon 37 of the ATM gene. #### .0026 ATAXIA-TELANGIECTASIA [ATM, 4-BP DEL, 65-BP INS ] Pagani et al. (2002) found an unusual type of mutation in the ATM gene causing ataxia-telangiectasia (208900). The patient was a 20-year-old male of German-Polish descent who suffered from cerebellar ataxia, immunodeficiency, and cellular radiosensitivity. He was a compound heterozygote with respect to both a 2250G-A splicing mutation that caused complete skipping of exon 16 and an intron deletion that caused a cryptic exon inclusion between exons 20 and 21. No other mutation had been identified in a previous sequencing analysis of all exons of ATM in his genomic DNA (Sandoval et al., 1999). The deletion involved 4 nucleotides (GTAA) in intron 20 and resulted in the aberrant inclusion of a cryptic exon of 65 bp. The deletion was located 12 bp downstream and 53 bp upstream from the 5-prime and 3-prime ends of the cryptic exon, respectively. Through analysis of the splicing defect using a hybrid minigene system, Pagani et al. (2002) identified a new intron-splicing processing element (ISPE) complementary to U1 snRNA (180680), the RNA component of the U1 small nuclear ribonucleoprotein (snRNP). They found that the element mediates accurate intron processing and interacts specifically with U1 snRNP particles. The 4-nucleotide deletion completely abolished this interaction, causing activation of the cryptic exon. On the basis of the analysis in this instructive case, Pagani et al. (2002) described a new type of U1 snRNP binding site in an intron that is essential for accurate intron removal. Deletion of this sequence is directly involved in the splicing processing defect. Eng et al. (2004) referred to this type of mutation as a pseudoexon insertion and in a discussion of nonclassic splicing mutations in ataxia-telangiectasia patients referred to this as type II. They described 4 patients of diverse ethnicity with the mutation IVS20-579delAAGT and found that they all shared a common founder haplotype. #### .0027 ATAXIA-TELANGIECTASIA [ATM, 2250G-A ] See 607585.0026 and Pagani et al. (2002). #### .0028 ATAXIA-TELANGIECTASIA VARIANT [ATM, TYR2677CYS ] In 2 sisters with variant AT (208900) with onset of ataxia at age 27 years, polyneuropathy, choreoathetosis, and absence of telangiectasia, immunodeficiency, and cancer, Saviozzi et al. (2002) identified compound heterozygosity for mutations in the ATM gene: an 8030A-G change in exon 57, resulting in a tyr2677-to-cys (Y2677C) substitution, and a 1-bp insertion at nucleotide 7481 (7481insA; 607585.0029) in exon 52, resulting in a frameshift. Western blot analysis showed a low level of ATM protein with residual phosphorylation activity, which the authors suggested contributed to the milder phenotype. #### .0029 ATAXIA-TELANGIECTASIA VARIANT [ATM, TYR2677CYS ] See 607585.0028 and Saviozzi et al. (2002). #### .0030 ATAXIA-TELANGIECTASIA VARIANT [ATM, ASP2625GLU, ALA2626PRO ] Dork et al. (2004) described a patient with an attenuated form of AT (208900) in whom the disorder was diagnosed at the age of 52 years and who died at the age of 60 years. He was found to be a compound heterozygote for a double missense mutation (asp2625 to glu and ala2626 to pro) and a novel splicing mutation (496+5G-A) of the ATM gene. Cytogenetic studies of the patient's lymphoblastoid cells revealed modest levels of bleomycin-induced chromosomal instability. Residual ATM protein was 10 to 20% of wildtype. Low residual ATM kinase activity could be demonstrated towards p53 (191170), whereas it was poorly detectable towards nibrin (602667). The results corroborated the view that the clinical variability of AT is partly determined by the mutation type and indicated that AT can present as a late adulthood disease. Although ataxia-telangiectasia was diagnosed at the age of 52 years, the patient had developed the first symptoms of ataxia at the age of 7 years. Ataxia had become prominent by the age of 14 years, and he had lost the ability to walk alone by the age of 22 years. He became permanently wheelchair-bound by the age of 45 years. Clinical diagnosis was made at the age of 52 years and confirmed by cytogenetic analysis 3 years later. His clinical phenotype thereafter was progressively dominated by chronic obstipation associated with megacolon and gastroenteritis. #### .0031 ATAXIA-TELANGIECTASIA VARIANT [ATM, IVS7, G-A, +5 ] The patient with an attenuated form of AT reported by Dork et al. (2004) was a compound heterozygote for a double missense mutation (607585.0030) and a novel splicing mutation (496+5G-A) in the splice donor site of intron 7. ### SEE ALSO Boder (1985); Imai (1996) ### REFERENCES 1. Allen, D. M.; van Praag, H.; Ray, J.; Weaver, Z.; Winrow, C. J.; Carter, T. A.; Braquet, R.; Harrington, E.; Ried, T.; Brown, K. D.; Gage, F. H.; Barlow, C. : Ataxia telangiectasia mutated is essential during adult neurogenesis. Genes Dev. 15: 554-566, 2001. PubMed ID : 11238376 2. Baker, B. S.; Boyd, J. B.; Carpenter, A. T. C.; Green, M. M.; Nguyen, T. D.; Ripoll, P.; Smith, P. D. : Genetic controls of meiotic recombination and somatic DNA metabolism in Drosophila melanogaster. Proc. Nat. Acad. Sci. 73: 4140-4144, 1976. PubMed ID : 825857 3. Bakkenist, C. J.; Kastan, M. B. : DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421: 499-506, 2003. PubMed ID : 12556884 4. Banga, S. S.; Shenkar, R.; Boyd, J. B. : Hypersensitivity of Drosophila mei-41 mutants to hydroxyurea is associated with reduced mitotic chromosome stability. Mutat. Res. 163: 157-165, 1986. PubMed ID : 3093854 5. Banin, S.; Moyal, L.; Shieh, S.-Y.; Taya, Y.; Anderson, C. W.; Chessa, L.; Smorodinsky, N. I.; Prives, C.; Reiss, Y.; Shiloh, Y.; Ziv, Y. : Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281: 1674-1677, 1998. PubMed ID : 9733514 6. Bao, S.; Tibbetts, R. S.; Brumbaugh, K. M.; Fang, Y.; Richardson, D. A.; Ali, A.; Chen, S. M.; Abraham, R. T.; Wang, X.-F. : ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature 411: 969-974, 2001. PubMed ID : 11418864 7. Barlow, C.; Dennery, P. A.; Shigenaga, M. K.; Smith, M. A.; Morrow, J. D.; Roberts, L. J., II; Wynshaw-Boris, A.; Levine, R. L. : Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc. Nat. Acad. Sci. 96: 9915-9919, 1999. PubMed ID : 10449794 8. Barlow, C.; Eckhaus, M. A.; Schaffer, A. A.; Wynshaw-Boris, A. : Atm haploinsufficiency results in increased sensitivity to sublethal doses of ionizing radiation in mice. Nature Genet. 21: 359-360, 1999. PubMed ID : 10192382 9. Barlow, C.; Hirotsune, S.; Paylor, R.; Liyanage, M.; Eckhaus, M.; Collins, F.; Shiloh, Y.; Crawley, J. N.; Ried, T.; Tagle, D.; Wynshaw-Boris, A. : Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86: 159-171, 1996. PubMed ID : 8689683 10. Bay, J.-O.; Uhrhammer, N.; Pernin, D.; Presneau, N.; Tchirkov, A.; Vuillaume, M.; Laplace, V.; Grancho, M.; Verrelle, P.; Hall, J.; Bignon, Y.-J. : High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer. Hum. Mutat. 14: 485-492, 1999. PubMed ID : 10571946 11. Beamish, H.; Kedar, P.; Kaneko, H.; Chen, P.; Fukao, T.; Peng, C.; Beresten, S.; Gueven, N.; Purdie, D.; Lees-Miller, S.; Ellis, N.; Kondo, N.; Lavin, M. F. : Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM. J. Biol. Chem. 277: 30515-30523, 2002. PubMed ID : 12034743 12. Boder, E. : Ataxia-telangiectasia: some historic, clinical and pathologic observations.In: Bergsma, D. (ed.) : Immunodeficiency in Man and Animals. New York: National Foundation-March of Dimes (pub.) 1975. Pp. 255-300. 13. Boder, E. : Ataxia-telangiectasia: an overview.In: Gatti, R. A.; Swift, M. : Ataxia-telangiectasia: Genetics, Neuropathology and Immunology of a Degenerative Disease of Childhood. New York: Alan R. Liss (pub.) 1985. Pp. 1-63. 14. Borghesani, P. R.; Alt, F. W.; Bottaro, A.; Davidson, L.; Aksoy, S.; Rathbun, G. A.; Roberts, T. M.; Swat, W.; Segal, R. A.; Gu, Y. : Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc. Nat. Acad. Sci. 97: 3336-3341, 2000. PubMed ID : 10716718 15. Boyd, J. B.; Golino, M. D.; Nguyen, T. D.; Green, M. M. : Isolation and characterization of X-linked mutants of Drosophila melanogaster which are sensitive to mutagens. Genetics 84: 485-506, 1976. PubMed ID : 187527 16. Broeks, A.; de Klein, A.; Floore, A. N.; Muijtjens, M.; Kleijer, W. J.; Jaspers, N. G.; van't Veer, L. J. : ATM germline mutations in classical ataxia-telangiectasia patients in the Dutch population. Hum. Mutat. 12: 330-337, 1998. PubMed ID : 9792409 17. Broeks, A.; Urbanus, J. H. M.; de Knijff, P.; Devilee, P.; Nicke, M.; Klopper, K.; Dork, T.; Floore, A. N.; van't Veer, L. J. : IVS10-6T-G, an ancient ATM germline mutation linked with breast cancer. Hum. Mutat. 21: 521-528, 2003. PubMed ID : 12673794 18. Broeks, A.; Urbanus, J. H. M.; Floore, A. N.; Dahler, E. C.; Klijn, J. G. M.; Rutgers, E. J. Th.; Devilee, P.; Russell, N. S.; van Leeuwen, F. E.; van't Veer, L. J. : ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am. J. Hum. Genet. 66: 494-500, 2000. PubMed ID : 10677309 19. Brown, K. D.; Ziv, Y.; Sadanandan, S. N.; Chessa, L.; Collins, F. S.; Shiloh, Y.; Tagle, D. A. : The ataxia-telangiectasia gene product, a constitutively expressed nuclear protein that is not up-regulated following genome damage. Proc. Nat. Acad. Sci. 94: 1840-1845, 1997. PubMed ID : 9050866 20. Brzoska, P. M.; Chen, H.; Zhu, Y.; Levin, N. A.; Disatnik, M.-H.; Mochly-Rosen, D.; Murnane, J. P.; Christman, M. F. : The product of the ataxia-telangiectasia group D complementing gene, ATDC, interacts with a protein kinase C substrate and inhibitor. Proc. Nat. Acad. Sci. 92: 7824-7828, 1995. PubMed ID : 7644499 21. Byrd, P. J.; McConville, C. M.; Cooper, P.; Parkhill, J.; Stankovic, T.; McGuire, G. M.; Thick, J. A.; Taylor, A. M. R. : Mutations revealed by sequencing the 5-prime half of the gene for ataxia telangiectasia. Hum. Molec. Genet. 5: 145-149, 1996. PubMed ID : 8789452 22. Canman, C. E.; Lim, D.-S.; Cimprich, K. A.; Taya, Y.; Tamai, K.; Sakaguchi, K.; Appella, E.; Kastan, M. B.; Siliciano, J. D. : Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281: 1677-1679, 1998. PubMed ID : 9733515 23. Chen, P.; Imray, F. P.; Kidson, C. : Gene dosage and complementation analysis of ataxia telangiectasia lymphoblastoid cell lines assayed by induced chromosome aberrations. Mutat. Res. 129: 165-172, 1984. PubMed ID : 6504056 24. Chong, M. J.; Murray, M. R.; Gosink, E. C.; Russell, H. R. C.; Srinivasan, A.; Kapsetaki, M.; Korsmeyer, S. J.; McKinnon, P. J. : Atm and Bax cooperate in ionizing radiation-induced apoptosis in the central nervous system. Proc. Nat. Acad. Sci. 97: 889-894, 2000. PubMed ID : 10639175 25. Chou, P. Y.; Fasman, G. D. : Prediction of the secondary structure of proteins from their amino acid sequence. Adv. Enzymol. Relat. Areas Molec. Biol. 47: 45-148, 1978. 26. Concannon, P.; Gatti, R. A. : Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum. Mutat. 10: 100-107, 1997. PubMed ID : 9259193 27. Cooper, D. N.; Youssoufian, H. : The CpG dinucleotide and human genetic disease. Hum. Genet. 78: 151-155, 1988. PubMed ID : 3338800 28. Cortez, D.; Wang, Y.; Qin, J.; Elledge, S. J. : Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 286: 1162-1166, 1999. PubMed ID : 10550055 29. Curry, C. J. R.; Tsai, J.; Hutchinson, H. T.; Jaspers, N. G. J.; Wara, D.; Gatti, R. A. : AT-Fresno: a phenotype linking ataxia-telangiectasia with the Nijmegen breakage syndrome. Am. J. Hum. Genet. 45: 270-275, 1989. PubMed ID : 2491181 30. Dork, T.; Bendix-Waltes, R.; Wegner, R.-D.; Stumm, M. : Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations. Am. J. Med. Genet. 126A: 272-277, 2004. 31. Ejima, Y.; Sasaki, M. S. : Mutations of the ATM gene detected in Japanese ataxia-telangiectasia patients: possible preponderance of the two founder mutations 4612del165 and 7883del5. Hum. Genet. 102: 403-408, 1998. PubMed ID : 9600235 32. Elson, A.; Wang, Y.; Daugherty, C. J.; Morton, C. C.; Zhou, F.; Campos-Torres, J.; Leder, P. : Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Nat. Acad. Sci. 93: 13084-13089, 1996. PubMed ID : 8917548 33. Eng, L.; Coutinho, G.; Nahas, S.; Yeo, G.; Tanouye, R.; Babaei, M.; Dork, T.; Burge, C.; Gatti, R. A. : Nonclassical splicing mutations in the coding and noncoding regions of the ATM gene: maximum entropy estimates of splice junction strengths. Hum. Mutat. 23: 67-76, 2004. PubMed ID : 14695534 34. Falck, J.; Mailand, N.; Syljuasen, R. G.; Bartek, J.; Lukas, J. : The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410: 842-847, 2001. PubMed ID : 11298456 35. Falck, J.; Petrini, J. H. J.; Williams, B. R.; Lukas, J.; Bartek, J. : The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genet. 30: 290-294, 2002. PubMed ID : 11850621 36. Fang, N. Y.; Greiner, T. C.; Weisenburger, D. D.; Chan, W. C.; Vose, J. M.; Smith, L. M.; Armitage, J. O.; Mayer, R. A.; Pike, B. L.; Collins, F. S.; Hacia, J. G. : Oligonucleotide microarrays demonstrate the highest frequency of ATM mutations in the mantle cell subtype of lymphoma. Proc. Nat. Acad. Sci. 100: 5372-5377, 2003. PubMed ID : 12697903 37. Garnier, J.; Osguthorpe, D. J.; Robson, B. : Analysis of the accuracy and implications of simple methods for predicting the secondary structure of globular proteins. J. Molec. Biol. 120: 97-120, 1978. PubMed ID : 642007 38. Gatei, M.; Young, D.; Cerosaletti, K. M.; Desai-Mehta, A.; Spring, K.; Kozlov, S.; Lavin, M. F.; Gatti, R. A.; Concannon, P.; Khanna, K. : ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nature Genet. 25: 115-119, 2000. PubMed ID : 10802669 39. Gatti, R. A.; Berkel, I.; Boder, E.; Braedt, G.; Charmley, P.; Concannon, P.; Ersoy, R.; Foroud, T.; Jaspers, N. G. J.; Lange, K.; Lathrop, G. M.; Leppert, M.; Nakamura, Y.; O'Connell, P.; Paterson, M.; Salser, W.; Sanal, O.; Silver, J.; Sparkes, R. S.; Susi, E.; Weeks, D. E.; Wei, S.; White, R.; Yoder, F. : Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 336: 577-580, 1988. PubMed ID : 3200306 40. Gatti, R. A.; Boder, E.; Vinters, H. V.; Sparkes, R. S.; Norman, A.; Lange, K. : Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine 70: 99-117, 1991. PubMed ID : 2005780 41. Gatti, R. A.; Peterson, K. L.; Novak, J.; Chen, X.; Yang-Chen, L.; Liang, T.; Lange, E.; Lange, K. : Prenatal genotyping of ataxia-telangiectasia. (Letter) Lancet 342: 376, 1993. PubMed ID : 8101622 42. Gilad, S.; Bar-Shira, A.; Harnik, R.; Shkedy, D.; Ziv, Y.; Khosravi, R.; Brown, K.; Vanagaite, L.; Xu, G.; Frydman, M.; Lavin, M. F.; Hill, D.; Tagle, D. A.; Shiloh, Y. : Ataxia-telangiectasia: founder effect among North African Jews. Hum. Molec. Genet. 5: 2033-2037, 1996. PubMed ID : 8968760 43. Gilad, S.; Chessa, L.; Khosravi, R.; Russell, P.; Galanty, Y.; Piane, M.; Gatti, R. A.; Jorgensen, T. J.; Shiloh, Y.; Bar-Shira, A. : Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am. J. Hum. Genet. 62: 551-561, 1998. PubMed ID : 9497252 44. Gilad, S.; Khosravi, R.; Shkedy, D.; Uziel, T.; Ziv, Y.; Savitsky, K.; Rotman, G.; Smith, S.; Chessa, L.; Jorgensen, T. J.; Harnik, R.; Frydman, M.; Sanal, O.; Portnoi, S.; Goldwicz, Z.; Jaspers, N. G. J.; Gatti, R. A.; Lenoir, G.; Lavin, M. F.; Tatsumi, K.; Wegner, R. D.; Shiloh, Y.; Bar-Shira, A. : Predominance of null mutations in ataxia-telangiectasia. Hum. Molec. Genet. 5: 433-439, 1996. PubMed ID : 8845835 45. Greenwell, P. W.; Kronmal, S. L.; Porter, S. E.; Gassbenhuber, J.; Obermaier, B.; Petes, T. D. : TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell 82: 823-829, 1995. PubMed ID : 7671310 46. Hande, M. P.; Balajee, A. S.; Tchirkov, A.; Wynshaw-Boris, A.; Lansdorp, P. M. : Extra-chromosomal telomeric DNA in cells from Atm-/- mice and patients with ataxia-telangiectasia. Hum. Molec. Genet. 10: 519-528, 2001. PubMed ID : 11181576 47. Hari, K. L.; Santerre, A.; Sekelsky, J. J.; McKim, K. S.; Boyd, J. B.; Hawley, R. S. : The mei-41 gene of D. melanogaster is a structural and functional homolog of the human ataxia telangiectasia gene. Cell 82: 815-821, 1995. PubMed ID : 7671309 48. Hawley, R. S.; Friend, S. H. : Strange bedfellows in even stranger places: the role of ATM in meiotic cells, lymphocytes, tumors, and its functional links to p53. Genes Dev. 10: 2383-2388, 1996. PubMed ID : 8843191 49. Imai, T. : Personal Communication. Chiba, Japan, 9/12/1996. 50. Ito, K.; Hirao, A.; Arai, F.; Matsuoka, S.; Takubo, K.; Hamaguchi, I.; Nomiyama, K.; Hosokawa, K.; Sakurada, K.; Nakagata, N.; Ikeda, Y.; Mak, T. W.; Suda, T. : Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431: 997-1002, 2004. PubMed ID : 15496926 51. Kapp, L. N.; Painter, R. B.; Yu, L.-C.; van Loon, N.; Richard, C. W., III; James, M. R.; Cox, D. R.; Murnane, J. P. : Cloning of a candidate gene for ataxia-telangiectasia group D. Am. J. Hum. Genet. 51: 45-54, 1992. PubMed ID : 1609804 52. Kastan, K. : Clinical implications of basic research: ataxia-telangiectasia--broad implications for a rare disorder. New Eng. J. Med. 333: 662-663, 1995. PubMed ID : 7637733 53. Khanna, K. K.; Keating, K. E.; Kozlov, S.; Scott, S.; Gatei, M.; Hobson, K.; Taya, Y.; Gabrielli, B.; Chan, D.; Lees-Miller, S. P.; Lavin, M. F. : ATM associates with and phosphorylates p53: mapping the region of interaction. Nature Genet. 20: 398-400, 1998. PubMed ID : 9843217 54. Laake, K.; Jansen, L.; Hahnemann, J. M.; Brondum-Nielsen, K.; Lonnqvist, T.; Kaariainen, H.; Sankila, R.; Lahdesmaki, A.; Hammarstrom, L.; Yuen, J.; Tretli, S.; Heiberg, A.; Olsen, J. H.; Tucker, M.; Kleinerman, R.; Borresen-Dale, A.-L. : Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum. Mutat. 16: 232-246, 2000. PubMed ID : 10980530 55. Laake, K.; Telatar, M.; Geitvik, G. A.; Hansen, R. O.; Heiberg, A.; Andresen, A. M.; Gatti, R.; Borresen-Dale, A.-L. : Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect. Europ. J. Hum. Genet. 6: 235-244, 1998. PubMed ID : 9781027 56. Lee, J.-H.; Paull, T. T. : ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 308: 551-554, 2005. PubMed ID : 15790808 57. Li, A.; Swift, M. : Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. Am. J. Med. Genet. 92: 170-177, 2000. PubMed ID : 10817650 58. Li, S.; Ting, N. S. Y.; Zheng, L.; Chen, P.-L.; Ziv, Y.; Shiloh, Y.; Lee, E. Y.-H. P.; Lee, W.-H. : Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406: 210-215, 2000. PubMed ID : 10910365 59. Liberzon, E.; Avigad, S.; Cohen, I. J.; Yaniv, I.; Michovitz, S.; Zaizov, R. : ATM gene mutations are not involved in medulloblastoma in children. Cancer Genet. Cytogenet. 146: 167-169, 2003. PubMed ID : 14553952 60. Lim, D.-S.; Kim, S.-T.; Xu, B.; Maser, R. S.; Lin, J.; Petrini, J. H. J.; Kastan, M. B. : ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404: 613-617, 2000. PubMed ID : 10766245 61. Lim, D.-S.; Kirsch, D. G.; Canman, C. E.; Ahn, J.-H.; Ziv, Y.; Newman, L. S.; Darnell, R. B.; Shiloh, Y.; Kastan, M. B. : ATM binds to beta-adaptin in cytoplasmic vesicles. Proc. Nat. Acad. Sci. 95: 10146-10151, 1998. PubMed ID : 9707615 62. Matsuda, Y.; Imai, T.; Shiomi, T.; Saito, T.; Yamauchi, M.; Fukao, T.; Akao, Y.; Seki, N.; Ito, H.; Hori, T. : Comparative genome mapping of the ataxia-telangiectasia region in mouse, rat, and Syrian hamster. Genomics 34: 347-352, 1996. PubMed ID : 8786135 63. McConville, C. M.; Stankovic, T.; Byrd, P. J.; McGuire, G. M.; Yao, Q.-Y.; Lennox, G. G.; Taylor, A. M. R. : Mutations associated with variant phenotypes in ataxia-telangiectasia. Am. J. Hum. Genet. 59: 320-330, 1996. PubMed ID : 8755918 64. Morrow, D. M.; Tagle, D. A.; Shiloh, Y.; Collins, F. S.; Hieter, P. : TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene MEC1. Cell 82: 831-840, 1995. PubMed ID : 7545545 65. Naito, T.; Matsuura, A.; Ishikawa, F. : Circular chromosome formation in a fission yeast mutant defective in two ATM homologues. Nature Genet. 20: 203-206, 1998. PubMed ID : 9771717 66. Nguyen, T. D.; Boyd, J. B.; Green, M. M. : Sensitivity of Drosophila mutants to chemical carcinogens. Mutat. Res. 63: 67-77, 1979. PubMed ID : 118375 67. Pagani, F.; Buratti, E.; Stuani, C.; Bendix, R.; Dork, T.; Baralle, F. E. : A new type of mutation causes a splicing defect in ATM. Nature Genet. 30: 426-429, 2002. PubMed ID : 11889466 68. Paulovich, A. G.; Hartwell, L. H. : A checkpoint regulates the rate of progression through S phase in S. cerevisiae in response to DNA damage. Cell 82: 841-847, 1995. PubMed ID : 7671311 69. Pecker, I.; Avraham, K. B.; Gilbert, D. J.; Savitsky, K.; Rotman, G.; Harnik, R.; Fukao, T.; Schrock, E.; Hirotsune, S.; Tagle, D. A.; Collins, F. S.; Wynshaw-Boris, A.; Ried, T.; Copeland, N. G.; Jenkins, N. A.; Shiloh, Y.; Ziv, Y. : Identification and chromosomal localization of Atm, the mouse homolog of the ataxia-telangiectasia gene. Genomics 35: 39-45, 1996. PubMed ID : 8661102 70. Sandoval, N.; Platzer, M.; Rosenthal, A.; Dork, T.; Bendix, R.; Skawran, B.; Stuhrmann, M.; Wegner, R.-D.; Sperling, K.; Banin, S.; Shiloh, Y.; Baumer, A.; Bernthaler, U.; Sennefelder, H.; Brohm, M.; Weber, B. H. F.; Schindler, D. : Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum. Molec. Genet. 8: 69-79, 1999. PubMed ID : 9887333 71. Saviozzi, S.; Saluto, A.; Taylor, A. M. R.; Last, J. I. L.; Trebini, F.; Paradiso, M. C.; Grosso, E.; Funaro, A.; Ponzio, G.; Migone, N.; Brusco, A. : A late onset variant of ataxia-telangiectasia with a compound heterozygous genotype, A8030G/7481insA. J. Med. Genet. 39: 57-61, 2002. PubMed ID : 11826028 72. Savitsky, K.; Bar-Shira, A.; Gilad, S.; Rotman, G.; Ziv, Y.; Vanagaite, L.; Tagle, D. A.; Smith, S.; Uziel, T.; Sfez, S.; Ashkenazi, M.; Pecker, I.; and 18 others : A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268: 1749-1753, 1995. PubMed ID : 7792600 73. Savitsky, K.; Sfez, S.; Tagle, D. A.; Ziv, Y.; Sartiel, A.; Collins, F. S.; Shiloh, Y.; Rotman, G. : The complete sequence of the coding region of the ATM gene reveals similarity to cell cycle regulators in different species. Hum. Molec. Genet. 4: 2025-2032, 1995. PubMed ID : 8589678 74. Schaffner, C.; Idler, I.; Stilgenbauer, S.; Dohner, H.; Lichter, P. : Mantle cell lymphoma is characterized by inactivation of the ATM gene. Proc. Nat. Acad. Sci. 97: 2773-2778, 2000. PubMed ID : 10706620 75. Schaffner, C.; Stilgenbauer, S.; Rappold, G. A.; Dohner, H.; Lichter, P. : Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood 94: 748-753, 1999. PubMed ID : 10397742 76. Scott, S. P.; Bendix, R.; Chen, P.; Clark, R.; Dork, T.; Lavin, M. F. : Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc. Nat. Acad. Sci. 99: 925-930, 2002. PubMed ID : 11805335 77. Spring, K.; Ahangari, F.; Scott, S. P.; Waring, P.; Purdie, D. M.; Chen, P. C.; Hourigan, K.; Ramsay, J.; McKinnon, P. J.; Swift, M.; Lavin, M. F. : Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nature Genet. 32: 185-190, 2002. PubMed ID : 12195425 78. Stankovic, T.; Kidd, A. M. J.; Sutcliffe, A.; McGuire, G. M.; Robinson, P.; Weber, P.; Bedenham, T.; Bradwell, A. R.; Easton, D. F.; Lennox, G. G.; Haites, N.; Byrd, P. J.; Taylor, A. M. R. : ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am. J. Hum. Genet. 62: 334-345, 1998. PubMed ID : 9463314 79. Stern, N.; Hochman, A.; Zemach, N.; Weizman, N.; Hammel, I.; Shiloh, Y.; Rotman, G.; Barzilai, A. : Accumulation of DNA damage and reduced levels of nicotine adenine dinucleotide in the brains of Atm-deficient mice. J. Biol. Chem. 277: 602-608, 2002. PubMed ID : 11679583 80. Stilgenbauer, S.; Schaffner, C.; Litterst, A.; Liebisch, P.; Gilad, S.; Bar-Shira, A.; James, M. R.; Lichter, P.; Dohner, H. : Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nature Med. 3: 1155-1159, 1997. PubMed ID : 9334731 81. Stilgenbauer, S.; Winkler, D.; Ott, G.; Schaffner, C.; Leupolt, E.; Bentz, M.; Moller, P.; Muller-Hermelink, H.-K.; James, M. R.; Lichter, P.; Dohner, H. : Molecular characterization of 11q deletions points to a pathogenic role of the ATM gene in mantle cell lymphoma. Blood 94: 3262-3264, 1999. PubMed ID : 10556216 82. Sutton, I. J.; Last, J. I. K.; Ritchie, S. J.; Harrington, H. J.; Byrd, P. J.; Taylor, A. M. R. : Adult-onset ataxia telangiectasia due to ATM 5762ins137 mutation homozygosity. Ann. Neurol. 55: 891-895, 2004. PubMed ID : 15174027 83. Taniguchi, T.; Garcia-Higuera, I.; Xu, B.; Andreassen, P. R.; Gregory, R. C.; Kim, S.-T.; Lane, W. S.; Kastan, M. B.; D'Andrea, A. D. : Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways. Cell 109: 459-472, 2002. PubMed ID : 12086603 84. Tchirkov, A; Lansdorp, P. M. : Role of oxidative stress in telomere shortening in cultured fibroblasts from normal individuals and patients with ataxia-telangiectasia. Hum. Molec. Genet. 12: 227-232, 2003. PubMed ID : 12554677 85. Telatar, M.; Teraoka, S.; Wang, Z.; Chun, H. H.; Liang, T.; Castellvi-Bel, S.; Udar, N.; Borresen-Dale, A.-L.; Chessa, L.; Bernatowska-Matuskiewicz, E.; Porras, O.; Watanabe, M.; Junker, A.; Concannon, P.; Gatti, R. A. : Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am. J. Hum. Genet. 62: 86-97, 1998. PubMed ID : 9443866 86. Teraoka, S. N.; Telatar, M.; Becker-Catania, S.; Liang, T.; Onengut, S.; Tolun, A.; Chessa, L.; Sanal, O.; Bernatowska, E.; Gatti, R. A.; Concannon, P. : Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences. Am. J. Hum. Genet. 64: 1617-1631, 1999. PubMed ID : 10330348 87. Toyoshima, M.; Hara, T.; Zhang, H.; Yamamoto, T.; Akaboshi, S.; Nanba, E.; Ohno, K.; Hori, N.; Sato, K.; Takeshita, K. : Ataxia-telangiectasia without immunodeficiency: novel point mutations within and adjacent to the phosphatidylinositol 3-kinase-like domain. Am. J. Med. Genet. 75: 141-144, 1998. PubMed ID : 9450874 88. Uziel, T.; Savitsky, K.; Platzer, M.; Ziv, Y.; Helbitz, T.; Nehls, M.; Boehm, T.; Rosenthal, A.; Shiloh, Y.; Rotman, G. : Genomic organization of the ATM gene. Genomics 33: 317-320, 1996. PubMed ID : 8660985 89. van Belzen, M. J.; Hiel, J. A. P.; Weemaes, C. M. R.; Gabreels, F. J. M.; van Engelen, B. G. M.; Smeets, D. F. C. M.; van den Heuvel, L. P. W. J. : A double missense mutation in the ATM gene of a Dutch family with ataxia telangiectasia. Hum. Genet. 102: 187-191, 1998. PubMed ID : 9521587 90. Vorechovsky, I.; Luo, L.; Dyer, M. J. S.; Catovsky, D.; Amlot, P. L.; Yaxley, J. C.; Foroni, L.; Hammarstrom, L.; Webster, A. D. B.; Yuille, M. A. R. : Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nature Genet. 17: 96-99, 1997. PubMed ID : 9288106 91. Vorechovsky, I.; Luo, L.; Lindblom, A.; Negrini, M.; Webster, A. D.; Croce, C. M.; Hammarstrom, L. : ATM mutations in cancer families. Cancer Res. 56: 4130-4133, 1996. PubMed ID : 8797579 92. Wang, Y.; Cortez, D.; Yazdi, P.; Neff, N.; Elledge, S. J.; Qin, J. : BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14: 927-939, 2000. PubMed ID : 10783165 93. Wang, Y. A.; Elson, A.; Leder, P. : Loss of p21 increases sensitivity to ionizing radiation and delays the onset of lymphoma in atm-deficient mice. Proc. Nat. Acad. Sci. 94: 14590-14595, 1997. PubMed ID : 9405657 94. Westphal, C. H.; Rowan, S.; Schmaltz, C.; Elson, A.; Fisher, D. E.; Leder, P. : atm and p53 cooperate in apoptosis and suppression of tumorigenesis, but not in resistance to acute radiation toxicity. Nature Genet. 16: 397-401, 1997. PubMed ID : 9241281 95. Wong, K.-K.; Maser, R. S.; Bachoo, R. M.; Menon, J.; Carrasco, D. R.; Gu, Y.; Alt, F. W.; DePinho, R. A. : Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421: 643-648, 2003. PubMed ID : 12540856 96. Wright, J.; Teraoka, S.; Onengut, S.; Tolun, A.; Gatti, R. A.; Ochs, H. D.; Concannon, P. : A high frequency of distinct ATM gene mutations in ataxia-telangiectasia. Am. J. Hum. Genet. 59: 839-846, 1996. PubMed ID : 8808599 97. Wu, X.; Ranganathan, V.; Weisman, D. S.; Heine, W. F.; Ciccone, D. N.; O'Neill, T. B.; Crick, K. E.; Pierce, K. A.; Lane, W. S.; Rathbun, G.; Livingston, D. M.; Weaver, D. T. : ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405: 477-482, 2000. PubMed ID : 10839545 98. Xia, Y.-R.; Welch, C. L.; Warden, C. H.; Lange, E.; Fukao, T.; Lusis, A. J.; Gatti, R. A. : Assignment of the mouse ataxia-telangiectasia gene (Atm) to mouse chromosome 9. Mammalian Genome 7: 554-555, 1996. PubMed ID : 8672141 99. Xu, Y.; Ashley, T; Brainerd, E. E.; Bronson, R. T.; Meyn, M. S.; Baltimore, D. : Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10: 2411-2422, 1996. PubMed ID : 8843194 100. Xu, Y.; Baltimore, D. : Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10: 2401-2410, 1996. PubMed ID : 8843193 101. Zakian, V. A. : ATM-related genes: what do they tell us about functions of the human gene? Cell 82: 685-687, 1995. PubMed ID : 7671296 102. Zhang, N.; Chen, P.; Khanna, K. K.; Scott, S.; Gatei, M.; Kozlov, S.; Watters, D.; Spring, K.; Yen, T.; Lavin, M. F. : Isolation of full-length ATM cDNA and correction of the ataxia-telangiectasia cellular phenotype. Proc. Nat. Acad. Sci. 94: 8021-8026, 1997. PubMed ID : 9223307 103. Zhao, S.; Weng, Y.-C.; Yuan, S.-S. F.; Lin, Y.-T.; Hsu, H.-C.; Lin, S.-C. J.; Gerbino, E.; Song, M.; Zdzienicka, M. Z.; Gatti, R. A.; Shay, J. W.; Ziv, Y.; Shiloh, Y.; Lee, E. Y.-H. P. : Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405: 473-477, 2000. PubMed ID : 10839544 104. Ziv, Y.; Frydman, M.; Lange, E.; Zelnik, N.; Rotman, G.; Julier, C.; Jaspers, N. G. J.; Dagan, Y.; Abeliovicz, D.; Dar, H.; Borochowitz, Z.; Lathrop, M.; Gatti, R. A.; Shiloh, Y. : Ataxia-telangiectasia: linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome. Hum. Genet. 88: 619-626, 1992. PubMed ID : 1551665 ### CONTRIBUTORS Ada Hamosh - updated : 5/3/2005 Ada Hamosh - updated : 1/26/2005 George E. Tiller - updated : 12/10/2004 Cassandra L. Kniffin - updated : 8/3/2004 Victor A. McKusick - updated : 4/14/2004 Victor A. McKusick - updated : 2/3/2004 Victor A. McKusick - updated : 1/15/2004 Cassandra L. Kniffin - updated : 10/16/2003 Victor A. McKusick - updated : 6/13/2003 Victor A. McKusick - updated : 6/11/2003 ### CREATION DATE Cassandra L. Kniffin : 2/27/2003 ### EDIT HISTORY alopez : 5/4/2005 terry : 5/3/2005 mgross : 4/14/2005 terry : 4/6/2005 tkritzer : 2/9/2005 terry : 1/26/2005 alopez : 12/10/2004 tkritzer : 8/9/2004 ckniffin : 8/3/2004 alopez : 4/16/2004 terry : 4/14/2004 cwells : 2/9/2004 terry : 2/3/2004 cwells : 1/20/2004 terry : 1/15/2004 carol : 10/19/2003 carol : 10/19/2003 ckniffin : 10/16/2003 terry : 6/13/2003 carol : 6/13/2003 terry : 6/11/2003 alopez : 3/25/2003 carol : 3/11/2003 ckniffin : 3/7/2003 ckniffin : 3/7/2003 carol : 3/7/2003 ckniffin : 3/4/2003 ckniffin : 3/3/2003 ckniffin : 3/3/2003 ckniffin : 3/3/2003 Copyright © 1966-2005 Johns Hopkins University
2: | #208900 | GeneTests, Links
| ATAXIA-TELANGIECTASIA; AT
#### Alternative titles; symbols AT1 LOUIS-BAR SYNDROME AT, COMPLEMENTATION GROUP A, INCLUDED; ATA, INCLUDED AT, COMPLEMENTATION GROUP C, INCLUDED; ATC, INCLUDED AT, COMPLEMENTATION GROUP D, INCLUDED; ATD, INCLUDED AT, COMPLEMENTATION GROUP E, INCLUDED; ATE, INCLUDED ATAXIA-TELANGIECTASIA VARIANT, INCLUDED ### TABLE OF CONTENTS #### TEXT DESCRIPTION CLINICAL FEATURES OTHER FEATURES INHERITANCE DIAGNOSIS CLINICAL MANAGEMENT CYTOGENETICS MAPPING HETEROGENEITY MOLECULAR GENETICS PATHOGENESIS POPULATION GENETICS ANIMAL MODEL SEE ALSO REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Clinical Synopsis Gene map locus 11q22.3 ### TEXT A number sign (#) is used with this entry because ataxia-telangiectasia is caused by mutation in the ataxia-telangiectasia mutated gene (ATM; 607585). #### DESCRIPTION Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene. #### CLINICAL FEATURES #### Homozygotes Patients present in early childhood with progressive cerebellar ataxia and later develop conjunctival telangiectases, other progressive neurologic degeneration, sinopulmonary infection, and malignancies. Telangiectases typically develop between 3 and 5 years of age. The earlier ataxia can be misdiagnosed as ataxic cerebral palsy before the appearance of oculocutaneous telangiectases. Gatti et al. (1991) contended that oculocutaneous telangiectases eventually occur in all patients, while Maserati et al. (1988) wrote that patients without telangiectases are not uncommon. A characteristic oculomotor apraxia, i.e., difficulty in the initiation of voluntary eye movements, frequently precedes the development of telangiectases. Gonadal dysfunction in ataxia-telangiectasia was discussed by Miller and Chatten (1967), Zadik et al. (1978), and others. Thibaut et al. (1994) reviewed cases of necrobiosis lipoidica in association with ataxia-telangiectasia. According to Boder (1985), the oldest known AT patients were a man who died in November 1978 at age 52 years and his sister who died in July 1979 at the age of almost 49 years. The sister was the subject of the report by Saxon et al. (1979) on T-cell leukemia in AT. The possibility of heteroalleles at the ataxia-telangiectasia loci might be suggested. #### Neurologic Manifestations AT may be the most common syndromic progressive cerebellar ataxia of early childhood. Truncal ataxia precedes appendicular ataxia. Oculomotor apraxia is progressive and opticokinetic nystagmus is absent. Choreoathetosis and/or dystonia occur in 90% of patients and can be severe. Deep tendon reflexes become diminished or absent by age 8 and patients later develop diminished large-fiber sensation. Gatti et al. (1991) pointed out that 'a significant proportion of older patients in their twenties and early thirties develop progressive spinal muscular atrophy, affecting mostly hands and feet, and dystonia.' Interosseous muscular atrophy in the hands in combination with the early-onset dystonic posturing leads to striking combined flexion-extension contractures of the fingers, which they illustrated. Mental retardation is not a feature of AT, although some older patients have a severe loss of short-term memory. Neurologic dysfunction is a clinically invariable feature in homozygotes. Woods and Taylor (1992) studied 70 affected persons in the British Isles, 29 females and 41 males with an age range of 2 to 42 years. Most presented by 3 years of age with truncal ataxia. All had ataxia, ocular motor apraxia, an impassive face, and dysarthria, although clinical immune deficiency was present only in 43 of 70 patients. Ocular telangiectases was seen in all but one. All 60 tested showed increased sensitivity to ionizing radiation, 43 of 48 had an elevated alpha-fetoprotein level, and 14 of 21 had an immunoglobulin deficiency. #### Malignancy Patients with AT have a strong predisposition to malignancy. Hecht et al. (1966) observed lymphocytic leukemia in patients with AT. A nonleukemic sib and 2 unrelated patients with AT had multiple chromosomal breaks and impaired responsiveness to phytohemagglutinin. This was the first report of chromosomal breakage in AT. Leukemia and chromosomal abnormalities occur in at least 2 other mendelian disorders--Fanconi pancytopenia (FA; 227650) and Bloom syndrome (BS; 210900). Saxon et al. (1979) demonstrated thymic origin of the neoplastic cells in a 48-year-old woman with AT and chronic lymphatic leukemia. The neoplastic cells had the specific 14q+ translocation and showed both helper and suppressor function, suggesting that the malignant transformation had occurred in an uncommitted T-lymphocyte precursor that was capable of differentiation. This is a situation comparable to chronic myeloid leukemia in which the Philadelphia chromosome occurs in a stem cell progenitor of both polymorphs and megakaryocytes. In general, lymphomas in AT patients tend to be of B-cell origin (B-CLL), whereas the leukemias tend to be of the T-CLL type. Rosen and Harris (1987) discussed the case of a 30-year-old man with AT who developed a malignant lymphoma of B-cell type involving the tonsil and lungs. Haerer et al. (1969) described a black sibship of 12, of whom 5 had ataxia-telangiectasia; 2 of those affected died of mucinous adenocarcinoma of the stomach at ages 21 and 19 years. Bigbee et al. (1989) demonstrated an increased frequency of somatic cell mutation in vivo in individuals with AT. Obligate heterozygotes for the disease did not appear to have a significantly increased frequency of such mutations. The authors speculated that the predisposition to somatic cell mutation may be related to the increased susceptibility to cancer in AT homozygotes. Other solid tumors, including medulloblastomas and gliomas, occur with increased frequency in AT (Gatti et al., 1991). #### Immune Disorders Defects of the immune mechanism and hypoplasia of the thymus have been demonstrated. Serum IgG2 or IgA levels are diminished or absent in 80% and 60% of patients, respectively (Gatti et al., 1991). IgE levels can be diminished, IgM levels diminished or normal. Peripheral lymphopenia as well as decreased cellular immunity to intradermally injected test antigens can be seen early in the disorder. Sinopulmonary infections are frequent, but their severity cannot be simply correlated with the degree of immunodeficiency. Carbonari et al. (1990) found that patients with AT have more circulating T cells bearing gamma/delta receptors characteristic of immature cells than alpha/beta receptors typical of mature cells. Normal ratios were found in the patients with other immune deficits, except for 1 child with a primary T-cell defect. Peterson and Funkhouser (1990) proposed that these findings are consistent with a defect in genetic recombination leading to the switch from gamma/delta to alpha/beta. There may also be a defect in DNA ligation or some other aspect of DNA repair. Elucidation of the molecular abnormalities of lymphocytes may demonstrate fundamental molecular mechanisms for cellular differentiation not only of lymphocytes but of other cell systems such as the nervous system. #### Variant Ataxia-Telangiectasia (Atypical) Ying and Decoteau (1981) described a family in which a brother and sister may have had an allelic (and milder) form of AT. The proband, a 58-year-old male of Saskatchewan Mennonite origin, had spinocerebellar degeneration associated with choreiform movements beginning at about age 10 years. Despite considerable physical handicap, he was able to work as a delivery man in the family store. No telangiectases were found at age 44 (they were carefully sought because of typical AT in a niece) or on later examinations. He showed total absence of IgA in serum and concentrated saliva and low IgE in serum. He was anergic on skin testing. Glucose tolerance was markedly decreased. Serum alpha-fetoprotein was 840 ng per ml (normal, less than 10 ng per ml). Lymphocyte response to phytohemagglutinin was blunted. He died of lymphoma at age 58. He showed cytogenetic abnormalities typical of AT; 4 abnormal clones were identified, all involving chromosome 14 in some way. The proband had 4 brothers and 2 sisters. A brother died of leukemia at age 16. A sister was likewise diagnosed as having spinocerebellar degeneration with choreiform movements at age 46; she died at age 55 of breast cancer. The proband's niece with typical AT had telangiectases of the bulbar conjunctivae and earlobes noted at age 3, when she began to have recurrent and severe sinopulmonary infections. She died at age 20 of staphylococcal pneumonia superimposed on bronchiectasis. The brother and sister who died in their 50s may have been genetic compounds. Their parents denied consanguinity. Taylor et al. (1987) described 3 patients who were atypical in terms of clinical features and cellular features as observed in vitro. One of the patients was a 45-year-old woman with onset of neurologic manifestations in her early twenties. Maserati et al. (1988) described 2 sisters, aged 9 and 11 years, with a progressive neurologic disorder similar to AT, chromosome instability with rearrangements involving chromosomes 7 and 14, but no telangiectases or immunologic anomalies typical of AT. Byrne et al. (1984) reported similar cases of ataxia without telangiectases with selective IgE deficiency but normal IgA and alpha-fetoprotein. Ziv et al. (1989) described 2 Turkish sibs with an atypically prolonged course and atypical behavior of cultured fibroblasts. See 208910 and 208920 for AT-like syndromes. Rare cases of AT patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported and have been designated 'AT variants.' Gilad et al. (1998) quantified ATM protein levels in 6 patients with an AT variant and searched their ATM genes for mutations. Cell lines from these patients exhibited considerable variability in radiosensitivity while showing the typical radioresistant DNA synthesis of AT cells. Unlike classic AT patients, however, these patients exhibited 1 to 17% of the normal level of ATM. The underlying genotypes were either homozygous for mutations expected to produce mild phenotypes or compound heterozygous for a mild and a severe mutation. In an attempt to determine whether the AT(Fresno) variation correlated with ATM mutations and levels of ATM protein expression, Gilad et al. (1998) searched for ATM mutations in a cell line derived from one of the sisters studied by Curry et al. (1989). This cell line was found to be devoid of the ATM protein and homozygous for a severe ATM mutation. Gilad et al. (1998) concluded that certain AT variant phenotypes, including some of those without telangiectasia, represent ATM mutations. Saviozzi et al. (2002) noted that milder cases of AT, termed 'AT variants,' comprise a heterogeneous group characterized by later onset of clinical symptoms, slower progression, extended life span compared to most AT patients, and decreased levels of chromosomal instability and cellular radiosensitivity. In these patients, telangiectasia and/or immunodeficiency may be absent, while the neurologic features are present. The genotype of AT variants is most often compound heterozygous for a severe mutation together with a mild or leaky mutation, which expresses some ATM protein with residual function. In 2 sisters with variant AT with onset of ataxia at 27 years, polyneuropathy, choreoathetosis, and absence of telangiectasia, immunodeficiency, and cancer, Saviozzi et al. (2002) identified compound heterozygosity in the ATM gene for a missense (607585.0028) and a frameshift (607585.0029) mutation. Western blot analysis showed a low level of ATM protein with residual phosphorylation activity, which the authors suggested contributed to the milder phenotype. #### Cancer Risk in Heterozygotes Welshimer and Swift (1982) studied families of homozygotes for AT, Fanconi anemia (FA), and xeroderma pigmentosum (XP; 278700) to test the hypothesis that heterozygotes may be predisposed to some of the same congenital malformations and developmental disabilities that are common among homozygotes. Among XP relatives, 11 of 1,100 had unexplained mental retardation, whereas only 3 of 1,439 relatives of FA and AT homozygotes showed mental retardation. Four XP relatives but no FA or AT relatives had microcephaly. Idiopathic scoliosis and vertebral anomalies occurred in excess in AT relatives, while genitourinary and distal limb malformations were found in FA families. Swift (1980) defended, from the viewpoint of not causing anxiety, the usefulness and safety of cancer risk counseling of heterozygotes for AT. Swift et al. (1987) examined the cancer risk of heterozygotes for AT in 128 families, including 4 of Amish ancestry, 110 white non-Amish families, and 14 black families. They measured documented cancer incidence rather than cancer mortality based solely on death certificates and compared the cancer incidence in adult blood relatives of probands directly with that in spouse controls. The incidence rates in AT relatives were significantly elevated over those in spouse controls. In persons heterozygous for AT, the relative risk of cancer was estimated to be 2.3 for men and 3.1 for women. Breast cancer in women was the cancer most clearly associated with heterozygosity for AT. Swift et al. (1987) estimated that 8 to 18% of patients with breast cancer in the U.S. white population would be heterozygous for AT. Intuitively, it is difficult to believe that such a high proportion of breast cancer women are AT heterozygotes. Pippard et al. (1988) confirmed this observation, however. They reported an excess of breast cancer deaths in British mothers of AT patients (significant at the 5% level), but no excess mortality from malignant neoplasms in the grandparents. Morrell et al. (1990) reported cancer incidence measured retrospectively in 574 close blood relatives of AT patients and 213 spouse controls in 44 previously unreported families. For heterozygous carriers of the AT gene, the relative risk of cancer was estimated to be 6.1 as compared with non-heterozygotes. The most frequent cancer site in the blood relatives was the female breast, with 9 cancers observed. Gatti et al. (1991) provided a review in which they noted the possibly high frequency of breast cancer in AT heterozygotes. Swift et al. (1991) reported the results of a prospective study of 1,599 adult blood relatives of patients with AT and 821 of their spouses distributed in 161 families. Cancer rates were significantly higher among the blood relatives than in their spouses, specifically in the subgroup of 294 blood relatives who were known to be heterozygous for the AT gene. The estimated risk of cancer of all types among heterozygotes as compared with noncarriers was 3.8 in men and 3.5 in women, and that for breast cancer in carrier women was 5.1. Among the blood relatives, women with breast cancer were more likely to have been exposed to selected sources of ionizing radiation than controls without cancer. Male and female blood relatives also had 3-fold and 2.6-fold excess mortality from all causes, respectively, from the ages of 20 through 59 years. Swift et al. (1991) suggested that diagnostic or occupational exposure to ionizing radiation increases the risk of breast cancer in women heterozygous for AT. The work of Swift et al. (1991) on the frequency of breast cancer in AT was critiqued by numerous authors, including Bridges and Arlett (1992). Since the genes responsible for most cases of AT are located on 11q, Wooster et al. (1993) typed 5 DNA markers in the AT region in 16 breast cancer families. They found no evidence for linkage between breast cancer and these markers and concluded that the contribution of AT to familial breast cancer is likely to be minimal. Athma et al. (1996) determined the AT gene carrier status of 776 blood relatives in 99 AT families by tracing the ATM gene in each family through tightly linked flanking DNA markers. There were 33 women with breast cancer who could be genotyped; 25 of these were AT heterozygotes, compared to an expected 14.9. For 21 breast cancers with onset before age 60, the odds ratio was 2.9 and for 12 cases with onset at age 60 or older, the odds ratio was 6.4. Thus, the breast cancer risk for AT heterozygous women is not limited to young women but appeared to be even higher at older ages. Athma et al. (1996) estimated that, of all breast cancers in the U.S., 6.6% may occur in women who are AT heterozygotes. This proportion is several times greater than the estimated proportion of carriers of BRCA1 mutations (113705) in breast cancer cases with onset at any age. The reported increased risk for breast cancer for AT family members has been most evident among younger women, leading to an age-specific relative risk model predicting that 8% of breast cancer in women under age 40 arises in AT carriers, compared with 2% of cases between 40 and 59 years (Easton, 1994). To test this hypothesis, FitzGerald et al. (1997) undertook a germline mutational analysis of the ATM gene in a population of women with early onset of breast cancer, using a protein truncation (PTT) assay to detect chain-terminating mutations, which account for 90% of mutations identified in children with AT. They detected a heterozygous ATM mutation in 2 of 202 (1%) controls, consistent with the frequency of AT carriers predicted from epidemiologic studies. ATM mutations were present in only 2 of 401 (0.5%) women with early onset of breast cancer (P = 0.6). FitzGerald et al. (1997) concluded that heterozygous ATM mutations do not confer genetic predisposition to early onset of breast cancer. The results of FitzGerald et al. (1997) are discrepant with those of Athma et al. (1996), who conducted a study 'from the other direction' by following identified AT mutations through the families of those with clinically recognized AT. Analysis of DNA markers flanking the AT gene allowed them to identify precisely which female relatives with breast cancer carried the AT mutation. On the basis of the genetic relationship between each case and the AT proband, the a priori probability that these 2 share the AT mutation was calculated. This led to an estimated relative risk of 3.8 as compared to noncarriers. This result was similar to that found by Easton (1994), who reanalyzed the previous studies of breast cancer risk in mothers (and other close relatives) of AT cases. Bishop and Hopper (1997) analyzed these 2 studies and suggested that they may not be discrepant. Indeed, they estimated that the study of FitzGerald et al. (1997) yielded an upper limit of the 95% confidence interval for the proportion of early onset breast cancer occurring in AT heterozygotes as 2.4% (assuming that their assay identified 75% of all mutations). In a family with multiple cancers, Bay et al. (1999) described heterozygosity for a mutant allele of ATM that caused skipping of exon 61 in the mRNA (607585.0020) and was associated with a previously undescribed polymorphism in intron 61. The mutation was inherited by 2 sisters, one of whom developed breast cancer at age 39 years and the second at age 44 years, from their mother, who developed kidney cancer at age 67 years. Studies of irradiated lymphocytes from both sisters revealed elevated numbers of chromatid breaks, typical of AT heterozygotes. In the breast tumor of the older sister, loss of heterozygosity (LOH) was found in the ATM region of 11q23.1, indicating that the normal ATM allele was lost in the breast tumor. LOH was not seen at the BRCA1 (113705) or BRCA2 (600185) loci. BRCA2 was considered an unlikely cancer-predisposing gene in this family because each sister inherited different chromosomes 13 from each parent. The findings suggested that haploinsufficiency at ATM may promote tumorigenesis, even though LOH at the ATM locus supported a more classic 2-hit tumor suppressor gene model. The finding that ATM heterozygotes have an increased relative risk for breast cancer had been supported by some studies but not confirmed by others. Broeks et al. (2000) analyzed germline mutations of the ATM gene in a group of Dutch patients with breast cancer using normal blood lymphocytes and the protein truncation test followed by genomic sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer before the age of 45 years and had survived 5 years or more (mean, 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients, 7 (8.5%) had germline mutations of the ATM gene, of which 5 were distinct. One splice site mutation, IVS10-6T-G (607585.0021), was detected 3 times in this series. Four heterozygous carriers had bilateral breast cancer. Broeks et al. (2000) concluded that ATM heterozygotes have an approximately 9-fold increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. They suggested that the characteristics of this population of patients may explain why such a high frequency was found here and not in other series. Although the defining characteristic of recessive diseases is the absence of a phenotype in heterozygous carriers, Watts et al. (2002) suggested that expression profiling by microarray techniques might reveal subtle manifestations. Individual carriers of AT cannot be identified; as a group, however, carriers of a mutant AT allele have a phenotype that distinguishes them from normal control individuals: increased radiosensitivity and risk of cancer. Watts et al. (2002) showed that the phenotype was also detectable, in lymphoblastoid cells from AT carriers, as changes in expression level of many genes. The differences were manifested both in baseline expression levels and in response to ionizing radiation. The findings showed that carriers of the recessive disease may have an 'expression phenotype,' which suggested a new approach to the identification of carriers and enhanced understanding of their increased cancer risk. #### OTHER FEATURES Waldmann and McIntire (1972) showed raised alpha-fetoprotein in the blood of patients with AT. This, they felt, suggests immaturity of the liver and is consistent with the view that the primary defect is in tissue differentiation, specifically, a defect in the interaction necessary for differentiation of gut-associated organs such as the thymus and liver. Ishiguro et al. (1986) concluded that the elevated alpha-fetoprotein in patients with AT probably originates in the liver. On the circulating monocytes of AT patients, Bar et al. (1978) demonstrated an 80 to 85% decrease in insulin receptor affinity. This decrease was not observed in the cultured fibroblasts of AT patients or in the monocytes and fibroblasts of relatives of these patients. In addition, they found that whole plasma and immunoglobulin-enriched fractions of plasma from AT patients inhibited the normal binding of insulin to its receptors on cultured human lymphocytes and on human placental membranes. This suggested the presence of antireceptor immunoglobulins. AT and type B acanthosis nigricans have several features in common that suggest the possibility of similar causes for the insulin resistance each demonstrates. Shaham and Becker (1981) showed that the AT clastogenic (chromosome breaking) factor present in plasma of AT patients and in the culture medium of AT skin fibroblasts is a peptide with a molecular weight in the range of 500 to 1000. No clastogenic activity could be demonstrated in extracts of cultured AT fibroblasts. Mohamed et al. (1987) found marked reduction of topoisomerase II (126430) in some but not all AT cell lines. DNA topoisomerases I and II are enzymes that introduce transient single- and double-strand breaks into DNA and thus are capable of interconverting various DNA conformations. The isolation of mutants of the 2 enzymes in yeast and the increased levels of DNA topoisomerase II in cells undergoing DNA synthesis provide evidence for the role of these enzymes in DNA replication and in chromosome segregation and organization. #### INHERITANCE In a study of 47 families ascertained throughout the United Kingdom, Woods et al. (1990) found a low parental consanguinity rate; no parents were first cousins or more closely related, whereas 10% had been expected. Furthermore, the incidence of the disorder in 79 sibs of index cases was 1 in 7, rather than the expected 1 in 4. #### DIAGNOSIS The presence of early-onset ataxia with oculocutaneous telangiectases permits diagnosis of AT. The clinical diagnosis of AT can be problematic before the appearance of telangiectases. Oculomotor apraxia is a useful aid to early clinical diagnosis. Early-onset cerebellar ataxia and oculomotor apraxia are also typical of X-linked Pelizaeus-Merzbacher disease (312080) and can be seen in Joubert syndrome (213300). These disorders can be distinguished by leukoencephalopathy in the former, and by profound cerebellar hypoplasia in the latter. See also 257550. Elevated levels of alpha-fetoprotein (126430) and carcinoembryonic antigen are the most useful readily available markers for confirmation of the diagnosis of AT (Gatti et al., 1991). Dysgammaglobulinemia, decreased cellular immune responses, and peripheral lymphopenia are supportive findings but are not invariable. Henderson et al. (1985) devised a rapid diagnostic method based on the hypersensitivity of AT lymphocytes to killing by gamma irradiation. Similar studies in fibroblasts require skin biopsy and a prolonged culture time. Llerena et al. (1989) concluded that in chorionic villus sampling, gamma radiation is a reliable way of discriminating between unaffected fetuses and those with AT. The reliability of this approach is in question, however. Painter and Young (1980) suggested that the radiosensitivity of AT cells may be caused by their failure to respond to DNA damage with a delay in DNA synthesis that could give time for repair to take place. Shiloh et al. (1989) presented evidence that the extent of chromatid damage induced in the G2 phase of the cell cycle by moderate dosage of x-rays is markedly higher in AT heterozygous cells than in normal controls. They used this as a test of heterozygosity. Rosin and Ochs (1986) applied the exfoliated cell micronucleus test to the question of in vivo chromosomal instability in AT. This test is performed on exfoliated cells from the oral cavity collected by swabbing the mucosa with a moistened tongue depressor and also on urinary bladder cells obtained by centrifugation of freshly voided urine specimens. Micronuclei in these cells result from fragmentation of chromosomes in the dividing cells from the epithelium, resulting in acentric fragments which are excluded from the main nucleus when the cell divides. These fragments form their own membrane and can be identified as extranuclear Feulgen-positive bodies in daughter cells which migrate up through the epithelium to be exfoliated. Rosin and Ochs (1986) found that AT homozygotes had a 5- to 14-fold increase in the frequency of exfoliated cell micronuclei. Heterozygotes could be reliably identified by this method (Rosin et al., 1989). Using X-radiation with 1 Gy on G2-phase lymphocytes from 7 AT patients, 13 obligate AT heterozygotes, and 14 normal controls, Tchirkov et al. (1997) found that both AT homozygotes and heterozygotes showed significantly increased levels of radiation-induced chromatid damage relative to that of normal controls. #### CLINICAL MANAGEMENT Patients with AT and their cultured cells are unusually sensitive to x-ray just as patients and cells with xeroderma pigmentosum are sensitive to ultraviolet. Treatment of malignancy with conventional dosages of radiation can be fatal to AT patients. #### CYTOGENETICS Oxford et al. (1975) found that chromosome 14 was often involved in rearrangements in AT and that band 14q12 was a highly specific exchange point. In addition to the changes in chromosome 14, a pericentric inversion of chromosome 7 is characteristic. McCaw et al. (1975) described t(14;14)(q11;q32) translocation in T-cell malignancies of patients with AT. T cells show a t(14;14)q12q32 rearrangement in about 10% of AT patients. Croce et al. (1985) assigned the alpha subunit of the T-cell antigen receptor (TCRA; 186880) to the region of one of the common breakpoints in AT (14q11.2) and suggested that the oncogene TCL1 (186960) is located in the region of the other breakpoint (14q32.3). It is thought that the TCL1 gene may be activated by chromosome inversion or translocation, either of which results in juxtaposition of the TCL1 gene and the TCRA gene. In AT, circulating lymphocytes show characteristic rearrangements involving the site of the T-cell receptor gamma gene (7p15) (TCRG; 186970), T-cell receptor beta genes (7q35) (TCRB; 186930), T-cell receptor alpha genes (14q11), and immunoglobulin heavy chain genes (14q32) (IGHG1; 147100) (McFarlin et al., 1972; Ying and Decoteau, 1981). Aurias et al. (1986) described a possible 'new' type of chromosome rearrangement, namely, telomere-centromere translocation (tct) followed by double duplication. This type of rearrangement was found between chromosomes 7 and 14 in cases of AT. Gatti et al. (1985) and Aurias and Dutrillaux (1986) found that the sites of breaks in rearrangements (7p14, 7q35, 14q12, 14qter, 2p11, 2p12, and 22q11-q12) are those where members of the immunoglobulin superfamily are located: IGK, IGH, IGL, TCRA, TCRB, TCRG. The somatic gene rearrangement must precede expression of these genes. Kennaugh et al. (1986) studied a patient with an inversion of 14q which had been present for many years in T cells. It was found that the breakpoint in 14q32 lay outside the IgH locus and proximal to it. The constant region gene of the T-cell receptor alpha chain (TCRA) locus was translocated to the 14q32 position. Johnson et al. (1986) found that the 14q32 breakpoint in the 14/14 translocation found in T-CLL cells and in an AT patient occurred within the immunoglobulin gene cluster. The AT patient had the characteristic chromosome 14 tandem translocation in 100% of karyotyped T cells 10 years before her death from T-cell leukemia. (This was the same patient described earlier by Saxon et al. (1979).) Stern et al. (1988) used in situ chromosomal hybridization to map the TCRA gene in 3 different nonmalignant T-cell clones derived from patients with AT. The constant region was translocated in each clone; the variable region remained in its original position in 2 clones and was deleted in 1 which lost the derivative chromosome 14. Stern et al. (1988) mapped the 14q32.1 recurrent breakpoint of AT clones by in situ hybridization. They found that the breakpoint lay between D14S1 (107750) and PI (107400). In a t(14;14) clone they found an interstitial duplication including D14S1 and a part of the IGH locus. Studying the chromosomes by R-banding, Zhang et al. (1988) concluded that the distal breakpoint in the chromosome 14 inversion in an AT clone was different from that in the chromosome 14 inversion in a malignant T-cell line; specifically, in AT, the breakpoint was centromeric to both the immunoglobulin heavy chain locus and the D14S1 anonymous locus (107750). They suggested that this finding favors the existence of an unknown oncogene in band 14q32.1. Russo et al. (1989) presented evidence for a cluster of breakpoints in the 14q32.1 region, the site of the putative oncogene TCL1, in cases of ataxia-telangiectasia with chronic lymphocytic leukemia. The 14q32.1 breakpoint is at least 10,000 kb centromeric to the immunoglobulin heavy chain locus. In a cell line with a translocation t(14;14)(q11;q32) from an AT patient with T-cell chronic lymphocytic leukemia, Russo et al. (1989) showed that a J(alpha) sequence from the TCRA locus was involved. This was again the patient first reported by Saxon et al. (1979). Humphreys et al. (1989) found some rearrangements involving chromosomes 7 and 14 at the usual 4 sites associated with AT--7p14, 7q35, 14q12, and 14q32--all sites of T-cell receptor genes. Kojis et al. (1989) suggested that the very high frequency of lymphocyte-associated rearrangements (LARs) in peripheral blood chromosome preparations is a diagnostic criterion of the disease. They pointed out a striking difference in the types of rearrangements observed in lymphocytes and fibroblasts. LARs are not commonly observed in fibroblasts, despite the increased but random instability of chromosomes from these cells relative to lymphocytes. The region of location of the AT gene, 11q22-q23, is not involved in site-specific rearrangements in either lymphocytes or fibroblasts. Lipkowitz et al. (1990) showed that an abnormal V(D)J recombination, joining V segments of the T-cell receptor gamma gene (186970) with J segments of the T-cell receptor beta gene (186930), occurs in peripheral blood lymphocytes of AT patients at a frequency 50- to 100-fold higher than normal. This frequency is roughly the same as the increase in the risk for lymphoid malignancy in these individuals. There is also an increase in the frequency of the lymphocyte-specific cytogenetic abnormalities thought to be due to interlocus recombination in non-AT patients with non-Hodgkin lymphoma, further suggesting a relationship between these translocations and lymphoid malignancies. Agriculture workers occupationally exposed to pesticides used in the production and storage of grain have a high frequency of cytogenetic abnormalities in peripheral blood lymphocytes in a pattern reminiscent of those in AT patients. Furthermore, these agriculture workers have an increased risk of developing T- and D-lymphoid malignancies. Lipkowitz et al. (1992) used a PCR-based assay developed for the study of AT patients to demonstrate a 10- to 20-fold increased frequency of hybrid antigen-receptor genes in peripheral blood lymphocytes of agriculture workers with chemical exposure. #### MAPPING By linkage to RFLP markers, Gatti et al. (1988) localized the AT gene to 11q22-q23. They had previously excluded 171 markers, comprising approximately 35% of the genome. The most promising marker in a large Amish pedigree was found to be THY1 (188230), which is located at 11q22.3; it showed linkage with maximum lod = 1.8 at theta = 0.00. When data from the other 4 informative group A AT families were added, the maximum lod score rose to 3.63 with no observed recombinants. The maximum lod score for all 31 families studied for linkage of AT to THY1 was 4.34 at theta = 0.10. The large Amish pedigree diagrammed in their Figure 1 is the kindred reported by McKusick and Cross (1966), Ginter and Tallapragada (1975), and Rary et al. (1975). By further mapping with a panel of 10 markers, Sanal et al. (1990) concluded that the AT locus is in band 11q23. The site of the AT1 gene (11q22-q23) is the same as or adjacent to the region occupied by the CD3 (186790), THY1, and NCAM (116930) genes, all of which are members of the immunoglobulin-gene superfamily and therefore may be subject to the same defect that afflicts the T-cell receptor and immunoglobulin molecules in AT. Concannon et al. (1990) excluded the AT1 gene from a region extending 15 cM to either side of ETS1 (164720), which maps to 11q24. According to Gatti (1990), the gene in families from complementation groups A, C, and D, representing approximately 97% of all families, has been mapped to 11q23. Thus, a single gene may exist with various intragenic defects permitting complementation. In studies of 35 consecutively obtained families in the British Isles, McConville et al. (1990) found support for linkage with THY1 at zero recombination. They found evidence suggesting a second AT locus on 11q, centromeric to the site previously postulated. With 3 exceptions, the families had not been assigned to complementation groups. The series of families included the only group E family described to date. They quoted Jaspers et al. (1988) as giving the proportion of group A, group C, and group D cases as approximately 56%, 28%, and 14%, respectively. By linkage studies in a Jewish-Moroccan family with AT of the group C type, Ziv et al. (1991) found that the disorder was linked to the same region (11q22-q23) as found in group A families. McConville et al. (1990) located the AT1 gene to a 5-cM region in 11q22-q23, flanked by NCAM and DRD2 (126450) on one side and STMY1 (185250) on the other. On the basis of an 18-point map of the 11q23 region of 11q, derived from linkage analysis of 40 CEPH families, Foroud et al. (1991) analyzed 111 AT families from Turkey, Israel, England, Italy, and the United States, localizing the gene to an 8-cM sex-averaged interval between the markers STMY1 and D11S132/NCAM. Ziv et al. (1992) obtained results from linkage study indicating that the ATA gene in 3 large Arab families was located in 11q23. However, in a Druze family unassigned to a specific complementation group, several recombinants between AT and the same markers were observed. Sobel et al. (1992) pointed to linkage evidence suggesting that there are 2 AT loci on 11q and that group D AT may be located distal to the site of groups A and C in the 11q23 region. In linkage studies of 14 Turkish families, 12 of which were consanguineous, Sanal et al. (1992) obtained results indicating that the most likely location for a single AT locus is within a 6-cM sex-averaged interval defined by STMY and the marker CJ77. However, it appeared that there are at least 2 distinct AT loci (ATA and ATD) at 11q22-q23, with perhaps a third locus, ATC, located very near the ATA gene. Hernandez et al. (1993) described a large inbred family in which 2 adult cousins had AT with a somewhat milder clinical course than usual. Since genetic linkage analysis did 'not provide any evidence that the gene for AT in this family is located at 11q22-23,' further locus heterogeneity was suggested. In 2 families clinically diagnosed with AT and previously reported by Hernandez et al. (1993) and Klein et al. (1996), respectively, Stewart et al. (1999) identified mutations in the MRE11A gene (600814). Consistent with the clinical outcome of these mutations, cells established from the affected individuals within the 2 families exhibited many of the features characteristic of both AT and Nijmegen breakage syndrome (251260), including chromosomal instability, increased sensitivity to ionizing radiation, defective induction of stress-activated signal transduction pathways, and radioresistant DNA synthesis. The authors designated the disorder ATLD, for AT-like disorder (604391). Because the MRE11A gene maps to 11q21 and the ATM gene maps to 11q23, Stewart et al. (1999) concluded that only a very detailed linkage analysis would separate ATLD from AT purely on the basis of genetic data. Assuming that the mutation rate is proportional to the length of the coding sequences of the 2 genes, they suggested that approximately 6% of AT cases might be expected to have MRE11A mutations. Gatti et al. (1993) reported prenatal genotyping in this disorder. They pointed out that although at least 5 complementation groups have been defined, linkage studies of more than 160 families from various parts of the world have failed to show linkage heterogeneity. All but 2 families were linked to a 6-cM (sex-averaged) region at 11q22.3 defined by the markers STMY1 and D11S385. A further analysis of 50 British families narrowed the localization to a 4-cM (sex-averaged) region defined by D11S611 and D11S535. The demonstrated complementation groups may represent different intragenic mutations or separate ataxia-telangiectasia genes clustered within the 11q22.3 region, neither of which would challenge the validity of linkage or haplotyping studies. A possible reinterpretation of the complementation data is that the radiosensitivity of AT fibroblasts can be complemented by many genes besides the AT gene or genes. Gatti et al. (1993) used the flanking markers to show that the haplotypes in a fetus were identical to those in a previously born affected child. The parents chose to continue the pregnancy. #### HETEROGENEITY #### Complementation Groups On the basis of complementation studies of DNA repair in cultured fibroblasts, Paterson et al. (1977) suggested the existence of 2 distinct types of ataxia-telangiectasia. By genetic complementation analysis, Jaspers and Bootsma (1982) concluded that extensive genetic heterogeneity exists in AT. Their method involved cell fusion and was based on the observation that the rate of DNA synthesis is inhibited by x-rays to a lesser extent in AT cells than in normal cells. At least 5 complementation groups have been identified (Murnane and Painter, 1982; Jaspers and Bootsma, 1982). Heterogeneity in AT has also been indicated by the clinical work of Fiorilli et al. (1983). Jaspers et al. (1988) reported the results of complementation studies on fibroblast strains from 50 patients with AT or Nijmegen breakage syndrome (NBS; 251260), using the radioresistant DNA replication characteristic as a marker. Six different genetic complementation groups were identified. Four of these, called AB, C, D, and E (of which AB is the largest), represented patients with clinical signs of AT. (According to Gatti (1990), the frequencies of these 4 groups are approximately 55%, 28%, 14%, and 3%, respectively.) Patients having NBS fell into 2 groups, designated V1 and V2. A patient with clinical symptoms of both AT and NBS was found in group V1, indicating that the 2 disorders are closely related (Curry et al., 1989). No group-specific patterns of clinical characteristics or ethnic origin were apparent among the AT cases. In addition to the radiosensitive ATs, a separate category of patients was found, characterized by a relatively mild clinical course and weak radiosensitivity. Jaspers et al. (1988) concluded that a defect in 1 of at least 6 different genes may underlie inherited radiosensitivity in humans. Curry et al. (1989) used the designation AT(Fresno) (607585.0014) for the V1 disorder in twin girls who had clinical features combining those of ataxia-telangiectasia and the Nijmegen breakage syndrome. Complementation studies with Sendai virus-mediated fusion of fibroblast cell lines showed complementation with AT groups A, C, and E but not with the cell line from a patient with the Nijmegen breakage syndrome. Hernandez et al. (1993) cited evidence for the existence of 4 complementation groups: AB, C, D, and E. Loci for AB, C, and D have been identified on 11q. However, Komatsu et al. (1996) could demonstrate that the gene for the V2 form of Nijmegen breakage syndrome is not located on chromosome 11. They found that cells from a patient with this form were highly sensitive to radiation and that the sensitivity was unchanged after the transfer of an extra copy of normal chromosome 11. Gatti et al. (1988) noted the existence of at least 4 clinically indistinguishable complementation groups (A, C, D, and E) among 80 affected individuals (Jaspers et al., 1985; Jaspers et al., 1988). The Amish pedigree represents group A. This locus was designated ATA (HGM9). Since the Thy-1 glycoproteins are major cell surface constituents of rodent thymocytes and neurons (Tse et al., 1985), the question might be raised as to whether mutation in the THY1 gene is the basis of AT. The fact that recombination was found between THY1 and AT in the overall study may indicate that AT is not due to a defect in THY1 or it may mean that complementation group A is caused by mutation in THY1 but a mutation at another site is responsible for other forms of the disorder. When genetic linkage data from group C families are pooled, it appears that group C also may be linked to 11q22-q23 (Gatti, 1989). The group D defect is correctable by transfer of chromosome 11 into an SV40-transformed fibroblast cell line (Komatsu et al., 1990). Ejima et al. (1990) corrected the radiosensitivity of a group D fibroblast line by introducing an 11q fragment into these cells. Lambert et al. (1991) showed by microcell-mediated chromosome transfer that immortalized AT cells from complementation group D were corrected by genetic material from region 11q22-q23. A deoxyribophosphodiesterase deficiency has been identified in cells from group E patients. Together, groups A and C encompass about 85% of AT patients. Genetic linkage studies should also clarify whether AT variant families are linked to chromosome 11q22-q23 or to group D or E defects. #### MOLECULAR GENETICS Savitsky et al. (1995) identified mutations in the ATM gene in ataxia-telangiectasia cases of complementation groups A, C, D, and E and in 4 other patients in whom the complementation group was not determined (see, e.g., 607585.0001). Thus it appears that the complementation that is observed is intragenic and that all AT patients have mutations in a single gene. Concannon and Gatti (1997) discussed the genetic heterogeneity in AT and provided an update of mutations in the ATM gene. They noted that most AT patients from nonconsanguineous families were compound heterozygotes. Mutation detection at the ATM locus is difficult because of the large size of the gene (66 exons), the fact that mutations are located throughout the gene with no hotspots, and the difficulty of distinguishing mutations from polymorphisms. Buzin et al. (2003) used a method called DOVAM-S (Detection of Virtually All Mutations by SSCP), a robotically-enhanced, multiplexed scanning method that is a highly sensitive modification of SSCP. They studied 43 unrelated patients and 4 obligate carriers. The results of this complete scan showed that 86% of causative ATM mutations were truncating and 14% were missense. See MOLECULAR GENETICS section in 607585. #### PATHOGENESIS Using 2 recombination vectors to study recombination in AT and control human fibroblast lines, Meyn (1993) found that the spontaneous intrachromosomal recombination rates were 30 to 200 times higher in AT fibroblast lines than in normal cells, whereas extrachromosomal recombination frequencies were near normal. Increased recombination is thus a component of genetic instability in AT and may contribute to the cancer risk. Other evidence of in vitro and in vivo genomic instability includes increased frequencies of translocations and other chromosomal aberrations in lymphocytes and fibroblasts, micronucleus formation in epithelial cells, and loss of heterozygosity in erythrocytes. Hyperrecombination is a specific feature of the AT phenotype rather than a genetic consequence of defective DNA repair because a xeroderma pigmentosum cell line exhibited normal spontaneous recombination rates. At least 2 stages in the cell cycle are regulated in response to DNA damage, the G1-S and the G2-M transitions (Hartwell, 1992). These transitions serve as checkpoints at which cells delay progress through the cell cycle to allow repair of damage before entering either S-phase, when damage would be perpetuated, or M-phase, when breaks would result in the loss of genomic material. Checkpoints are thought to consist of surveillance mechanisms that can detect DNA damage, signal transduction pathways that transmit and amplify the signal to the replication or segregation machinery, and possibly repair activities. Both the G1-S and G2-M checkpoints are known to be under genetic control, since there are mutants that abolish the arrest or delay occurring in normal cells in response to DNA damage. Painter et al. (1982) showed that the G1-S checkpoint is abolished in cells from AT patients. Kastan et al. (1992) provided strong evidence that the tumor-suppressor protein p53 (191170) is necessary for the G1-S checkpoint. They found that the AT gene(s) is upstream of the p53 gene in a pathway that activates the G1-S checkpoint. p53 levels increase 3- to 5-fold by a posttranscriptional mechanism after gamma-irradiation, coincident with a delay of the G1-S transition (Kastan et al., 1991); the induction of p53 does not occur in AT cells (Kastan et al., 1992). Induction by ionizing radiation of the GADD45 gene (126335), an induction that is also defective in AT cells, is dependent on wildtype p53 function (Kastan et al., 1992). Thus, Kastan et al. (1992) identified 3 participants--AT gene(s), p53, and GADD45--in a signal transduction pathway that controls cell cycle arrest following DNA damage. Abnormalities in this pathway probably contribute to tumor development. Kastan et al. (1992) pointed out that lymphoid malignancies are the most common tumor seen both in AT patients and in p53-deficient mice. Lymphoid cells normally experience DNA strand breaks during gene rearrangements. The G1 checkpoint may be important in the avoidance of errors in that process. Breast cancer and other nonlymphoid cancers are increased in individuals heterozygous for germline mutations of either p53 (e.g., the Li-Fraumeni syndrome; 191170.0001) or the AT gene(s) (157,156:Swift et al., 1987, 1991). P53 is a sequence-specific DNA-binding transcription factor that induces cell cycle arrest or apoptosis in response to genotoxic stress. Activation of p53 by DNA-damaging agents is critical for eliminating cells with damaged genomic DNA and underlies the apoptotic response of human cancers treated with ionizing radiation and radiomimetic drugs. Both the levels of p53 protein and its affinity for specific DNA sequences increase in response to genotoxic stress. In vitro, the affinity of p53 for DNA is regulated by its carboxyl terminus. Waterman et al. (1998) therefore examined whether this region of p53 is targeted by DNA-damage signaling pathways in vivo. In nonirradiated cells, serines 376 and 378 of p53 were phosphorylated. IR led to dephosphorylation of ser376, creating a consensus binding site for 14-3-3 proteins (113508) and leading to association of p53 with 14-3-3. In turn, this increased the affinity of p53 for sequence-specific DNA. Consistent with the lack of p53 activation by ionizing radiation in AT, neither ser376 dephosphorylation nor the interaction of p53 with 14-3-3 proteins occurred in AT cells. Brown et al. (1999) reviewed studies identifying direct downstream targets of ATM and providing clues about the biologic function of these interactions. They placed the findings in the context of the pleiotropic phenotype displayed by patients with ataxia-telangiectasia and by Atm-deficient mice. The identified targets include ABL (189980), replication protein A (179835), p53, and beta-adaptin (see 600157). Since these targets are located in the nucleus and in the cytoplasm, the ATM protein is most likely involved in several distinct signaling pathways. In the thymus, p53 is phosphorylated directly by ATM after ionizing radiation, probably in the nucleus, leading to transcriptional activation of p21 and consequential cell cycle arrest. In the absence of ATM, this pathway is disrupted, and this defect perhaps results in the immunodeficiency and abnormal cellular responses to IR seen in patients with AT. Furthermore, the infertility noted in both AT patients and Atm-deficient mice is due to abnormal meiotic progression and subsequent germ-cell degeneration, a phenotype that is partially corrected by concomitant loss of p53 and p21 function. ATM interactions with beta-adaptin in the cytoplasm might mediate axonal transport and vesicle trafficking in the central nervous system and so account for the neuronal dysfunction and eventual neurodegeneration seen in ataxia-telangiectasia. Thus, the phenotypic pleiotropy of ataxia-telangiectasia results from the fact that different tissues express different ATM targets and perhaps also express a different complement of ATM family members whose functions may overlap with those of ATM and partially replace ATM. Jung et al. (1995) isolated cDNA that corrected the radiation sensitivity and DNA synthesis defects in fibroblasts from an AT1 group D patient by expression cloning, and showed that the cDNA encoded NFKBI, a truncated form of I-kappa-B (164008), which is an inhibitor of NFKB1, the nuclear factor kappa-B transcriptional activator (164011). The parental AT1 fibroblast expressed large amounts of the NFKBI transcript and showed constitutive activation of NFKB1. The AT1 fibroblast transfected with the truncated NFKBI expressed normal amounts of the NFKBI transcript and showed regulated activation of NFKB1. Since the NFKBI gene is located on chromosome 14 and not chromosome 11, it is probably not the site of the primary defect; Jung et al. (1995) hypothesized that its contribution to the ataxia-telangiectasia phenotype may work downstream of the gene representing the primary defect. Shackelford et al. (2001) investigated the possibility that the AT phenotype is a consequence, at least in part, of an inability to respond appropriately to oxidative damage. In comparison to normal human fibroblasts, AT dermal fibroblasts exhibited increased sensitivity to t-butyl hydroperoxide toxicity. These cells failed to show G1 to G2 phase checkpoint functions or to induce p53 in response to oxidative challenge. #### POPULATION GENETICS On the basis of a 'vigorous case finding' in the United States in 2 time periods, Swift et al. (1986) estimated the incidence and gene frequency of AT. The highest observed incidence was in the state of Michigan for the period 1965 to 1969 when white AT patients were born at the rate of 11.3 per million births. Based on the incidence data, the minimum frequency of a single hypothetical AT gene in the U.S. white population was estimated to be 0.0017. Pedigree analysis, which estimates the gene frequency from the proportion of affected close blood relatives of homozygous probands, estimated the most likely gene frequency to be 0.007 on the assumption that AT is a single homogeneous genetic syndrome. Given that complementation analysis has demonstrated genetic heterogeneity in AT, the AT heterozygote frequency might fall between 0.68% and 7.7%, with 2.8% being a likely estimate. In the West Midlands of England, the birth frequency of AT was estimated to be about 1 in 300,000. Stankovic et al. (1998) reported the spectrum of 59 ATM mutations observed in AT patients in the British Isles. Of the 51 ATM mutations identified in families native to the British Isles, 11 were founder mutations, and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features. In 2 AT families, a 7271T-G mutation of the ATM gene appeared to be associated with an increased risk of breast cancer in both homozygotes and heterozygotes, although there was a less severe AT phenotype in terms of the degree of cerebellar degeneration. This mutation was associated with expression of full-length ATM protein at a level comparable to that in unaffected individuals. In addition, Stankovic et al. (1998) studied 18 AT patients, in 15 families, who developed leukemia, lymphoma, preleukemic T-cell proliferation, or Hodgkin lymphoma, mostly in childhood. A wide variety of ATM mutation types, including missense mutations and in-frame deletions, were seen in this group of patients. The authors showed that 25% of all AT patients carried in-frame deletions or missense mutations, many of which were also associated with expression of mutant ATM protein. Ejima and Sasaki (1998) studied 8 unrelated Japanese families with ataxia-telangiectasia for mutations in the ATM gene. Six different mutations were found on 12 of the 16 alleles examined. Two mutations, 4612del165 (607585.0014) and 7883del5, were found more frequently than the others; 7 of 16 (44%) of the mutant alleles had 1 of these 2 mutations. Microsatellite genotyping demonstrated that a common haplotype was shared by the mutant alleles for both common mutations. The authors suggested that the 2 founder mutations may be predominant among Japanese ATM mutant alleles. Telatar et al. (1998) found that 4 mutations accounted for 86 to 93% of 41 Costa Rican AT patients studied. They suggested that the Costa Rican population might be useful for analyzing the role of ATM heterozygosity in cancer. Sasaki et al. (1998) presented the results of a mutation screen in 14 unrelated AT patients, most of them Japanese. They used a hierarchical strategy in which they extensively analyzed the entire coding region of the cDNA. In the first stage, point mutations were sought by PCR-SSCP in short patches. In the second and third stages, the products of medium- and long-patch PCR, each covering the entire region, were examined by agarose gel electrophoresis to search for length changes. They found a total of 15 mutations (including 12 new) and 4 polymorphisms. Abnormal splicing of ATM was frequent among Japanese, and no hotspot was obvious, suggesting no strong founder effects in that ethnic group. Eleven patients carried either 1 homozygous or 2 compound heterozygous mutations, 1 patient carried only 1 detectable heterozygous mutation, and no mutation was found in 2 patients. Overall, mutations were found in at least 75% of the different ATM alleles examined. Sandoval et al. (1999) investigated the mutation spectrum of the ATM gene in a cohort of AT patients living in Germany. They amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. They identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene; 34 mutations had not previously been described in other populations. Seven mutations occurred in more than 1 family, but none of these accounted for more than 5 alleles in the patient group. Most of the mutations were truncating, which confirmed that the absence of full-length ATM protein is the most common molecular basis of AT. Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for 2 mutations. In 4 cases, immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein. One of these mutations, a valine deletion proximal to the kinase domain (607585.0017), resulted in ATM protein levels more than 20% of normal in an AT lymphoblastoid cell line. Castellvi-Bel et al. (1999) used SSCP analysis to screen the ATM gene in 92 AT patients from different populations. Of 177 expected mutations, approximately 70% were identified using this technique. Thirty-five new mutations and 34 new intragenic polymorphisms or rare variants were described. Laake et al. (2000) screened 41 AT families from Denmark, Finland, Norway, and Sweden for ATM mutations. They were able to characterize 67 of the 82 disease-causing alleles. Of the 37 separate mutations detected, 25 had not previously been reported. In 28 of the probands, mutations were found in both alleles; in 11 of the probands only 1 mutated allele was detected; and in 2 Finnish probands, no mutations were detected. One-third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygous with at least 1 identified allele. Ten alleles were found more than once; 1 Norwegian founder mutation, 3245-3247delATCinsTGAT (607585.0016), an insdel mutation, constituted 57% of the Norwegian alleles. Due to the large size of the ATM gene and the existence of over 400 mutations, identifying mutations in patients with ataxia-telangiectasia is labor intensive. Campbell et al. (2003) compared the single-nucleotide polymorphism (SNP) and short tandem repeat (STR) haplotypes of AT patients from varying ethnicities who were carrying common ATM mutations. They used SSCP to determine SNP haplotypes. To their surprise, all of the most common ATM mutations in their large multiethnic cohort were associated with specific SNP haplotypes, whereas the STR haplotypes varied, suggesting that ATM mutations predate STR haplotypes but not SNP haplotypes. They concluded that these frequently observed ATM mutations are not hotspots, but have occurred only once and spread with time to different ethnic populations. More generally, a combination of SNP and STR haplotyping could be used as a screening strategy for identifying mutations in other large genes by first determining the ancestral SNP and STR haplotypes in order to identify specific founder mutations. Campbell et al. (2003) estimated that this approach will identify approximately 30% of mutations in AT patients across all ethnic groups. See monographs edited by Bridges and Harnden (1982) and Gatti and Swift (1985) for a perspective on the development of this disorder. #### ANIMAL MODEL Barlow et al. (1996) created a murine model of ataxia-telangiectasia by disrupting the Atm locus via gene targeting. Mice homozygous for the disrupted Atm allele displayed growth retardation, neurologic dysfunction, male and female infertility secondary to the absence of mature gametes, defects in T lymphocyte maturation, and extreme sensitivity to gamma-irradiation. Most of the animals developed malignant thymic lymphomas between 2 and 4 months of age. Several chromosomal anomalies were detected in one of these tumors. Fibroblasts from these mice grew slowly and exhibited abnormal radiation-induced G1 checkpoint function. Atm-disrupted mice recapitulated the ataxia-telangiectasia phenotype in humans. The authors noted that humans also show incomplete sexual maturation in ATM (Boder, 1975). Elson et al. (1996) generated a mouse model for ataxia-telangiectasia using gene targeting to generate mice that did not express the Atm protein. Atm-deficient mice were retarded in growth, did not produce mature sperm, and exhibited severe defects in T-cell maturation while going on to develop thymomas. Atm-deficient fibroblasts grew poorly in culture and displayed a high level of double-stranded chromosome breaks. Atm-deficient thymocytes underwent spontaneous apoptosis in vitro significantly more often than controls. Atm-deficient mice then exhibited many of the same symptoms found in ataxia-telangiectasia patients and in cells derived from them. Furthermore, Elson et al. (1996) demonstrated that the Atm protein exists as 2 discrete molecular species, and that loss of 1 or both of these can lead to the development of the disease. Xu and Baltimore (1996) disrupted the mouse ATM gene by homologous recombination. Xu et al. (1996) reported that Atm -/- mice are viable, growth-retarded, and infertile. The infertility results from meiotic failure, as meiosis is arrested at the zygotene/pachytene stage of prophase I as a result of abnormal chromosomal synapsis and subsequent chromosome fragmentation. The cerebella of Atm -/- mice appear normal by histologic examination, and the mice have no gross behavioral abnormalities. Atm -/- mice exhibit multiple immune defects similar to those of AT patients, and most develop thymic lymphomas at 3 to 4 months of age and die of the tumors by 4 months. Xu and Baltimore (1996) showed that mouse Atm -/- cells are hypersensitive to gamma irradiation and defective in cell cycle arrest following radiation, and Atm -/- thymocytes are more resistant to apoptosis induced by gamma radiation than normal thymocytes. They also provide direct evidence that ATM acts as an upregulator of p53. Ataxia-telangiectasia is characterized by markedly increased sensitivity to ionizing radiation. Ionizing radiation oxidizes macromolecules and causes tissue damage through the generation of reactive oxygen species (ROS). Barlow et al. (1999) therefore hypothesized that AT is due to oxidative damage resulting from loss of function of the ATM gene product. To assess this hypothesis, they employed an animal model of AT, i.e., the mouse with a disrupted Atm gene. They showed that organs that develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and that cerebellar Purkinje cells are particularly affected. They suggested that these observations provide a mechanistic basis for the AT phenotype and lay a rational foundation for therapeutic intervention. Barlow et al. (1999) exposed Atm +/+ and Atm +/- littermates to a sublethal dose, 4 Gy (400 Rad) of ionizing radiation. The Atm +/- mice had premature graying and decreased life expectancy (median survival 99 weeks vs 71 weeks in wildtype and heterozygous mice, respectively, P = 0.0042). Tumors and infections of similar type were found in all autopsied animals, regardless of genotype. Worgul et al. (2002) noted that in vitro studies have shown that cells from individuals homozygous for AT are much more radiosensitive than cells from unaffected individuals. Although cells heterozygous for the ATM gene may be slightly more radiosensitive in vitro, it remained to be determined whether their greater susceptibility translated into an increased sensitivity for late effects in vivo, although there was a suggestion that radiotherapy patients heterozygous for the ATM gene may be more at risk of developing late normal tissue damage. Worgul et al. (2002) chose cataract formation in the lens as a means of assaying the effects of ATM deficiency in a late-responding tissue. One eye each of wildtype, Atm heterozygous, and Atm homozygous knockout mice was exposed to various levels of x-rays. Cataract development in the mice of all 3 groups was strongly dependent on dose. The lenses of homozygous mice were the first to opacify at any given dose. Cataracts appeared earlier in heterozygous versus wildtype mice. The data suggested that ATM heterozygotes in the human population may also be radiosensitive. Worgul et al. (2002) proposed that this information may influence the choice of individuals destined to be exposed to higher than normal doses of radiation, such as astronauts, and may also suggest that radiotherapy patients who are ATM heterozygotes could be predisposed to increased late normal tissue damage. Wong et al. (2003) examined the impact of Atm deficiency as a function of progressive telomere attrition at both the cellular and whole-organism level in mice doubly null for Atm and Terc. These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency. A generalized proliferation defect was evident in all cell types and tissues examined, and this defect extended to tissue stem/progenitor cell compartments, thereby providing a basis for progressive multiorgan system compromise, accelerated aging, and premature death. Wong et al. (2003) showed that Atm deficiency and telomere dysfunction act together to impair cellular and whole-organism viability, thus supporting the view that aspects of ataxia-telangiectasia pathophysiology are linked to the functional state of telomeres and its adverse effects on stem/progenitor cell reserves. (See also ANIMAL MODEL in 607585). ### SEE ALSO Al Saadi et al. (1980); Ammann et al. (1969); Amromin et al. (1979); Aurias and Dutrillaux (1986); Aurias et al. (1980); Aurias et al. (1983); Becker et al. (1989); Bender et al. (1985); Bender et al. (1985); Bernstein et al. (1981); Bochkov et al. (1974); Boder and Sedgwick (1958); Chen et al. (1984); Cohen et al. (1979); Cohen et al. (1975); Cooper and Youssoufian (1988); Cornforth and Bedford (1985); Cox et al. (1978); DeLeon et al. (1976); Feigin et al. (1970); Fiorilli et al. (1985); Ford and Lavin (1981); Frais (1979); Gatti et al. (1982); Hagberg et al. (1970); Hansen et al. (1977); Harnden (1974); Hoar and Sargent (1976); Hodge et al. (1980); Huang and Sheridan (1981); Johnson et al. (1985); Korein et al. (1961); Krishna Kumar et al. (1979); Levin and Perlov (1971); Lisker and Cobo (1970); Littlefield et al. (1981); McConville et al. (1990); Oxelius et al. (1982); Paterson et al. (1976); Paterson and Smith (1979); Peterson and Funkhouser (1989); Peterson et al. (1964); Rary et al. (1974); Reye and Mosman (1960); Richkind et al. (1982); Schalch et al. (1970); Scheres et al. (1980); Sedgwick and Boder (1972); Shultz et al. (1982); Shuster et al. (1966); Sourander et al. (1966); Stern et al. (1988); Sugimoto et al. (1982); Swift et al. (1976); Tadjoedin and Fraser (1965); Taylor et al. (1975); Taylor et al. (1976); Teplitz (1978); Toledano and Lang (1980); Vincent et al. (1975); Waldmann et al. (1983); Watanabe et al. (1977); Weinstein et al. (1985); Yount (1982) ### REFERENCES 1. Al Saadi, A.; Palutke, M.; Krishna Kumar, G. : Evolution of chromosomal abnormalities in sequential cytogenetic studies of ataxia telangiectasia. Hum. Genet. 55: 23-29, 1980. PubMed ID : 7450753 2. Ammann, A. J.; Cain, W. A.; Ishizaka, K.; Hong, R.; Good, R. A. : Immunoglobulin E deficiency in ataxia-telangiectasia. New Eng. J. Med. 281: 469-472, 1969. PubMed ID : 4183711 3. Amromin, G. D.; Boder, E.; Teplitz, R. : Ataxia-telangiectasia with a 32-year survival: a clinicopathological report. J. Neuropath. Exp. Neurol. 38: 621-643, 1979. PubMed ID : 533861 4. Athma, P.; Rappaport, R.; Swift, M. : Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet. Cytogenet. 92: 130-134, 1996. PubMed ID : 8976369 5. Aurias, A.; Croquette, M. F.; Nuyts, J. P.; Griscelli, C.; Dutrillaux, B. : New data on clonal anomalies of chromosome 14 in ataxia telangiectasia: tct(14;14) and inv(14). Hum. Genet. 72: 22-24, 1986. PubMed ID : 3943860 6. Aurias, A.; Dutrillaux, B. : A possible new type of chromosome rearrangement: telomere-centromere translocation (tct) followed by double duplication. Hum. Genet. 72: 25-26, 1986. PubMed ID : 3943861 7. Aurias, A.; Dutrillaux, B. : Probable involvement of immunoglobulin superfamily genes in most recurrent chromosomal rearrangements from ataxia telangiectasia. Hum. Genet. 72: 210-214, 1986. PubMed ID : 3456975 8. Aurias, A.; Dutrillaux, B.; Buriot, D.; Lejeune, J. : High frequencies of inversions and translocations of chromosomes 7 and 14 in ataxia-telangiectasia. Mutat. Res. 69: 369-374, 1980. PubMed ID : 7360152 9. Aurias, A.; Dutrillaux, B.; Griscelli, C. : Tandem translocation t(14;14) in isolated and clonal cells in ataxia telangiectasia are different. Hum. Genet. 63: 320-322, 1983. PubMed ID : 6862436 10. Bar, R. S.; Levis, W. R.; Rechler, M. M.; Harrison, L. C.; Siebert, C.; Podskalny, J.; Roth, J.; Muggeo, M. : Extreme insulin resistance in ataxia telangiectasia: defect in affinity of insulin receptors. New Eng. J. Med. 298: 1164-1171, 1978. PubMed ID : 651946 11. Barlow, C.; Dennery, P. A.; Shigenaga, M. K.; Smith, M. A.; Morrow, J. D.; Roberts, L. J., II; Wynshaw-Boris, A.; Levine, R. L. : Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs. Proc. Nat. Acad. Sci. 96: 9915-9919, 1999. PubMed ID : 10449794 12. Barlow, C.; Eckhaus, M. A.; Schaffer, A. A.; Wynshaw-Boris, A. : Atm haploinsufficiency results in increased sensitivity to sublethal doses of ionizing radiation in mice. Nature Genet. 21: 359-360, 1999. PubMed ID : 10192382 13. Barlow, C.; Hirotsune, S.; Paylor, R.; Liyanage, M.; Eckhaus, M.; Collins, F.; Shiloh, Y.; Crawley, J. N.; Ried, T.; Tagle, D.; Wynshaw-Boris, A. : Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 86: 159-171, 1996. PubMed ID : 8689683 14. Bay, J.-O.; Uhrhammer, N.; Pernin, D.; Presneau, N.; Tchirkov, A.; Vuillaume, M.; Laplace, V.; Grancho, M.; Verrelle, P.; Hall, J.; Bignon, Y.-J. : High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer. Hum. Mutat. 14: 485-492, 1999. PubMed ID : 10571946 15. Becker, Y.; Tabor, E.; Asher, Y. : Ataxia-telangiectasia fibroblasts have less fibronectin mRNA than control cells but have the same levels of integrin and beta-actin mRNA. Hum. Genet. 81: 165-170, 1989. PubMed ID : 2783578 16. Bender, M. A.; Rary, J. M.; Kale, R. P. : G(2) chromosomal radiosensitivity in ataxia telangiectasia lymphocytes. Mutat.Res. 152: 39-47, 1985. PubMed ID : 4047083 17. Bender, M. A.; Rary, J. M.; Kale, R. P. : G(0) chromosomal radiosensitivity in ataxia telangiectasia lymphocytes. Mutat. Res. 150: 277-282, 1985. PubMed ID : 4000160 18. Bernstein, R.; Pinto, M.; Jenkins, T. : Ataxia telangiectasia with evolution of monosomy 14 and emergence of Hodgkin's disease. Cancer Genet. Cytogenet. 4: 31-37, 1981. PubMed ID : 7284988 19. Bigbee, W. L.; Langlois, R. G.; Swift, M.; Jensen, R. H. : Evidence for an elevated frequency of in vivo somatic cell mutations in ataxia telangiectasia. Am. J. Hum. Genet. 44: 402-408, 1989. PubMed ID : 2916583 20. Bishop, D. T.; Hopper, J. : AT-tributable risks? Nature Genet. 15: 226 only, 1997. PubMed ID : 9054927 21. Bochkov, N. P.; Lopukhin, Y. M.; Kuleshov, N. P.; Kovalchuk, L. V. : Cytogenetic study of patients with ataxia-telangiectasia. Humangenetik 24: 115-128, 1974. PubMed ID : 4430492 22. Boder, E. : Ataxia-telangiectasia: an overview.In: Gatti, R. A.; Swift, M. : Ataxia-telangiectasia: Genetics, Neuropathology and Immunology of a Degenerative Disease of Childhood. New York: Alan R. Liss (pub.) 1985. Pp. 1-63. 23. Boder, E. : Ataxia-telangiectasia: some historic, clinical and pathologic observations.In: Bergsma, D. (ed.) : Immunodeficiency in Man and Animals. New York: National Foundation-March of Dimes (pub.) 1975. Pp. 255-300. 24. Boder, E.; Sedgwick, R. P. : Ataxia-telangiectasia: a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 21: 526-554, 1958. PubMed ID : 13542097 25. Bridges, B. A.; Arlett, C. F. : Risk of breast cancer in ataxia-telangiectasia. (Letter) New Eng. J. Med. 326: 1357-1361, 1992. PubMed ID : 1304718 26. Bridges, B. A.; Harnden, D. G. : Ataxia-telangiectasia: A Cellular and Molecular Link between Cancer, Neuropathology, and Immune Deficiency. New York: John Wiley (pub.) 1982. 27. Broeks, A.; Urbanus, J. H. M.; Floore, A. N.; Dahler, E. C.; Klijn, J. G. M.; Rutgers, E. J. Th.; Devilee, P.; Russell, N. S.; van Leeuwen, F. E.; van't Veer, L. J. : ATM-heterozygous germline mutations contribute to breast cancer-susceptibility. Am. J. Hum. Genet. 66: 494-500, 2000. PubMed ID : 10677309 28. Brown, K. D.; Barlow, C.; Wynshaw-Boris, A. : Multiple ATM-dependent pathways: an explanation for pleiotropy. (Editorial) Am. J. Hum. Genet. 64: 46-50, 1999. PubMed ID : 9915942 29. Buzin, C. H.; Gatti, R. A.; Nguyen, V. Q.; Wen, C. Y.; Mitui, M.; Sanal, O.; Chen, J. S.; Nozari, G.; Mengos, A.; Li, X.; Fujimura, F.; Sommer, S. S. : Comprehensive scanning of the ATM gene with DOVAM-S. Hum. Mutat. 21: 123-131, 2003. PubMed ID : 12552559 30. Byrne, E.; Hallpike, J. F.; Manson, J. F.; Sutherland, G. R.; Thong, Y. H. : Ataxia-without-telangiectasia: progressive multisystem degeneration with IgE deficiency and chromosome instability. J. Neurol. Sci. 66: 307-317, 1984. PubMed ID : 6597863 31. Campbell, C.; Mitui, M.; Eng, L.; Coutinho, G.; Thorstenson, Y.; Gatti, R. A. : ATM mutations on distinct SNP and STR haplotypes in ataxia-telangiectasia patients of differing ethnicities reveal ancestral founder effects. Hum. Mutat. 21: 80-85, 2003. PubMed ID : 12497634 32. Carbonari, M.; Cherchi, M.; Paganelli, R.; Giannini, G.; Galli, E.; Gaetano, C.; Papetti, C.; Fiorilli, M. : Relative increase of T cells expressing the gamma/delta rather than the alpha/beta receptor in ataxia-telangiectasia. New Eng. J. Med. 322: 73-76, 1990. PubMed ID : 2136770 33. Castellvi-Bel, S.; Sheikhavandi, S.; Telatar, M.; Tai, L.-Q.; Hwang, M.; Wang, Z.; Yang, Z.; Cheng, R.; Gatti, R. A. : New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy. Hum. Mutat. 14: 156-162, 1999. PubMed ID : 10425038 34. Chen, P.; Imray, F. P.; Kidson, C. : Gene dosage and complementation analysis of ataxia telangiectasia lymphoblastoid cell lines assayed by induced chromosome aberrations. Mutat. Res. 129: 165-172, 1984. PubMed ID : 6504056 35. Cohen, M. M.; Sagi, M.; Ben-Zur, Z.; Schaap, T.; Voss, R.; Kohn, G.; Ben-Bassat, H. : Ataxia telangiectasia: chromosomal stability in continuous lymphoblastoid cell lines. Cytogenet. Cell Genet. 23: 44-52, 1979. PubMed ID : 761484 36. Cohen, M. M.; Shaham, M.; Dagan, J.; Shmueli, E.; Kohn, G. : Cytogenetic investigations in families with ataxia-telangiectasia. Cytogenet. Cell Genet. 15: 338-356, 1975. PubMed ID : 1222588 37. Concannon, P.; Gatti, R. A. : Diversity of ATM gene mutations detected in patients with ataxia-telangiectasia. Hum. Mutat. 10: 100-107, 1997. PubMed ID : 9259193 38. Concannon, P.; Malhotra, U.; Charmley, P.; Reynolds, J.; Lange, K.; Gatti, R. A. : The ataxia-telangiectasia gene (ATA) on chromosome 11 is distinct from the ETS-1 gene. Am. J. Hum. Genet. 46: 789-794, 1990. PubMed ID : 1969227 39. Cooper, D. N.; Youssoufian, H. : The CpG dinucleotide and human genetic disease. Hum. Genet. 78: 151-155, 1988. PubMed ID : 3338800 40. Cornforth, M. N.; Bedford, J. S. : On the nature of a defect in cells from individuals with ataxia-telangiectasia. Science 227: 1589-1591, 1985. PubMed ID : 3975628 41. Cox, R.; Hosking, G. P.; Wilson, J. : Ataxia telangiectasia: evaluation of radiosensitivity in cultured skin fibroblasts as a diagnostic test. Arch. Dis. Child. 53: 386-390, 1978. PubMed ID : 666352 42. Croce, C. M.; Isobe, M.; Palumbo, A.; Puck, J.; Ming, J.; Tweardy, D.; Erikson, J.; Davis, M.; Rovera, G. : Gene for alpha-chain of human T-cell receptor: location on chromosome 14 region involved in T-cell neoplasms. Science 227: 1044-1047, 1985. PubMed ID : 3919442 43. Curry, C. J. R.; Tsai, J.; Hutchinson, H. T.; Jaspers, N. G. J.; Wara, D.; Gatti, R. A. : AT-Fresno: a phenotype linking ataxia-telangiectasia with the Nijmegen breakage syndrome. Am. J. Hum. Genet. 45: 270-275, 1989. PubMed ID : 2491181 44. DeLeon, G. A.; Grover, W. D.; Huff, D. S. : Neuropathologic changes in ataxia-telangiectasia. Neurology 26: 947-951, 1976. PubMed ID : 986586 45. Easton, D. F. : Cancer risks in A-T heterozygotes. Int. J. Rad. Biol. 66: S177-S182, 1994. PubMed ID : 7836845 46. Ejima, Y.; Oshimura, M.; Sasaki, M. S. : Establishment of a novel immortalized cell line from ataxia-telangiectasia fibroblasts and its use for the chromosomal assignment of radiosensitivity gene. Int. J. Radiat. Biol. 58: 989-997, 1990. PubMed ID : 1978855 47. Ejima, Y.; Sasaki, M. S. : Mutations of the ATM gene detected in Japanese ataxia-telangiectasia patients: possible preponderance of the two founder mutations 4612del165 and 7883del5. Hum. Genet. 102: 403-408, 1998. PubMed ID : 9600235 48. Elson, A.; Wang, Y.; Daugherty, C. J.; Morton, C. C.; Zhou, F.; Campos-Torres, J.; Leder, P. : Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc. Nat. Acad. Sci. 93: 13084-13089, 1996. PubMed ID : 8917548 49. Feigin, R. D.; Vietti, T. J.; Wyatt, R. G.; Kaufman, D. G.; Smith, C. H. : Ataxia telangiectasia with granulocytopenia. J. Pediat. 77: 431-438, 1970. PubMed ID : 4925908 50. Fiorilli, M.; Antonelli, A.; Russo, G.; Crescenzi, M.; Carbonari, M.; Petrinelli, P. : Variant of ataxia-telangiectasia with low-level radiosensitivity. Hum. Genet. 70: 274-277, 1985. PubMed ID : 2410349 51. Fiorilli, M.; Businco, L.; Pandolfi, F.; Paganelli, R.; Russo, G.; Aiuti, F. : Heterogeneity of immunological abnormalities in ataxia-telangiectasia. J. Clin. Immun. 3: 135-141, 1983. PubMed ID : 6222062 52. FitzGerald, M. G.; Bean, J. M.; Hedge, S. R.; Unsal, H.; MacDonald, D. J.; Harkin, D. P.; Finkelstein, D. M. : Isselbacher, K. J.; Haber, D. A.: Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nature Genet. 15: 307-310, 1997. PubMed ID : 9054948 53. Ford, M. D.; Lavin, M. F. : Ataxia telangiectasia: an anomaly in DNA replication after irradiation. Nucleic Acids Res. 9: 1395-1404, 1981. PubMed ID : 7232219 54. Foroud, T.; Wei, S.; Ziv, Y.; Sobel, E.; Lange, E.; Chao, A.; Goradia, T.; Huo, Y.; Tolun, A.; Chessa, L.; Charmley, P.; Sanal, O.; Salman, N.; Julier, C.; Concannon, P.; McConville, C.; Taylor, A. M. R.; Shiloh, Y.; Lange, K.; Gatti, R. A. : Localization of an ataxia-telangiectasia locus to a 3-cM interval on chromosome 11q23: linkage analysis of 111 families by an international consortium. Am. J. Hum. Genet. 49: 1263-1279, 1991. PubMed ID : 1746555 55. Frais, M. A. : Gastric adenocarcinoma due to ataxia-telangiectasia (Louis-Bar syndrome). J. Med. Genet. 16: 160-161, 1979. PubMed ID : 458837 56. Gatti, R. A. : Personal Communication. Los Angeles, Calif., 6/1990. 57. Gatti, R. A. : Personal Communication. Los Angeles, Calif., 6/13/1989. 58. Gatti, R. A.; Aurias, A.; Griscelli, C.; Sparkes, R. S. : Translocations involving chromosomes 2p and 22q in ataxia-telangiectasia. Dis. Markers 3: 169-195, 1985. 59. Gatti, R. A.; Berkel, I.; Boder, E.; Braedt, G.; Charmley, P.; Concannon, P.; Ersoy, R.; Foroud, T.; Jaspers, N. G. J.; Lange, K.; Lathrop, G. M.; Leppert, M.; Nakamura, Y.; O'Connell, P.; Paterson, M.; Salser, W.; Sanal, O.; Silver, J.; Sparkes, R. S.; Susi, E.; Weeks, D. E.; Wei, S.; White, R.; Yoder, F. : Localization of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 336: 577-580, 1988. PubMed ID : 3200306 60. Gatti, R. A.; Bick, M.; Tam, C. F.; Medici, M. A.; Oxelius, V.-A.; Holland, M.; Goldstein, A. L.; Boder, E. : Ataxia-telangiectasia: a multiparameter analysis of eight families. Clin. Immun. Immunopath. 23: 501-516, 1982. PubMed ID : 6213343 61. Gatti, R. A.; Boder, E.; Vinters, H. V.; Sparkes, R. S.; Norman, A.; Lange, K. : Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis. Medicine 70: 99-117, 1991. PubMed ID : 2005780 62. Gatti, R. A.; Peterson, K. L.; Novak, J.; Chen, X.; Yang-Chen, L.; Liang, T.; Lange, E.; Lange, K. : Prenatal genotyping of ataxia-telangiectasia. (Letter) Lancet 342: 376, 1993. PubMed ID : 8101622 63. Gatti, R. A.; Swift, M. : Ataxia-telangiectasia: Genetics, Neuropathology, and Immunology of a Degenerative Disease of Childhood. New York: Alan R. Liss (pub.) 1985. 64. Gilad, S.; Chessa, L.; Khosravi, R.; Russell, P.; Galanty, Y.; Piane, M.; Gatti, R. A.; Jorgensen, T. J.; Shiloh, Y.; Bar-Shira, A. : Genotype-phenotype relationships in ataxia-telangiectasia and variants. Am. J. Hum. Genet. 62: 551-561, 1998. PubMed ID : 9497252 65. Ginter, D. N.; Tallapragada, R. : Ataxia-telangiectasia. Birth Defects Orig. Art. Ser. XI(2): 408-409, 1975. 66. Haerer, A. F.; Jackson, J. F.; Evers, C. G. : Ataxia-telangiectasia with gastric adenocarcinoma. J.A.M.A. 210: 1884-1887, 1969. PubMed ID : 4311128 67. Hagberg, A.; Hansson, O.; Liden, S.; Nilsson, K. : Familial ataxic diplegia with deficient cellular immunity: a new clinical entity. Acta Paediat. Scand. 59: 545-550, 1970. PubMed ID : 5455521 68. Hansen, R. L.; Marx, J. J.; Ptacek, L. J.; Roberts, R. C. : Immunological studies on an aberrant form of ataxia-telangiectasia. Am. J. Dis. Child. 131: 518-521, 1977. PubMed ID : 857652 69. Harnden, D. G. : Ataxia-telangiectasia syndrome: cytogenetic and cancer aspects.In: German, J. : Chromosomes and Cancer. New York: Wiley (pub.) 1974. Pp. 619-636. 70. Hartwell, L. : Defects in a cell cycle checkpoint may be responsible for the genomic instability of cancer cells. Cell 71: 543-546, 1992. PubMed ID : 1423612 71. Hecht, F.; Koler, R. D.; Rigas, D. A.; Dahnke, G. S.; Case, M. P.; Tisdale, V.; Miller, R. W. : Leukemia and lymphocytes in ataxia-telangiectasia. (Letter) Lancet II: 1193, 1966. 72. Henderson, L.; Cole, H.; Arlett, C.; James, S. E.; Cole, J.; Lehmann, A.; Rosenbloom, L.; Redmond, T.; Meller, S. : Diagnosis of ataxia-telangiectasia by T-lymphocyte cloning assay. (Letter) Lancet II: 1242, 1985. 73. Hernandez, D.; McConville, C. M.; Stacey, M.; Woods, C. G.; Brown, M. M.; Shutt, P.; Rysiecki, G.; Taylor, A. M. R. : A family showing no evidence of linkage between the ataxia telangiectasia gene and chromosome 11q22-23. J. Med. Genet. 30: 135-140, 1993. PubMed ID : 8445618 74. Hoar, D. I.; Sargent, P. : Chemical mutagen hypersensitivity in ataxia-telangiectasia. Nature 261: 590-592, 1976. PubMed ID : 180416 75. Hodge, S. E.; Berkel, A. I.; Gatti, R. A.; Boder, E.; Spence, M. A. : Ataxia-telangiectasia and xeroderma pigmentosum: no evidence of linkage to HLA. Tissue Antigens 15: 313-317, 1980. PubMed ID : 7466773 76. Huang, P. C.; Sheridan, R. B., III : Genetic and biochemical studies with ataxia telangiectasia. Hum. Genet. 59: 1-9, 1981. PubMed ID : 10819014 77. Humphreys, M. W.; Nevin, N. C.; Wooldridge, M. A. W. : Cytogenetic investigations in a family with ataxia telangiectasia. Hum. Genet. 83: 79-82, 1989. PubMed ID : 2767681 78. Ishiguro, T.; Taketa, K.; Gatti, R. A. : Tissue of origin of elevated alpha-fetoprotein in ataxia-telangiectasia. Dis. Markers 4: 293-297, 1986. PubMed ID : 2454778 79. Jaspers, N. G. J.; Bootsma, D. : Genetic heterogeneity in ataxia-telangiectasia studied by cell fusion. Proc. Nat. Acad. Sci. 79: 2641-2644, 1982. PubMed ID : 6953420 80. Jaspers, N. G. J.; Gatti, R. A.; Baan, C.; Linssen, P. C. M. L.; Bootsma, D. : Genetic complementation analysis of ataxia telangiectasia and Nijmegen breakage syndrome: a survey of 50 patients. Cytogenet. Cell Genet. 49: 259-263, 1988. PubMed ID : 3248383 81. Jaspers, N. G. J.; Painter, R. B.; Paterson, M. C.; Kidson, C.; Inoue, T. : Complementation analysis of ataxia-telangiectasia.In: Gatti, R. A.; Swift, M. : Ataxia-telangiectasia: Genetics, Neuropathology and Immunology of a Degenerative Disease of Childhood. New York: Alan R. Liss (pub.) 1985. Pp. 147-162. 82. Johnson, J. P.; Gatti, R. A.; Sears, T. S.; White, R. L. : Inverted duplication of J(H) associated with chromosome 14 translocation and T-cell leukemia in ataxia-telangiectasia. Am. J. Hum. Genet. 39: 787-796, 1986. PubMed ID : 3026175 83. Johnson, J. P.; White, R. L.; Gatti, R. A. : Rearrangement of J(H) genes in a patient with ataxia telangiectasia, chromosome 14 translocation, and T-cell leukemia. (Abstract) Am. J. Hum. Genet. 37: A100, 1985. 84. Jung, M.; Zhang, Y.; Lee, S.; Dritschilo, A. : Correction of radiation sensitivity in ataxia telangiectasia cells by a truncated I-kappa-B-alpha. Science 268: 1619-1621, 1995. PubMed ID : 7777860 85. Kastan, M. B.; Onyekwere, O.; Sidransky, D.; Vogelstein, B.; Craig, R. W. : Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51: 6304-6311, 1991. PubMed ID : 1933891 86. Kastan, M. B.; Zhan, Q.; El-Deiry, W. S.; Carrier, F.; Jacks, T.; Walsh, W. V.; Plunkett, B. S.; Vogelstein, B.; Fornace, A. J., Jr. : A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587-597, 1992. PubMed ID : 1423616 87. Kennaugh, A. A.; Butterworth, S. V.; Hollis, R.; Baer, R.; Rabbitts, T. H.; Taylor, A. M. R. : The chromosome breakpoint at 14q32 in an ataxia telangiectasia t(14;14) T cell clone is different from the 14q32 breakpoint in Burkitts and an inv(14) T cell lymphoma. Hum. Genet. 73: 254-259, 1986. PubMed ID : 3488254 88. Klein, C.; Wenning, G. K.; Quinn, N. P.; Marsden, C. D. : Ataxia without telangiectasia masquerading as benign hereditary chorea. Mov. Disord. 11: 217-220, 1996. PubMed ID : 8684395 89. Kojis, T. L.; Schreck, R. R.; Gatti, R. A.; Sparkes, R. S. : Tissue specificity of chromosomal rearrangements in ataxia-telangiectasia. Hum. Genet. 83: 347-352, 1989. PubMed ID : 2807275 90. Komatsu, K.; Kodama, S.; Okumura, Y.; Koi, M.; Oshimura, M. : Restoration of radiation resistance in ataxia-telangiectasia cells by the introduction of normal human chromosome 11. Mutat. Res. 235: 59-63, 1990. PubMed ID : 2155385 91. Komatsu, K.; Matsuura, S.; Tauchi, H.; Endo, S.; Kodama, S.; Smeets, D.; Weemaes, C.; Oshimura, M. : The gene for Nijmegen breakage syndrome (V2) is not located on chromosome 11. (Letter) Am. J. Hum. Genet. 58: 885-888, 1996. PubMed ID : 8644753 92. Korein, J.; Steinman, P. A.; Senz, E. H. : Ataxia-telangiectasia: report of a case and review of the literature. Arch. Neurol. 4: 272-280, 1961. PubMed ID : 13753133 93. Krishna Kumar, G.; Al Saadi, A.; Yang, S. S.; McCaughey, R. S. : Ataxia-telangiectasia and hepatocellular carcinoma. Am. J. Med. Sci. 278: 157-160, 1979. PubMed ID : 92892 94. Laake, K.; Jansen, L.; Hahnemann, J. M.; Brondum-Nielsen, K.; Lonnqvist, T.; Kaariainen, H.; Sankila, R.; Lahdesmaki, A.; Hammarstrom, L.; Yuen, J.; Tretli, S.; Heiberg, A.; Olsen, J. H.; Tucker, M.; Kleinerman, R.; Borresen-Dale, A.-L. : Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia. Hum. Mutat. 16: 232-246, 2000. PubMed ID : 10980530 95. Lambert, C.; Schultz, R. A.; Smith, M.; Wagner-McPherson, C.; McDaniel, L. D.; Donlon, T.; Stanbridge, E. J.; Friedberg, E. C. : Functional complementation of ataxia-telangiectasia group D (AT-D) cells by microcell-mediated chromosome transfer and mapping of the AT-D locus to the region 11q22-23. Proc. Nat. Acad. Sci. 88: 5907-5911, 1991. PubMed ID : 2062869 96. Levin, S.; Perlov, S. : Ataxia-telangiectasia in Israel, with observations on its relationship to malignant disease. Israel J. Med. Sci. 7: 1535-1541, 1971. PubMed ID : 5291441 97. Lipkowitz, S.; Garry, V. F.; Kirsch, I. R. : Interlocus V-J recombination measures genomic instability in agriculture workers at risk for lymphoid malignancies. Proc. Nat. Acad. Sci. 89: 5301-5305, 1992. PubMed ID : 1608939 98. Lipkowitz, S.; Stern, M.-H.; Kirsch, I. R. : Hybrid T cell receptor genes formed by interlocus recombination in normal and ataxia-telangiectasia lymphocytes. J. Exp. Med. 172: 409-418, 1990. PubMed ID : 1695665 99. Lisker, R.; Cobo, A. : Chromosome breakage in ataxia-telangiectasia. (Letter) Lancet I: 618, 1970. 100. Littlefield, L. G.; Colyer, S. P.; Joiner, E. E.; DuFrain, R. J.; Frome, E.; Cohen, M. M. : Chromosomal radiation sensitivity in ataxia telangiectasia long-term lymphoblastoid cell lines. Cytogenet. Cell Genet. 31: 203-213, 1981. PubMed ID : 6978798 101. Llerena, J., Jr.; Murer-Orlando, M.; McGuire, M.; Zahed, L.; Sheridan, R. J.; Berry, A. C.; Bobrow, M. : Spontaneous and induced chromosome breakage in chorionic villus samples: a cytogenetic approach to first trimester prenatal diagnosis of ataxia telangiectasia syndrome. J. Med. Genet. 26: 174-178, 1989. PubMed ID : 2468772 102. Maserati, E.; Ottolini, A.; Veggiotti, P.; Lanzi, G.; Pasquali, F. : Ataxia-without-telangiectasia in two sisters with rearrangements of chromosomes 7 and 14. Clin. Genet. 34: 283-287, 1988. PubMed ID : 3228996 103. McCaw, B. K.; Hecht, F.; Harden, D. G.; Teplitz, R. L. : Somatic rearrangement of chromosome 14 in human lymphocytes. Proc. Nat. Acad. Sci. 72: 2071-2075, 1975. PubMed ID : 1056013 104. McConville, C. M.; Formstone, C. J.; Hernandez, D.; Thick, J.; Taylor, A. M. : Fine mapping of the chromosome 11q22-23 region using PFGE, linkage and haplotype analysis; localization of the gene for ataxia telangiectasia to a 5cM region flanked by NCAM/DRD2 and STMY/CJ52.75, phi 2.22. Nucleic Acids Res. 18: 4335-4343, 1990. PubMed ID : 1975092 105. McConville, C. M.; Woods, C. G.; Farrall, M.; Metcalfe, J. A.; Taylor, A. M. R. : Analysis of 7 polymorphic markers at chromosome 11q22-23 in 35 ataxia telangiectasia families; further evidence of linkage. Hum. Genet. 85: 215-220, 1990. PubMed ID : 2370052 106. McFarlin, D. E.; Strober, W.; Waldmann, T. A. : Ataxia-telangiectasia. Medicine 51: 281-314, 1972. PubMed ID : 5033506 107. McKusick, V. A.; Cross, H. E. : Ataxia-telangiectasia and Swiss-type agammaglobulinemia. Two genetic disorders of the immune mechanism in related Amish sibships. J.A.M.A. 195: 739-745, 1966. PubMed ID : 5951879 108. Meyn, M. S. : High spontaneous intrachromosomal recombination rates in ataxia-telangiectasia. Science 260: 1327-1330, 1993. PubMed ID : 8493577 109. Miller, M. E.; Chatten, J. : Ovarian changes in ataxia-telangiectasia. Acta Paediat. Scand. 56: 559-561, 1967. PubMed ID : 6050359 110. Mohamed, R.; Singh, S. P.; Kumar, S.; Lavin, M. F. : A defect in DNA topoisomerase II activity in ataxia-telangiectasia cells. Biochem. Biophys. Res. Commun. 149: 233-238, 1987. PubMed ID : 2825700 111. Morrell, D.; Chase, C. L.; Swift, M. : Cancers in 44 families with ataxia-telangiectasia. Cancer Genet. Cytogenet. 50: 119-123, 1990. PubMed ID : 2253179 112. Murnane, J. P.; Painter, R. B. : Complementation of the effects in DNA synthesis in irradiated and unirradiated ataxia-telangiectasia cells. Proc. Nat. Acad. Sci. 79: 1960-1963, 1982. PubMed ID : 6952246 113. Oxelius, V.-A.; Berkel, A. I.; Hanson, L. A. : IgG2 deficiency in ataxia-telangiectasia. New Eng. J. Med. 306: 515-517, 1982. PubMed ID : 7057859 114. Oxford, J. M.; Harnden, D. G.; Parrington, J. M.; Delhanty, J. D. A. : Specific chromosome aberrations in ataxia-telangiectasia. J. Med. Genet. 12: 251-262, 1975. PubMed ID : 1177276 115. Painter, R. B.; Cramer, P.; Howard, R.; Young, B. R. : Two forms of inhibition of DNA replicon initiation in human cells.In: Harris, C. C.; Cerutti, P. C. : Mechanisms of Chemical Carcinogenesis. New York: Alan R. Liss (pub.) 1982. Pp. 383-386. 116. Painter, R. B.; Young, B. R. : Radiosensitivity in ataxia-telangiectasia: a new explanation. Proc. Nat. Acad. Sci. 77: 7315-7317, 1980. PubMed ID : 6938978 117. Paterson, M. C.; Smith, B. P.; Knight, P. A.; Anderson, A. K. : Ataxia telangiectasia: an inherited human disease involving radiosensitivity, malignancy and defective DNA repair.In: Castellani, A. (ed.) : Research in Photobiology. New York: Plenum (pub.) 1977. Pp. 207-218. 118. Paterson, M. C.; Smith, B. P.; Lohman, P. H. M.; Anderson, A. K.; Fishman, L. : Defective excision repair of gamma-ray-damaged DNA in human (ataxia-telangiectasia) fibroblasts. Nature 260: 444-447, 1976. PubMed ID : 1256588 119. Paterson, M. C.; Smith, P. J. : Ataxia telangiectasia: an inherited human disorder involving hypersensitivity to ionizing radiation and related DNA-damaging chemicals. Ann. Rev. Genet. 13: 291-318, 1979. PubMed ID : 395894 120. Peterson, R. D. A.; Funkhouser, J. D. : Speculations on ataxia-telangiectasia: defective regulation of the immunoglobulin gene superfamily. Immun. Today 10: 313-315, 1989. PubMed ID : 2686680 121. Peterson, R. D. A.; Funkhouser, J. D. : Ataxia-telangiectasia: an important clue. (Editorial) New Eng. J. Med. 322: 124-125, 1990. PubMed ID : 2136769 122. Peterson, R. D. A.; Kelly, W. D.; Good, R. A. : Ataxia-telangiectasia: its association with a defective thymus, immunological-deficiency disease and malignancy. Lancet I: 1189-1193, 1964. 123. Pippard, E. C.; Hall, A. J.; Barker, D. J. P.; Bridges, B. A. : Cancer in homozygotes and heterozygotes of ataxia-telangiectasia and xeroderma pigmentosum in Britain. Cancer Res. 48: 2929-2932, 1988. PubMed ID : 3359449 124. Rary, J. M.; Bender, M. A.; Kelly, T. E. : A 14/14 marker chromosome lymphocyte clone in ataxia telangiectasis. J. Hered. 66: 33-35, 1975. PubMed ID : 1141685 125. Rary, J. M.; Bender, M. A.; Kelly, T. E. : Cytogenetic studies of ataxia-telangiectasia. (Abstract) Am. J. Hum. Genet. 26: 70, 1974. 126. Reye, C.; Mosman, N. S. W. : Ataxia-telangiectasia. Am. J. Dis. Child. 99: 238-247, 1960. 127. Richkind, K. E.; Boder, E.; Teplitz, R. L. : Fetal proteins in ataxia-telangiectasia. J.A.M.A. 248: 1346-1347, 1982. PubMed ID : 6180190 128. Rosen, F. S.; Harris, N. L. : Case records of the Massachusetts General Hospital: a 30-year-old man with ataxia-telangiectasia and dysphagia. New Eng. J. Med. 316: 91-100, 1987. PubMed ID : 3785360 129. Rosin, M. P.; Ochs, H. D. : In vivo chromosomal instability in ataxia-telangiectasia homozygotes and heterozygotes. Hum. Genet. 74: 335-340, 1986. PubMed ID : 3793095 130. Rosin, M. P.; Ochs, H. D.; Gatti, R. A.; Boder, E. : Heterogeneity of chromosomal breakage levels in epithelial tissue of ataxia-telangiectasia homozygotes and heterozygotes. Hum. Genet. 83: 133-138, 1989. PubMed ID : 2777252 131. Russo, G.; Isobe, M.; Gatti, R.; Finan, J.; Batuman, O.; Huebner, K.; Nowell, P. C.; Croce, C. M. : Molecular analysis of a t(14;14) translocation in leukemic T-cells of an ataxia telangiectasia patient. Proc. Nat. Acad. Sci. 86: 602-606, 1989. PubMed ID : 2783489 132. Sanal, O.; Lange, E.; Telatar, M.; Sobel, E.; Salazar-Novak, J.; Ersoy, F.; Morrison, A.; Concannon, P.; Tolun, A.; Gatti, R. A. : Ataxia-telangiectasia: linkage analysis of chromosome 11q22-23 markers in Turkish families. FASEB J. 6: 2848-2852, 1992. PubMed ID : 1634048 133. Sanal, O.; Wei, S.; Foroud, T.; Malhotra, U.; Concannon, P.; Charmley, P.; Salser, W.; Lange, K.; Gatti, R. A. : Further mapping of an ataxia-telangiectasia locus to the chromosome 11q23 region. Am. J. Hum. Genet. 47: 860-866, 1990. PubMed ID : 2220826 134. Sandoval, N.; Platzer, M.; Rosenthal, A.; Dork, T.; Bendix, R.; Skawran, B.; Stuhrmann, M.; Wegner, R.-D.; Sperling, K.; Banin, S.; Shiloh, Y.; Baumer, A.; Bernthaler, U.; Sennefelder, H.; Brohm, M.; Weber, B. H. F.; Schindler, D. : Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum. Molec. Genet. 8: 69-79, 1999. PubMed ID : 9887333 135. Sasaki, T.; Tian, H.; Kukita, Y.; Inazuka, M.; Tahira, T.; Imai, T.; Yamauchi, M.; Saito, T.; Hori, T.; Hashimoto-Tamaoki, T.; Komatsu, K.; Nikaido, O.; Hayashi, K. : ATM mutations in patients with ataxia telangiectasia screened by a hierarchical strategy. Hum. Mutat. 12: 186-195, 1998. PubMed ID : 9711876 136. Saviozzi, S.; Saluto, A.; Taylor, A. M. R.; Last, J. I. L.; Trebini, F.; Paradiso, M. C.; Grosso, E.; Funaro, A.; Ponzio, G.; Migone, N.; Brusco, A. : A late onset variant of ataxia-telangiectasia with a compound heterozygous genotype, A8030G/7481insA. J. Med. Genet. 39: 57-61, 2002. PubMed ID : 11826028 137. Savitsky, K.; Bar-Shira, A.; Gilad, S.; Rotman, G.; Ziv, Y.; Vanagaite, L.; Tagle, D. A.; Smith, S.; Uziel, T.; Sfez, S.; Ashkenazi, M.; Pecker, I.; and 18 others : A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268: 1749-1753, 1995. PubMed ID : 7792600 138. Saxon, A.; Stevens, R. H.; Golde, D. W. : Helper and suppressor T-lymphocyte leukemia in ataxia-telangiectasia. New Eng. J. Med. 300: 700-704, 1979. PubMed ID : 310962 139. Schalch, D. S.; McFarlin, D. E.; Barlow, M. H. : An unusual form of diabetes mellitus in ataxia-telangiectasia. New Eng. J. Med. 282: 1396-1402, 1970. PubMed ID : 4192270 140. Scheres, J. M. J. C.; Hustinx, T. W. J.; Weemaes, C. M. R. : Chromosome 7 in ataxia-telangiectasia. J. Pediat. 97: 440-441, 1980. PubMed ID : 7411307 141. Sedgwick, R. P.; Boder, E. : Ataxia-telangiectasia.In: Vinken, P. J.; Bruyn, G. W. (eds.) : Handbook of Clinical Neurology. Amsterdam: North-Holland Publishing Co. (pub.) 14 1972. Pp. 267-339. 142. Shackelford, R. E.; Innes, C. L.; Sieber, S. O.; Heinloth, A. N.; Leadon, S. A.; Paules, R. S. : The ataxia telangiectasia gene product is required for oxidative stress-induced G1 and G2 checkpoint function in human fibroblasts. J. Biol. Chem. 276: 21951-21959, 2001. PubMed ID : 11290740 143. Shaham, M.; Becker, Y. : The ataxia telangiectasia clastogenic factor is a low molecular weight peptide. Hum. Genet. 58: 422-424, 1981. PubMed ID : 7327565 144. Shiloh, Y.; Parshad, R.; Frydman, M.; Sanford, K. K.; Portnoi, S.; Ziv, Y.; Jones, G. M. : G(2) chromosomal radiosensitivity in families with ataxia-telangiectasia. Hum. Genet. 84: 15-18, 1989. PubMed ID : 2606472 145. Shultz, L. D.; Sweet, H. O.; Davisson, M. T.; Coman, D. R. : 'Wasted,' a new mutant of the mouse with abnormalities characteristic of ataxia telangiectasia. Nature 297: 402-404, 1982. PubMed ID : 7078649 146. Shuster, J.; Hart, Z.; Stimson, C. W.; Brough, A. J.; Poulik, M. D. : Ataxia-telangiectasia with cerebellar tumor. Pediatrics 37: 776-786, 1966. PubMed ID : 5326774 147. Sobel, E.; Lange, E.; Jaspers, N. G. J.; Chessa, L.; Sanal, O.; Shiloh, Y.; Taylor, A. M. R.; Weemaes, C. M. A.; Lange, K.; Gatti, R. A. : Ataxia-telangiectasia: linkage evidence for genetic heterogeneity. (Letter) Am. J. Hum. Genet. 50: 1343-1348, 1992. PubMed ID : 1598915 148. Sourander, P.; Bonnevier, J. O.; Olsson, Y. : A case of ataxia-telangiectasia with lesions in the spinal cord. Acta Neurol. Scand. 42: 354-366, 1966. PubMed ID : 5935908 149. Stankovic, T.; Kidd, A. M. J.; Sutcliffe, A.; McGuire, G. M.; Robinson, P.; Weber, P.; Bedenham, T.; Bradwell, A. R.; Easton, D. F.; Lennox, G. G.; Haites, N.; Byrd, P. J.; Taylor, A. M. R. : ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am. J. Hum. Genet. 62: 334-345, 1998. PubMed ID : 9463314 150. Stern, M.-H.; Zhang, F.; Griscelli, C.; Thomas, G.; Aurias, A. : Molecular characterization of different ataxia telangiectasia T-cell clones. I. A common breakpoint at the 14q11.2 band splits the T-cell receptor alpha-chain gene. Hum. Genet. 78: 33-36, 1988. PubMed ID : 3422210 151. Stern, M.-H.; Zhang, F.; Thomas, G.; Griscelli, C.; Aurias, A. : Molecular characterization of ataxia telangiectasia T cell clones. III. Mapping the 14q32.1 distal breakpoint. Hum. Genet. 81: 18-22, 1988. PubMed ID : 3264259 152. Stewart, G. S.; Maser, R. S.; Stankovic, T.; Bressan, D. A.; Kaplan, M. I.; Jaspers, N. G. J.; Raams, A.; Byrd, P. J.; Petrini, J. H. J.; Taylor, A. M. R. : The DNA double-strand break repair gene hMRE11 is mutated in individuals with an ataxia-telangiectasia-like disorder. Cell 99: 577-587, 1999. PubMed ID : 10612394 153. Sugimoto, T.; Kidowaki, T.; Sawada, T.; Ohtsuka-Urano, T.; Kusunoki, T. : Ataxia-telangiectasia associated with non-T, non-B cell acute lymphocytic leukemia. Acta Paediat. Scand. 71: 509-510, 1982. PubMed ID : 6958175 154. Swift, M. : Cancer risk counseling. (Letter) Science 210: 1074, 1980. PubMed ID : 7444436 155. Swift, M.; Morrell, D.; Cromartie, E.; Chamberlin, A. R.; Skolnick, M. H.; Bishop, D. T. : The incidence and gene frequency of ataxia-telangiectasia in the United States. Am. J. Hum. Genet. 39: 573-583, 1986. PubMed ID : 3788973 156. Swift, M.; Morrell, D.; Massey, R. B.; Chase, C. L. : Incidence of cancer in 161 families affected by ataxia-telangiectasia. New Eng. J. Med. 325: 1831-1836, 1991. PubMed ID : 1961222 157. Swift, M.; Reitnauer, P. J.; Morrell, D.; Chase, C. L. : Breast and other cancers in families with ataxia-telangiectasia. New Eng. J. Med. 316: 1289-1294, 1987. PubMed ID : 3574400 158. Swift, M. R.; Sholman, L.; Perry, M.; Chase, C. : Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res. 36: 209-215, 1976. PubMed ID : 1248000 159. Tadjoedin, M. K.; Fraser, F. C. : Heredity of ataxia-telangiectasia (Louis-Bar syndrome). Am. J. Dis. Child. 110: 64-68, 1965. PubMed ID : 14308125 160. Taylor, A. M. R.; Flude, E.; Laher, B.; Stacey, M.; McKay, E.; Watt, J.; Green, S. H.; Harding, A. E. : Variant forms of ataxia telangiectasia. J. Med. Genet. 24: 669-677, 1987. PubMed ID : 3430541 161. Taylor, A. M. R.; Harnden, D. G.; Arlett, C. F.; Harcourt, S. A.; Lehmann, A. R.; Stevens, S.; Bridges, B. A. : Ataxia-telangiectasia: a human mutation with abnormal radiation sensitivity. Nature 258: 427-429, 1975. PubMed ID : 1196376 162. Taylor, A. M. R.; Metcalfe, J. A.; Oxford, J. M.; Harnden, D. G. : Is chromatid-type damage in ataxia-telangiectasia after irradiation at G(0) a consequence of defective repair? Nature 260: 441-443, 1976. PubMed ID : 1256587 163. Tchirkov, A.; Bay, J.-O.; Pernin, D.; Bignon, Y.-J. Rio, P.; Grancho, M.; Kwiatkowski, F.; Giollant, M.; Malet, P.; Verrelle, P. : Detection of heterozygous carriers of the ataxia-telangiectasia (ATM) gene by G(2) phase chromosomal radiosensitivity of peripheral blood lymphocytes. Hum. Genet. 101: 312-316, 1997. PubMed ID : 9439660 164. Telatar, M.; Wang, Z.; Castellvi-Bel, S.; Tai, L.-Q.; Sheikhavandi, S.; Regueiro, J. R.; Porras, O.; Gatti, R. A. : A model for ATM heterozygote identification in a large population: four founder-effect ATM mutations identify most of Costa Rican patients with ataxia telangiectasia. Molec. Genet. Metab. 64: 36-43, 1998. 165. Teplitz, R. L. : Ataxia-telangiectasia. Arch. Neurol. 35: 553-554, 1978. PubMed ID : 687181 166. Thibaut, S.; Sass, U.; Khoury, A.; Simonart, J.-M. : Ataxia-telangiectasia and necrobiosis lipoidica: an explainable association. Europ. J. Derm. 4: 509-513, 1994. 167. Toledano, S. R.; Lang, B. J. : Ataxia-telangiectasia and acute lymphoblastic leukemia. Cancer 45: 1675-1678, 1980. PubMed ID : 6929216 168. Tse, A. G. D.; Barclay, A. N.; Watts, A.; Williams, A. F. : A glycophospholipid tail at the carboxyl terminus of the Thy-1 glycoprotein of neurons and thymocytes. Science 230: 1003-1008, 1985. PubMed ID : 2865810 169. Vincent, R. A., Jr.; Sheridan, R. B., III; Huang, P. C. : DNA strand breakage repair in ataxia-telangiectasia fibroblast-like cells. Mutat. Res. 33: 357-366, 1975. PubMed ID : 1214827 170. Waldmann, T. A.; McIntire, K. R. : Serum-alpha-fetoprotein levels in patients with ataxia-telangiectasia. Lancet II: 1112-1115, 1972. 171. Waldmann, T. A.; Misiti, J.; Nelson, D. L.; Kraemer, K. H. : Ataxia-telangiectasia: a multisystem hereditary disease with immunodeficiency, impaired organ maturation, x-ray hypersensitivity, and a high incidence of neoplasia. Ann. Intern. Med. 99: 367-379, 1983. PubMed ID : 6193747 172. Watanabe, A.; Hanazono, H.; Sogawa, H.; Takaya, H. : Stomach cancer in a 14-year-old-boy with ataxia-telangiectasia. Tohoku J. Exp. Med. 121: 127-131, 1977. PubMed ID : 191957 173. Waterman, M. J. F.; Stavridi, E. S.; Waterman, J. L. F.; Halazonetis, T. D. : ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins. Nature Genet. 19: 175-178, 1998. PubMed ID : 9620776 174. Watts, J. A.; Morley, M.; Burdick, J. T.; Fiori, J. L.; Ewens, W. J.; Spielman, R. S.; Cheung, V. G. : Gene expression phenotype in heterozygous carriers of ataxia telangiectasia. Am. J. Hum. Genet. 71: 791-800, 2002. PubMed ID : 12226795 175. Weinstein, S.; Scottolini, A. G.; Loo, S. Y. T.; Caldwell, P. C.; Bhagavan, N. V. : Ataxia telangiectasia with hepatocellular carcinoma in a 15-year-old girl and studies of her kindred. Arch. Path. Lab. Med. 109: 1000-1004, 1985. PubMed ID : 2996458 176. Welshimer, K.; Swift, M. : Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families. Am. J. Hum. Genet. 34: 781-793, 1982. PubMed ID : 7124732 177. Wong, K.-K.; Maser, R. S.; Bachoo, R. M.; Menon, J.; Carrasco, D. R.; Gu, Y.; Alt, F. W.; DePinho, R. A. : Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421: 643-648, 2003. PubMed ID : 12540856 178. Woods, C. G.; Bundey, S. E.; Taylor, A. M. R. : Unusual features in the inheritance of ataxia telangiectasia. Hum. Genet. 84: 555-562, 1990. PubMed ID : 2338342 179. Woods, C. G.; Taylor, A. M. R. : Ataxia telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals. Quart. J. Med. 82: 169-179, 1992. PubMed ID : 1377828 180. Wooster, R.; Ford, D.; Mangion, J.; Ponder, B. A. J.; Peto, J.; Easton, D. F.; Stratton, M. R. : Absence of linkage to the ataxia telangiectasia locus in familial breast cancer. Hum. Genet. 92: 91-94, 1993. PubMed ID : 8365732 181. Worgul, B. V.; Smilenov, L.; Brenner, D. J.; Junk, A.; Zhou, W.; Hall, E. J. : Atm heterozygous mice are more sensitive to radiation-induced cataracts than are their wild-type counterparts. Proc. Nat. Acad. Sci. 99: 9836-9839, 2002. PubMed ID : 12119422 182. Xu, Y.; Ashley, T; Brainerd, E. E.; Bronson, R. T.; Meyn, M. S.; Baltimore, D. : Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev. 10: 2411-2422, 1996. PubMed ID : 8843194 183. Xu, Y.; Baltimore, D. : Dual roles of ATM in the cellular response to radiation and in cell growth control. Genes Dev. 10: 2401-2410, 1996. PubMed ID : 8843193 184. Ying, K. L.; Decoteau, W. E. : Cytogenetic anomalies in a patient with ataxia, immune deficiency, and high alpha-fetoprotein in the absence of telangiectasia. Cancer Genet. Cytogenet. 4: 311-317, 1981. PubMed ID : 6174206 185. Yount, W. J. : IgG2 deficiency and ataxia-telangiectasia. (Editorial) New Eng. J. Med. 306: 541-543, 1982. PubMed ID : 7057862 186. Zadik, Z.; Levin, S.; Prager-Lewin, R.; Laron, Z. : Gonadal dysfunction in patients with ataxia telangiectasia. Acta Paediat. Scand. 67: 477-479, 1978. PubMed ID : 354315 187. Zhang, F.; Stern, M.-H.; Thomas, G.; Aurias, A. : Molecular characterization of ataxia telangiectasia T cell clones. II. The clonal inv(14) in ataxia telangiectasia differs from the inv(14) in T cell lymphoma. Hum. Genet. 78: 316-319, 1988. PubMed ID : 3258841 188. Ziv, Y.; Amiel, A.; Jaspers, N. G. J.; Berkel, A. I.; Shiloh, Y. : Ataxia-telangiectasia: a variant with altered in vitro phenotype of fibroblast cells. Mutat. Res. 210: 211-219, 1989. PubMed ID : 2911253 189. Ziv, Y.; Frydman, M.; Lange, E.; Zelnik, N.; Rotman, G.; Julier, C.; Jaspers, N. G. J.; Dagan, Y.; Abeliovicz, D.; Dar, H.; Borochowitz, Z.; Lathrop, M.; Gatti, R. A.; Shiloh, Y. : Ataxia-telangiectasia: linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome. Hum. Genet. 88: 619-626, 1992. PubMed ID : 1551665 190. Ziv, Y.; Rotman, G.; Frydman, M.; Dagan, J.; Cohen, T.; Foroud, T.; Gatti, R. A.; Shiloh, Y. : The ATC (ataxia-telangiectasia complementation group C) locus localizes to 11q22-q23. Genomics 9: 373-375, 1991. PubMed ID : 1672297 ### CONTRIBUTORS Cassandra L. Kniffin - updated : 10/19/2003 Cassandra L. Kniffin - reorganized : 5/7/2003 Victor A. McKusick - updated : 3/6/2003 Ada Hamosh - updated : 2/3/2003 Ada Hamosh - updated : 1/29/2003 Victor A. McKusick - updated : 1/15/2003 Patricia A. Hartz - updated : 12/17/2002 Victor A. McKusick - updated : 10/29/2002 Stylianos E. Antonarakis - updated : 9/25/2002 Victor A. McKusick - updated : 9/20/2002 Victor A. McKusick - updated : 8/29/2002 Ada Hamosh - updated : 3/28/2002 Victor A. McKusick - updated : 3/7/2002 Victor A. McKusick - updated : 2/6/2002 Victor A. McKusick - updated : 1/10/2002 Ada Hamosh - updated : 6/20/2001 George E. Tiller - updated : 5/24/2001 Ada Hamosh - updated : 4/18/2001 Ada Hamosh - updated : 4/10/2001 Paul J. Converse - updated : 11/16/2000 Victor A. McKusick - updated : 9/25/2000 Ada Hamosh - updated : 7/12/2000 Ada Hamosh - updated : 5/24/2000 Victor A. McKusick - updated : 5/22/2000 Victor A. McKusick - updated : 4/19/2000 Victor A. McKusick - updated : 4/18/2000 Victor A. McKusick - updated : 3/31/2000 Victor A. McKusick - updated : 2/9/2000 Victor A. McKusick - updated : 12/21/1999 Ada Hamosh - updated : 11/4/1999 Victor A. McKusick - updated : 10/27/1999 Victor A. McKusick - updated : 9/24/1999 Ada Hamosh - updated : 9/20/1999 Victor A. McKusick - updated : 5/28/1999 Ada Hamosh - updated : 3/30/1999 Victor A. McKusick - updated : 2/19/1999 Victor A. McKusick - updated : 2/9/1999 Victor A. McKusick - updated : 11/30/1998 Victor A. McKusick - updated : 11/5/1998 Victor A. McKusick - updated : 10/13/1998 Victor A. McKusick - updated : 10/1/1998 Victor A. McKusick - updated : 9/28/1998 Victor A. McKusick - updated : 8/14/1998 Victor A. McKusick - updated : 6/29/1998 Clair A. Francomano - updated : 5/27/1998 Victor A. McKusick - updated : 5/7/1998 Victor A. McKusick - updated : 4/14/1998 Victor A. McKusick - updated : 4/1/1998 Victor A. McKusick - updated : 2/19/1998 Victor A. McKusick - updated : 2/11/1998 Lori M. Kelman - updated : 9/30/1997 Victor A. McKusick - updated : 9/12/1997 Victor A. McKusick - updated : 9/2/1997 Lori M. Kelman - updated : 8/14/1997 Victor A. McKusick - updated : 7/31/1997 Victor A. McKusick - updated : 4/7/1997 Victor A. McKusick - updated : 3/2/1997 Victor A. McKusick - updated : 2/18/1997 Moyra Smith - updated : 1/30/1997 Moyra Smith - updated : 11/12/1996 Moyra Smith - updated : 10/1/1996 Alan F. Scott - updated : 8/22/1996 Alan F. Scott - updated : 5/24/1996 Moyra Smith - updated : 4/30/1996 Orest Hurko - updated : 6/22/1994 ### CREATION DATE Victor A. McKusick : 6/3/1986 ### EDIT HISTORY carol : 10/19/2003 carol : 10/19/2003 ckniffin : 10/16/2003 alopez : 5/16/2003 ckniffin : 5/7/2003 ckniffin : 3/7/2003 carol : 3/6/2003 terry : 3/6/2003 ckniffin : 3/3/2003 ckniffin : 3/3/2003 ckniffin : 3/3/2003 alopez : 2/4/2003 terry : 2/3/2003 alopez : 1/29/2003 terry : 1/29/2003 cwells : 1/15/2003 terry : 1/15/2003 mgross : 1/6/2003 terry : 12/17/2002 carol : 10/29/2002 tkritzer : 10/29/2002 terry : 10/29/2002 mgross : 9/25/2002 mgross : 9/25/2002 tkritzer : 9/23/2002 carol : 9/20/2002 tkritzer : 9/6/2002 tkritzer : 9/4/2002 terry : 8/29/2002 alopez : 4/12/2002 carol : 3/29/2002 carol : 3/29/2002 cwells : 3/29/2002 terry : 3/28/2002 alopez : 3/12/2002 terry : 3/7/2002 mgross : 2/11/2002 terry : 2/6/2002 carol : 1/14/2002 carol : 1/14/2002 terry : 1/10/2002 alopez : 6/21/2001 terry : 6/20/2001 cwells : 5/25/2001 cwells : 5/24/2001 cwells : 5/23/2001 alopez : 4/19/2001 terry : 4/18/2001 alopez : 4/11/2001 alopez : 4/11/2001 terry : 4/10/2001 joanna : 1/17/2001 mgross : 11/16/2000 mcapotos : 10/3/2000 mcapotos : 9/25/2000 mcapotos : 9/8/2000 alopez : 7/12/2000 alopez : 5/24/2000 terry : 5/22/2000 carol : 5/12/2000 mcapotos : 5/11/2000 mcapotos : 5/10/2000 terry : 4/19/2000 terry : 4/18/2000 mgross : 4/11/2000 terry : 3/31/2000 mgross : 3/2/2000 terry : 2/9/2000 mgross : 1/3/2000 mgross : 12/29/1999 terry : 12/21/1999 alopez : 11/5/1999 alopez : 11/4/1999 carol : 10/27/1999 carol : 10/22/1999 carol : 10/22/1999 terry : 9/24/1999 carol : 9/21/1999 terry : 9/20/1999 kayiaros : 7/13/1999 mgross : 6/3/1999 terry : 5/28/1999 alopez : 3/30/1999 mgross : 3/10/1999 mgross : 2/24/1999 mgross : 2/19/1999 alopez : 2/19/1999 alopez : 2/19/1999 carol : 2/18/1999 terry : 2/17/1999 terry : 2/9/1999 psherman : 1/26/1999 dkim : 12/10/1998 alopez : 12/1/1998 terry : 11/30/1998 carol : 11/15/1998 terry : 11/5/1998 carol : 10/18/1998 terry : 10/13/1998 carol : 10/7/1998 terry : 10/1/1998 alopez : 9/28/1998 joanna : 9/28/1998 terry : 8/21/1998 terry : 8/19/1998 carol : 8/14/1998 terry : 8/14/1998 terry : 8/11/1998 carol : 7/24/1998 terry : 7/9/1998 carol : 7/1/1998 terry : 6/29/1998 carol : 6/19/1998 terry : 6/16/1998 carol : 6/5/1998 terry : 6/4/1998 terry : 6/1/1998 dholmes : 5/28/1998 dholmes : 5/27/1998 dholmes : 5/21/1998 alopez : 5/13/1998 alopez : 5/13/1998 terry : 5/7/1998 carol : 4/14/1998 alopez : 4/1/1998 terry : 3/23/1998 terry : 3/20/1998 mark : 2/26/1998 terry : 2/19/1998 alopez : 2/11/1998 alopez : 2/11/1998 dholmes : 2/4/1998 dholmes : 11/11/1997 dholmes : 11/11/1997 dholmes : 9/30/1997 jenny : 9/19/1997 terry : 9/12/1997 mark : 9/5/1997 jenny : 9/3/1997 terry : 9/2/1997 terry : 9/2/1997 terry : 9/2/1997 dholmes : 8/14/1997 dholmes : 8/14/1997 dholmes : 8/14/1997 terry : 8/5/1997 terry : 7/31/1997 terry : 6/2/1997 terry : 4/14/1997 mark : 4/7/1997 terry : 4/1/1997 jamie : 3/4/1997 mark : 3/2/1997 terry : 2/28/1997 jenny : 2/18/1997 terry : 2/12/1997 terry : 1/30/1997 mark : 1/29/1997 mark : 1/8/1997 terry : 12/10/1996 terry : 12/5/1996 mark : 11/12/1996 mark : 11/12/1996 terry : 11/7/1996 terry : 11/4/1996 mark : 10/1/1996 mark : 9/26/1996 mark : 9/11/1996 terry : 9/6/1996 mark : 8/22/1996 marlene : 8/20/1996 mark : 7/22/1996 mark : 7/5/1996 terry : 6/26/1996 mark : 5/31/1996 terry : 5/24/1996 terry : 5/24/1996 carol : 5/4/1996 carol : 4/30/1996 mark : 4/25/1996 terry : 4/19/1996 mark : 3/12/1996 terry : 3/5/1996 mark : 2/15/1996 terry : 2/9/1996 mark : 12/20/1995 terry : 11/6/1995 mark : 10/27/1995 pfoster : 2/14/1995 davew : 8/16/1994 mimadm : 4/29/1994 Copyright © 1966-2005 Johns Hopkins University
3: | *602667 | GeneTests, Links
| NBS1 GENE; NBS1
#### Alternative titles; symbols NIBRIN p95 PROTEIN OF THE MRE11/RAD50 COMPLEX ### TABLE OF CONTENTS #### CLONING GENE FUNCTION GENE STRUCTURE MAPPING MOLECULAR GENETICS CYTOGENETICS ANIMAL MODEL ALLELIC VARIANTS View List REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 8q21 ### TEXT #### CLONING Varon et al. (1998) described the positional cloning of a gene encoding a novel protein, termed nibrin, that mapped within a 300-kb critical region for Nijmegen breakage syndrome (NBS; 251260) on chromosome 8q21. Northern blot analysis revealed mRNA transcripts of 2.4 and 4.4 kb in all tissues examined. The predicted 754-amino acid protein contains 2 domains found in cell cycle checkpoint proteins, a forkhead-associated domain and an adjacent breast cancer carboxy-terminal domain. Carney et al. (1998) independently isolated the gene for NBS. They characterized the gene encoding p95, a member of the MRE11/RAD50 double-strand break (DSB) repair complex. Comparison of the p95 cDNA to the NBS1 cDNA of Varon et al. (1998) indicated that the p95 and NBS1 genes are identical. Matsuura et al. (1998) reported the positional cloning of the gene responsible for the Nijmegen breakage syndrome, NBS1, from an 800-kb candidate region. They found that the gene is expressed at high levels in testis, suggesting that it may be involved in meiotic recombination. #### GENE FUNCTION The MRE11/RAD50 DSB repair complex consists of 5 proteins: p95 (NBS1), p200, p400, MRE11, and RAD50 (604040). Carney et al. (1998) found that p95 was absent from NBS cells established from NBS patients and that p95 deficiency in these cells completely abrogated the formation of MRE11/RAD50 ionizing radiation-induced foci. The implication of the MRE11/RAD50/p95 protein complex in NBS reveals a direct molecular link between DSB repair and cell cycle checkpoint functions. Zhong et al. (1999) demonstrated association of BRCA1 (113705) with the RAD50/MRE11/p95 complex. Upon irradiation, BRCA1 was detected in the nucleus, in discrete foci which colocalize with RAD50. Formation of irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent methyl methanesulfonate. These data suggested to the authors that BRCA1 is important for the cellular responses to DNA damage that are mediated by the RAD50-MRE11-p95 complex. Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. Because of the similarities between ataxia-telangiectasia (AT; 208900) and Nijmegen breakage syndrome, Lim et al. (2000) evaluated the functional interactions between the ataxia-telangiectasia mutated (ATM; 607585) and NBS1 genes. Activation of the ATM kinase by ionizing radiation and induction of ATM-dependent responses in NBS cells indicated that NBS1 may not be required for signaling to ATM after ionizing radiation. However, NBS1 was phosphorylated on serine-343 in an ATM-dependent manner in vitro and in vivo after ionizing radiation. An NBS1 construct mutated at the ATM phosphorylation site abrogated an S-phase checkpoint induced by ionizing radiation in normal cells and failed to compensate for this functional deficiency in NBS cells. These observations linked ATM and NBS1 in a common signaling pathway and provided an explanation for the phenotypic similarities between the 2 disorders. Gatei et al. (2000) demonstrated that nibrin is phosphorylated within 1 hour of treatment of cells with ionizing radiation. This response was abrogated in AT cells that either do not express ATM protein or express near full-length mutant protein. Gatei et al. (2000) also showed that ATM physically interacts with and phosphorylates nibrin on serine-343 both in vivo and in vitro. Phosphorylation of this site appears to be functionally important because mutated nibrin (S343A) does not completely complement radiosensitivity in NBS cells. ATM phosphorylation of nibrin does not affect nibrin-MRE11-RAD50 association, as revealed by radiation-induced foci formation. Gatei et al. (2000) concluded that their data provide a biochemical explanation for the similarity in phenotype between AT and NBS. Zhao et al. (2000) demonstrated that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. Zhao et al. (2000) identified 2 residues of NBS1, serine-278 and serine-343, that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mre11/Rad50 nuclear foci, and rescue of hypersensitivity to ionizing radiation. Zhao et al. (2000) concluded that together, these results demonstrated a biochemical link between cell cycle checkpoints activated by DNA damage and DNA repair in 2 genetic diseases with overlapping phenotypes. Zhu et al. (2000) showed by coimmunoprecipitation that a small fraction of RAD50, MRE11, and NBS1 is associated with the telomeric repeat-binding factor TRF2 (602027). Indirect immunofluorescence demonstrated the presence of RAD50 and MRE11 at interphase telomeres. NBS1 was associated with TRF2 and telomeres in S phase, but not in G1 or G2. Although the MRE11 complex accumulated in irradiation-induced foci (IRIFs) in response to gamma-irradiation, TRF2 did not relocate to IRIFs and irradiation did not affect the association of TRF2 with the MRE11 complex, arguing against a role for TRF2 in double-strand break repair. Zhu et al. (2000) proposed that the MRE11 complex functions at telomeres, possibly by modulating t-loop formation. Lombard and Guarente (2000) showed that p95 and MRE11 are specifically present on telomeres during meiosis. They suggested that p95 and MRE11 may have a role in telomere maintenance in mammals, analogous to the role their homologs play in yeast. Wu et al. (2000) reported that NBS is specifically phosphorylated in response to gamma-radiation, ultraviolet light, and exposure to hydroxyurea. Phosphorylation of NBS mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, NBS was phosphorylated on many serine residues, of which serine-343, serine-397, and serine-615 were phosphorylated by ATM in vitro. At least 2 of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated ATM-dependent phosphorylation. Reconstituting NBS cells with a mutant form of NBS that cannot be phosphorylated at selected ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Wu et al. (2000) concluded that phosphorylation of NBS by ATM is critical for certain responses of human cells to DNA damage. Wilda et al. (2000) studied the expression of Nbs1 in mouse embryos at different developmental stages as well as in adult mice. Although a low level of expression was observed in all tissues, highly specific expression was observed in organs with physiologic DNA double strand breakage (DSB), such as testis, thymus, and spleen. Enhanced expression was also found at sites of high proliferative activity: the subventricular layer of the telencephalon and diencephalon, the liver, lung, kidney, and gut, as well as striated and smooth muscle cells in various organs. In the adult cerebellum, the postmitotic Purkinje cells were marked specifically. The authors hypothesized that in addition to the role of the Nbs1 gene product as part of a DNA DSB repair complex, the Nbs1 gene product may serve further functions during development. Chen et al. (2000) reported that the NBS1 protein and histone gamma-H2AX (601772), which associate with irradiation-induced DNA DSBs, are also found at sites of V(D)J (variable, diversity, joining) recombination-induced DSBs. In developing thymocytes, NBS1 and gamma-H2AX form nuclear foci that colocalize with the T-cell receptor-alpha (TCRA; 186880) locus in response to recombination-activating gene-1 (RAG1; 179615) protein-mediated V(D)J cleavage. Chen et al. (2000) concluded that their results suggest that surveillance of T-cell receptor recombination intermediates by NBS1 and gamma-H2AX may be important for preventing oncogenic translocations. Class switch recombination (CSR) is a region-specific DNA recombination reaction that replaces one immunoglobulin heavy-chain constant region gene with another. This enables a single variable region gene to be used in conjunction with different downstream heavy-chain genes, each having a unique biologic activity. Activation-induced cytidine deaminase (AID; 605257), a putative RNA editing enzyme, is required for this action. Petersen et al. (2001) reported that the Nijmegen breakage syndrome protein and gamma-H2AX, which facilitate DNA double-strand break repair, form nuclear foci at the heavy-chain constant region in the G1 phase of the cell cycle in cells undergoing class switch recombination. Class switch recombination is impaired in H2AX -/- mice. Localization of NBS1 and gamma-H2AX to the immunoglobulin heavy-chain locus during class switch recombination is dependent on AID. In addition, AID is required for induction of switch region-specific DNA lesions that precede class switch recombination. Petersen et al. (2001) concluded that AID functions upstream of the DNA modifications that initiate class switch recombination. Falck et al. (2002) demonstrated that experimental blockade of either the NBS1-MRE11 function or the CHK2 (604373)-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A (116947)-CDK2 (116953) pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication. In mammalian cells, a conserved multiprotein complex of MRE11, RAD50, and NBS1 is important for double-strand break repair, meiotic recombination, and telomere maintenance. In the absence of the early region E4, the double-stranded genome of adenoviruses is joined into concatamers too large to be packaged. Stracker et al. (2002) investigated the cellular proteins involved in the concatamer formation and how they are inactivated by E4 products during a wildtype infection. They demonstrated that concatamerization requires functional MRE11 and NBS1, and that these proteins are found at foci adjacent to viral replication centers. Infection with wildtype virus results in both reorganization and degradation of members of the MRE11-RAD50-NBS1 complex. These activities are mediated by 3 viral oncoproteins that prevent concatamerization. This targeting of cellular proteins involved in the genomic stability suggested a mechanism for 'hit-and-run' transformation observed for these viral oncoproteins. Franchitto and Pichierri (2002) reviewed the roles of RECQL2 (604611) and RECQL3 (604610) in resolution of a stall in DNA replication, as well as their possible interaction with the MRE11-RAD50-NBS1 complex. Tauchi et al. (2002) established an Nbs1 knockout cell line by using the hyperrecombinogenic chick B-cell line DT40. Exon 4 of the 3 Nbs1 alleles in DT40 cells was targeted. The Nbs1 -/-/- cells were still viable, although they exhibited slow growth owing to a prolonged cell cycle time. The disruption of Nbs1 reduced gene conversion and sister chromatid exchanges, similar to other homologous recombination-deficient mutants. In fact, a site-specific double-strand break repair assay showed a notable reduction of homologous recombination events following generation of such breaks in Nbs1-disrupted cells. The rare recombinations observed in the Nbs1-disrupted cells were frequently found to have aberrant structures, which possibly arose from unusual crossover events, suggesting that the NBS1 complex might be required to process recombination intermediates. Thus, Tauchi et al. (2002) demonstrated that NBS1 is essential for homologous recombination-mediated repair in higher vertebrate cells. #### GENE STRUCTURE Varon et al. (1998) determined that the NBS1 gene spans more than 50 kb and contains 16 exons. #### MAPPING Varon et al. (1998) mapped the NBS1 gene to chromosome 8q21. Carney et al. (1998) mapped the NBS1 gene mapped to chromosome 8q21.3. By computer-assisted analysis of 5 BAC clones and an EST sequence, Tauchi et al. (1999) defined the genomic organization of an 800-kb region on chromosome 8q21 as 5-prime C8ORF1 (604598), 3-prime NBS1, 5-prime DECR1 (222745), and 3-prime CALB1 (114050). #### MOLECULAR GENETICS Varon et al. (1998) identified a truncating 5-bp deletion (602667.0001) in the NBS1 gene in the majority of NBS patients studied, all of whom carried a conserved marker haplotype. Five additional truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks (DSB). Matsuura et al. (1998) detected the 5-bp deletion (602667.0001) in NBS1 in 13 individuals of Slavic or German origin and concluded that it is likely to be a founder mutation. The findings that the ataxia-telangiectasia gene is involved in the pathogenesis of T-cell prolymphocytic leukemia and other forms of leukemia, the high predisposition of NBS patients to lymphoid malignancy, and the fact that NBS and ATM are indistinguishable at the cellular level, prompted Varon et al. (2001) to investigate whether the NBS1 gene is involved in the pathogenesis of acute lymphoblastic leukemia (ALL) and whether it influences the course of the disease and so has its place among the tumor suppressor genes. They analyzed samples from 47 children with first relapse of ALL for mutations in all 16 exons of the NBS1 gene and identified 4 novel amino acid substitutions in 7 children. Germline origin of an I171V (602667.0007) mutation was confirmed in 3 patients, whereas another change, D95N, was present only in leukemic cells. No additional mutations were found on the second allele in any of these 7 patients. Tanzarella et al. (2003) found that heterozygous individuals from 3 unrelated NBS families with distinct gene deletion mutations had spontaneous chromosome instability (chromatid and chromosomal breaks as well as rearrangements) in blood lymphocytes, but their lymphoblastoid cell lines were not different from controls in x-ray G2 sensitivity. Immunoprecipitation of nibrin detected the normal and variant proteins in carriers from all 3 families. Nakanishi et al. (2002) reported a patient diagnosed with Fanconi anemia (FA; 227650) on the basis of chromosome breakage induced by mitomycin C. The individual showed atypical FA features, including features of NBS. The clinical syndrome was severe, and the child died at 3 years of age, similar to an affected cousin. Immunoblot analysis of primary lymphocytes indicated expression of both unubiquinated and monoubiquinated isoforms of FANCD2 (227646); however, no NBS1 protein was expressed. Sequence analysis indicated that the patient cells contained a tyr363-to-ter mutation in NBS1 (602667.0008), which resulted in a truncated protein. Genomic sequence analysis showed that the mutation was homozygous. By coimmunoprecipitation, Nakanishi et al. (2002) found constitutive interaction between FANCD2 and NBS1, and they presented evidence that these proteins interact in 2 distinct assemblies to mediate S-phase checkpoint and resistance to mitomycin C-induced chromosome damage. NBS1, ATM, and MRE11 were required for FANCD2 phosphorylation in response to radiation-induced S-phase checkpoint. The assembly of NBS1, MRE11, RAD50, and FANCD2 within nuclear foci was required for mitomycin C resistance. Plisiecka-Halasa et al. (2002) looked for NBS1 gene alterations and changes in nibrin expression in 162 human gynecologic tumors, mostly ovarian. They identified the so-called Slavic mutation, 657del5, in 2 of 117 carcinomas studied (1.7%). In both cases it was present in the germline, and in 1 of these tumors there was loss of heterozygosity (LOH) for the 657del5 mutation and loss of nibrin expression. #### CYTOGENETICS Kleier et al. (2000) pointed out that rearrangements involving chromosomes 7 and 14 occur in both ataxia-telangiectasia and NBS. However, NBS patients show characteristic microcephaly, which is rare in ataxia-telangiectasia, and they do not develop ataxia and telangiectasia. #### ANIMAL MODEL Zhu et al. (2001) generated mice deficient in NBS1 by targeted disruption. Nbs1 -/- mice suffered early embryonic lethality and had poorly developed embryonic and extraembryonic tissues. Blastocysts showed greatly diminished expansion of the inner cell mass in culture, suggesting that NBS1 mediates essential functions during proliferation in the absence of externally induced damage. Zhu et al. (2001) concluded that the complex phenotypes observed in NBS patients and cell lines may not result from a complete inactivation of NBS1 but may instead result from hypomorphic truncation mutations compatible with cell viability. Frappart et al. (2005) developed mice with Nbs1 inactivation targeted to the central nervous system. Nbs1-deleted mice were viable and appeared normal at birth, but growth retardation was evident by postnatal day 7, and mutants were half the weight of control mice at weaning. All Nbs1-deleted mice showed balance disorders, tremors, altered gait, repetitive movements, and akinesis after postnatal day 7. Macroscopic examination of brains from mutant mice showed reduced cerebella lacking foliation. Histologic analysis indicated that Nbs1 loss caused proliferation arrest of granule cell progenitors and apoptosis of postmitotic cerebellar neurons. Nbs1-deficient neuroprogenitors showed proliferation defects in culture, but no increase in apoptosis. They also contained more chromosomal breaks, which were accompanied by Atm-mediated p53 (TP53; 191170) activation. Depletion of p53 substantially rescued the neurologic defects of Nbs1 mutant mice. ### ALLELIC VARIANTS (selected examples) #### .0001 NIJMEGEN BREAKAGE SYNDROME [NBS1, 5-BP DEL, NT657 ] In patients of Slavic origin with Nijmegen breakage syndrome (251260), Varon et al. (1998) identified a common deletion of 5 nucleotides in exon 6 of the NBS1 gene (657del5), resulting in a frameshift and a truncated protein. A total of 46 patients homozygous for this mutation were identified. The mutation was found exclusively on a specific 'Slavic' haplotype of linked polymorphic markers. Matsuura et al. (1998) found the same 5-bp deletion in the NBS1 gene in 13 NBS patients of Slavic or German origin. Twelve patients were homozygous for the deletion and 1 was heterozygous. The deletion introduced a premature termination signal at codon 218, which was predicted to result in a severely truncated polypeptide. Matsuura et al. (1998) concluded that they had identified the gene involved in NBS because complementation was effected by a YAC that contained the gene and because no (or extremely reduced) expression of the gene was found in a patient without the deletion but with the NBS phenotype. The presence of a founder mutation in 13 of 14 cases, with no demonstration of the deletion in 50 normal individuals of the same ethnic origin or in 7 normal chromosomes from NBS parents, supported this conclusion. The truncating 657del5 had been identified in 90% of NBS patients. NBS shares a number of features with ataxia-telangiectasia (208900), the most notable being high sensitivity to ionizing radiation and predisposition to cancer. Patients who are heterozygous for the ATM mutation are predisposed to breast cancer. Since the NBS phenotype at the cellular level is very similar to that of ataxia-telangiectasia, Carlomagno et al. (1999) screened 477 German breast cancer patients, aged under 51 years, and 866 matched controls for the common NBS mutation. They identified 1 carrier among the cases and 1 among the controls, indicating that the population frequency of this NBS mutation is 1 in 866 persons (95% CI = 1 in 34,376 to 1 in 156) and the estimated prevalence of NBS is thus 1 in 3 million persons. The proportion of breast cancer attributable to this mutation is less than 1%. Kleier et al. (2000) reported a 5-year-old Bosnian boy with severe microcephaly. Because of multiple structural aberrations involving chromosomes 7 and 14 typical for ataxia-telangiectasia, that disorder was diagnosed. However, the diagnosis of NBS was suggested by the boy's remarkable microcephaly, his facial appearance, and the absence of ataxia and telangiectasia. DNA analysis demonstrated homozygosity for the major mutation in the NBS1 gene, 657del5. Maser et al. (2001) tested the hypothesis that the NBS1 657del5 mutation was a hypomorphic defect. They showed that NBS cells harboring the 657del5 mutation contained a predicted 26-kD N-terminal protein, NBS1(p26), and a 70-kD NBS1 protein, NBS1(p70), lacking the native N terminus. The 26-kD protein is not physically associated with the MRE11 complex (600814), whereas the 70-kD species is physically associated with it. NBS1(p70) is produced by internal translation initiation within the NBS mRNA using an open reading frame generated by the 657del5 frameshift. Maser et al. (2001) proposed that the common NBS1 allele encodes a partially functional protein that diminishes the severity of the NBS phenotype. Tekin et al. (2002) reported a consanguineous Turkish family whose first son died of anal atresia and whose second son, the proband, presented with severe pre- and postnatal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosomal instability, and rhabdomyosarcoma in the anal region. The patient was homozygous for the 657del5 mutation in the NBS1 gene, which is responsible for NBS in most Slav populations. The family was the first diagnosed with NBS in the Turkish population and was one of the most severely affected examples of the syndrome. Drabek et al. (2002) presented PCR with sequence specific primers as a method for detection of the 657del5 mutation. They confirmed a high carrier frequency in the Czech population (1 in 106 persons; 95% CI = 1 in 331 to 1 in 46). In Russian children, Resnick et al. (2003) screened for the 657del5 NBS1 mutation in 548 controls and 68 patients with lymphoid malignancies. No carrier of the mutation was found in the control group. The mutation was found in heterozygous form in 2 of the 68 patients from the group of lymphoid malignancies, 1 with acute lymphoblastic leukemia (see 159555) and 1 with non-Hodgkin lymphoma (605027). Several relatives of the patient with non-Hodgkin lymphoma who carried the same mutation had cancer (acute lymphoblastic leukemia, breast cancer, gastrointestinal cancers), suggesting that heterozygosity may predispose to malignant disorders. #### .0002 NIJMEGEN BREAKAGE SYNDROME [NBS1, 4-BP DEL, NT698] In a patient of English origin with Nijmegen breakage syndrome (251260), Varon et al. (1998) identified a deletion of 4 nucleotides in exon 6 of the NBS1 gene, resulting in a frameshift and a truncated protein. #### .0003 NIJMEGEN BREAKAGE SYNDROME [NBS1, 4-BP DEL, NT835] In a patient of Italian origin with Nijmegen breakage syndrome (251260), Varon et al. (1998) identified a deletion of 4 nucleotides in exon 7 of the NBS1 gene, resulting in a frameshift and a truncated protein. #### .0004 NIJMEGEN BREAKAGE SYNDROME [NBS1, 1-BP INS ] In a patient of Mexican origin with Nijmegen breakage syndrome (251260), Varon et al. (1998) identified an insertion of 1 nucleotide in exon 7 of the NBS1 gene, resulting in a frameshift and a truncated protein. #### .0005 NIJMEGEN BREAKAGE SYNDROME [NBS1, 1-BP DEL, 1142C ] In a patient of Canadian origin with Nijmegen breakage syndrome (251260), Varon et al. (1998) identified a deletion of 1 nucleotide in exon 10 of the NBS1 gene, resulting in a frameshift and a truncated protein. #### .0006 NIJMEGEN BREAKAGE SYNDROME [NBS1, GLN326TER ] In a patient of Dutch origin with Nijmegen breakage syndrome (251260), Varon et al. (1998) identified a nonsense mutation, gln326 to ter, in exon 10 of the NBS1 gene, resulting in a truncated protein. #### .0007 LEUKEMIA, ACUTE LYMPHOBLASTIC [NBS1, ILE171VAL ] APLASTIC ANEMIA, INCLUDED In 3 patients with acute lymphoblastic leukemia, Varon et al. (2001) found germline heterozygosity for an A-to-G change at nucleotide 511, resulting in an ile171-to-val (I171V) mutation occurring in a domain of nibrin that is probably involved in protein-protein interactions. In an 11-year-old Japanese girl with aplastic anemia (609135) and no features of Nijmegen breakage syndrome (251260), Shimada et al. (2004) identified homozygosity for the I171V mutation in the NBS1 gene. Genetic analysis of the patient and her healthy parents indicated that she inherited the germline I171V mutation from her father and the wildtype allele from her mother, and that the second I171V hit occurred on the wildtype allele early in embryonic development. Cytogenetic analysis of lymphoblastic cell lines from the patient showed a marked increase in numeric and structural chromosomal aberrations in the absence of clastogens, suggesting genomic instability. Shimada et al. (2004) also screened 413 normal controls and found heterozygosity for I171V in 5 individuals, corresponding to 1.2% of the Japanese population. #### .0008 NIJMEGEN BREAKAGE SYNDROME [NBS1, TYR363TER ] Nakanishi et al. (2002) reported a patient diagnosed with Fanconi anemia (FA; 227650) on the basis of chromosome breakage induced by mitomycin C. The individual showed atypical FA features, including features of NBS (251260). The clinical syndrome was severe, and the child died at 3 years of age, similar to an affected cousin. In this patient, Nakanishi et al. (2002) identified a homozygous C-to-A mutation at nucleotide 1089 of the NBS1 gene, resulting in a tyr363-to-ter mutation and a truncated protein. ### REFERENCES 1. Carlomagno, F.; Chang-Claude, J.; Dunning, A. M.; Ponder, B. A. J. : Determination of the frequency of the common 675del5 Nijmegen breakage syndrome mutation in the German population: no association with risk of breast cancer. Genes Chromosomes Cancer 25: 393-395, 1999. PubMed ID : 10398434 2. Carney, J. P.; Maser, R. S.; Olivares, H.; Davis, E. M.; Le Beau, M.; Yates, J. R., III; Hays, L.; Morgan, W. F.; Petrini, J. H. J. : The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93: 477-486, 1998. PubMed ID : 9590181 3. Chen, H. T.; Bhandoola, A.; Difilippantonio, M. J.; Zhu, J.; Brown, M. J.; Tai, X.; Rogakou, E. P.; Brotz, T. M.; Bonner, W. M.; Ried, T.; Nussenzweig, A. : Response to RAG-mediated V(D)J cleavage by NBS1 and gamma-H2AX. Science 290: 1962-1964, 2000. PubMed ID : 11110662 4. Drabek, J.; Hajduch, M.; Gojova, L.; Weigl, E.; Mihal, V. : Frequency of 657del(5) mutation of the NBS1 gene in the Czech population by polymerase chain reaction with sequence specific primers. Cancer Genet. Cytogenet. 138: 157-159, 2002. PubMed ID : 12505263 5. Falck, J.; Petrini, J. H. J.; Williams, B. R.; Lukas, J.; Bartek, J. : The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genet. 30: 290-294, 2002. PubMed ID : 11850621 6. Franchitto, A.; Pichierri, P. : Protecting genomic integrity during DNA replication: correlation between Werner's and Bloom's syndrome gene products and the MRE11 complex. Hum. Molec. Genet. 11: 2447-2453, 2002. PubMed ID : 12351580 7. Frappart, P.-O.; Tong, W.-M.; Demuth, I.; Radovanovic, I.; Herceg, Z.; Aguzzi, A.; Digweed, M.; Wang, Z.-Q. : An essential function for NBS1 in the prevention of ataxia and cerebellar defects. Nature Med. 11: 538-544, 2005. PubMed ID : 15821748 8. Gatei, M.; Young, D.; Cerosaletti, K. M.; Desai-Mehta, A.; Spring, K.; Kozlov, S.; Lavin, M. F.; Gatti, R. A.; Concannon, P.; Khanna, K. : ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nature Genet. 25: 115-119, 2000. PubMed ID : 10802669 9. Kleier, S.; Herrmann, M.; Wittwer, B.; Varon, R.; Reis, A.; Horst, J. : Clinical presentation and mutation identification in the NBS1 gene in a boy with Nijmegen breakage syndrome. Clin. Genet. 57: 384-387, 2000. PubMed ID : 10852373 10. Lim, D.-S.; Kim, S.-T.; Xu, B.; Maser, R. S.; Lin, J.; Petrini, J. H. J.; Kastan, M. B. : ATM phosphorylates p95/nbs1 in an S-phase checkpoint pathway. Nature 404: 613-617, 2000. PubMed ID : 10766245 11. Lombard, D. B.; Guarente, L. : Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres. Cancer Res. 60: 2331-2334, 2000. PubMed ID : 10811102 12. Maser, R. S.; Zinkel, R.; Petrini, J. H. J. : An alternative mode of translation permits production of a variant NBS1 protein from the common Nijmegen breakage syndrome allele. Nature Genet. 27: 417-421, 2001. PubMed ID : 11279524 13. Matsuura, S.; Tauchi, H.; Nakamura, A.; Kondo, N.; Sakamoto, S.; Endo, S.; Smeets, D.; Solder, B.; Belohradsky, B. H.; Der Kaloustian, V. M.; Oshimura, M.; Isomura, M.; Nakamura, Y.; Komatsu, K. : Positional cloning of the gene for Nijmegen breakage syndrome. Nature Genet. 19: 179-181, 1998. PubMed ID : 9620777 14. Nakanishi, K.; Taniguchi, T.; Ranganathan, V.; New, H. V.; Moreau, L. A.; Stotsky, M.; Mathew, C. G.; Kastan, M. B.; Weaver, D. T.; D'Andrea, A. D. : Interaction of FANCD2 and NBS1 in the DNA damage response. Nature Cell Biol. 4: 913-920, 2002. PubMed ID : 12447395 15. Petersen, S.; Casellas, R.; Reina-San-Martin, B.; Chen, H. T.; Difilippantonio, M. J.; Wilson, P. C.; Hanitsch, L.; Celeste, A.; Muramatsu, M.; Pilch, D. R.; Redon, C.; Ried, T.; Bonner, W. M.; Honjo, T.; Nussenzweig, M. C.; Nussenzweig, A. : AID is required to initiate Nbs1/gamma-H2AX focus formation and mutations at sites of class switching. Nature 414: 660-665, 2001. PubMed ID : 11740565 16. Plisiecka-Halasa, J.; Dansonka-Mieszkowska, A.; Rembiszewska, A.; Bidzinski, M.; Steffen, J.; Kupryjanczyk, J. : Nijmegen breakage syndrome gene (NBS1) alterations and its protein (nibrin) expression in human ovarian tumours. Ann. Hum. Genet. 66: 353-359, 2002. PubMed ID : 12485469 17. Resnick, I. B.; Kondratenko, I.; Pashanov, E.; Maschan, A. A.; Karachunsky, A.; Togoev, O.; Timakov, A.; Polyakov, A.; Tverskaya, S.; Evgrafov, O.; Roumiantsev, A. G. : 657del5 mutation in the gene for Nijmegen breakage syndrome (NBS1) in a cohort of Russian children with lymphoid tissue malignancies and controls. Am. J. Med. Genet. 120A: 174-179, 2003. 18. Shimada, H.; Shimizu, K; Mimaki, S.; Sakiyama, T.; Mori, T.; Shimasaki, N.; Yokota, J.; Nakachi, K.; Ohta, T.; Ohki, M. : First case of aplastic anemia in a Japanese child with a homozygous missense mutation in the NBS1 gene (I171V) associated with genomic instability. Hum. Genet. 115: 372-376, 2004. PubMed ID : 15338273 19. Stracker, T. H.; Carson, C. T.; Weitzman, M. D. : Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex. Nature 418: 348-352, 2002. PubMed ID : 12124628 20. Tanzarella, C.; Antoccia, A.; Spadoni, E.; di Masi, A.; Pecile, V.; Demori, E.; Varon, R.; Marseglia, G. L.; Tiepolo, L.; Maraschio, P. : Chromosome instability and nibrin protein variants in NBS heterozygotes. Europ. J. Hum. Genet. 11: 297-303, 2003. PubMed ID : 12708449 21. Tauchi, H.; Kobayashi, J.; Morishima, K.; van Gent, D. C.; Shiraishi, T.; Verkaik, N. S.; vanHeems, D.; Ito, E.; Nakamura, A.; Sonoda, E.; Takata, M.; Takeda, S.; Matsuura, S.; Komatsu, K. : Nbs1 is essential for DNA repair by homologous recombination in higher vertebrate cells. Nature 420: 93-98, 2002. PubMed ID : 12422221 22. Tauchi, H.; Matsuura, S.; Isomura, M.; Kinjo, T.; Nakamura, A.; Sakamoto, S.; Kondo, N.; Endo, S.; Komatsu, K.; Nakamura, Y. : Sequence analysis of an 800-kb genomic DNA region on chromosome 8q21 that contains the Nijmegen breakage syndrome gene, NBS1. Genomics 55: 242-247, 1999. PubMed ID : 9933573 23. Tekin, M.; Dogu, F.; Tacyildiz, N.; Akar, E.; Ikinciogullari, A.; Ogur, G.; Yavuz, G.; Babacan, E.; Akar, N. : 657del5 mutation in the NBS1 gene is associated with Nijmegen breakage syndrome in a Turkish family. Clin. Genet. 62: 84-88, 2002. PubMed ID : 12123493 24. Varon, R.; Reis, A.; Henze, G.; Einsiedel, H. G.; Sperling, K.; Seeger, K. : Mutations in the Nijmegen breakage syndrome gene (NBS1) in childhood acute lymphoblastic leukemia (ALL). Cancer Res. 61: 3570-3572, 2001. PubMed ID : 11325820 25. Varon, R.; Vissinga, C.; Platzer, M.; Cerosaletti, K. M.; Chrzanowska, K. H.; Saar, K.; Beckmann, G.; Seemanova, E.; Cooper, P. R.; Nowak, N. J.; Stumm, M.; Weemaes, C. M. R.; Gatti, R. A.; Wilson, R. K.; Digweed, M.; Rosenthal, A.; Sperling, K.; Concannon, P.; Reis, A. : Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 93: 467-476, 1998. PubMed ID : 9590180 26. Wang, Y.; Cortez, D.; Yazdi, P.; Neff, N.; Elledge, S. J.; Qin, J. : BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14: 927-939, 2000. PubMed ID : 10783165 27. Wilda, M.; Demuth, I.; Concannon, P.; Sperling, K.; Hameister, H. : Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development. Hum. Molec. Genet. 9: 1739-1744, 2000. PubMed ID : 10915761 28. Wu, X.; Ranganathan, V.; Weisman, D. S.; Heine, W. F.; Ciccone, D. N.; O'Neill, T. B.; Crick, K. E.; Pierce, K. A.; Lane, W. S.; Rathbun, G.; Livingston, D. M.; Weaver, D. T. : ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 405: 477-482, 2000. PubMed ID : 10839545 29. Zhao, S.; Weng, Y.-C.; Yuan, S.-S. F.; Lin, Y.-T.; Hsu, H.-C.; Lin, S.-C. J.; Gerbino, E.; Song, M.; Zdzienicka, M. Z.; Gatti, R. A.; Shay, J. W.; Ziv, Y.; Shiloh, Y.; Lee, E. Y.-H. P. : Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products. Nature 405: 473-477, 2000. PubMed ID : 10839544 30. Zhong, Q.; Chen, C.-F.; Li, S.; Chen, Y.; Wang, C.-C.; Xiao, J.; Chen, P.-L.; Sharp, Z. D.; Lee, W.-H. : Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285: 747-750, 1999. PubMed ID : 10426999 31. Zhu, J.; Petersen, S.; Tessarollo, L.; Nussenzweig, A. : Targeted disruption of the Nijmegen breakage syndrome gene NBS1 leads to early embryonic lethality in mice. Curr. Biol. 11: 105-109, 2001. PubMed ID : 11231126 32. Zhu, X.-D.; Kuster, B.; Mann, M.; Petrini, J. H. J.; de Lange, T. : Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nature Genet. 25: 347-352, 2000. PubMed ID : 10888888 ### CONTRIBUTORS Patricia A. Hartz - updated : 5/16/2005 Marla J. F. O'Neill - updated : 4/25/2005 Victor A. McKusick - updated : 1/12/2005 Natalie E. Krasikov - updated : 6/1/2004 George E. Tiller - updated : 12/4/2003 Victor A. McKusick - updated : 3/12/2003 Patricia A. Hartz - updated : 3/10/2003 Victor A. McKusick - updated : 3/3/2003 Ada Hamosh - updated : 11/13/2002 Victor A. McKusick - updated : 8/21/2002 Ada Hamosh - updated : 7/24/2002 Ada Hamosh - updated : 3/28/2002 Ada Hamosh - updated : 1/2/2002 Victor A. McKusick - updated : 6/21/2001 Ada Hamosh - updated : 3/29/2001 Ada Hamosh - updated : 12/18/2000 Paul J. Converse - updated : 11/16/2000 George E. Tiller - updated : 9/21/2000 Victor A. McKusick -updated : 8/31/2000 Victor A. McKusick - updated : 6/27/2000 Victor A. McKusick - updated : 6/2/2000 Ada Hamosh - updated : 5/24/2000 Ada Hamosh - updated : 4/27/2000 Ada Hamosh - updated : 4/18/2000 Paul J. Converse - updated : 2/24/2000 Victor A. McKusick - updated : 9/24/1999 Ada Hamosh - updated : 7/30/1999 Victor A. McKusick - updated : 6/1/1998 ### CREATION DATE Stylianos E. Antonarakis : 5/28/1998 ### EDIT HISTORY mgross : 5/17/2005 terry : 5/16/2005 wwang : 4/29/2005 wwang : 4/27/2005 terry : 4/25/2005 mgross : 4/14/2005 wwang : 1/19/2005 wwang : 1/13/2005 terry : 1/12/2005 carol : 6/1/2004 mgross : 12/4/2003 cwells : 11/10/2003 carol : 10/27/2003 carol : 5/15/2003 carol : 5/15/2003 ckniffin : 3/13/2003 mgross : 3/12/2003 terry : 3/12/2003 terry : 3/10/2003 carol : 3/10/2003 tkritzer : 3/7/2003 terry : 3/3/2003 alopez : 11/14/2002 terry : 11/13/2002 tkritzer : 8/27/2002 tkritzer : 8/26/2002 terry : 8/21/2002 terry : 8/21/2002 cwells : 7/26/2002 terry : 7/24/2002 cwells : 3/29/2002 terry : 3/28/2002 alopez : 1/9/2002 terry : 1/2/2002 mcapotos : 7/5/2001 mcapotos : 6/27/2001 terry : 6/21/2001 alopez : 3/29/2001 terry : 3/29/2001 carol : 3/28/2001 joanna : 1/17/2001 mgross : 12/18/2000 mgross : 12/18/2000 mgross : 11/16/2000 alopez : 9/21/2000 mcapotos : 9/5/2000 mcapotos : 8/31/2000 alopez : 6/27/2000 mcapotos : 6/14/2000 terry : 6/2/2000 alopez : 5/24/2000 alopez : 4/29/2000 terry : 4/27/2000 alopez : 4/18/2000 carol : 2/24/2000 alopez : 10/26/1999 terry : 9/24/1999 alopez : 7/30/1999 alopez : 7/28/1999 alopez : 7/28/1999 terry : 7/16/1999 carol : 8/24/1998 carol : 6/10/1998 carol : 6/1/1998 carol : 5/29/1998 Copyright © 1966-2005 Johns Hopkins University
4: | +113705 | GeneTests, Links
| BREAST CANCER 1 GENE; BRCA1
#### Alternative titles; symbols BREAST CANCER, TYPE 1, INCLUDED BREAST CANCER 1, EARLY-ONSET, INCLUDED BREAST-OVARIAN CANCER, INCLUDED ### TABLE OF CONTENTS #### TEXT CLINICAL FEATURES INHERITANCE CLINICAL MANAGEMENT POPULATION GENETICS MAPPING MOLECULAR GENETICS GENOTYPE/PHENOTYPE CORRELATIONS GENE FUNCTION ANIMAL MODEL ALLELIC VARIANTS View List SEE ALSO REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 17q21 ### TEXT For a general discussion of hereditary breast cancer, see 114480. #### CLINICAL FEATURES #### Familial Breast Cancer Features characteristic of familial, versus sporadic, breast cancer are younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men Hall et al. (1990). According to the conclusions of the Breast Cancer Linkage Consortium (1997), the histology of breast cancers in women predisposed by reason of carrying BRCA1 and BRCA2 (600185) mutations differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings were interpreted as suggesting that breast cancer due to BRCA1 has a different natural history from BRCA2 or apparently sporadic disease, which may have implications for screening and management. #### Proliferative Breast Disease (PBD) In studies of 103 women from 20 kindreds that were selected for the presence of 2 first-degree relatives with breast cancer and of 31 control women, Skolnick et al. (1990) found, by 4-quadrant fine-needle breast aspirates, evidence of proliferative breast disease in 35% of clinically normal female first-degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggested that genetic susceptibility caused both PBD, a precursor lesion, and breast cancer in these kindreds. The study supported the hypothesis that this susceptibility is responsible for a considerable proportion of breast cancer, including unilateral and postmenopausal breast cancer. #### Ovarian Cancer Piver et al. (1993) presented data suggesting that mucinous carcinomas of the ovary may be underrepresented in familial ovarian cancer. Mutations in the BRCA1 gene account for most families with the hereditary breast-ovarian cancer syndrome. To address whether or not there is an association between the presence of a BRCA1 mutation and the subtype of epithelial ovarian carcinoma, Narod et al. (1994) reviewed the histology of 49 ovarian cancers seen in 16 hereditary breast-ovarian cancer families shown to be linked to BRCA1 markers. Of the 49 cancers, 5 (10.2%) were mucinous. By haplotype analysis with 17q markers, they determined the BRCA1 carrier status of 40 of the cases; 36 occurred in women who were BRCA1 mutation carriers and 4 were sporadic in that they occurred in noncarriers. Only 2 of the 36 ovarian cancers found in BRCA1 carriers were mucinous, compared with 3 or 4 mucinous carcinomas observed in BRCA1 noncarriers. The risk of ovarian cancer is reduced by 50% or more in unselected women with long-term use of oral contraceptives (Franceschi et al., 1991; Whittemore et al., 1992). To evaluate the potential benefit of oral contraceptive use in women at high risk for ovarian cancer, Narod et al. (1998) studied 207 patients with BRCA1 or BRCA2 mutations and ovarian cancer and 161 of their sisters, who served as controls. Their findings suggested that oral contraceptive use protects against ovarian cancer in carriers of either the BRCA1 or BRCA2 mutation. #### Papillary Serous Carcinoma of the Peritoneum (PSCP) Patients with germline BRCA1 mutations may develop papillary serous carcinoma of the peritoneum, a malignancy that diffusely involves peritoneal surfaces, sparing or only superficially involving the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oophorectomy. Schorge et al. (1998) used the androgen receptor (AR; 313700) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients with germline BRCA1 mutations develop multifocal PSCP. Specimens were studied from 22 women with PSCP. The AR gene locus was evaluated for patterns of loss of heterozygosity and X-chromosome inactivation. The methylation-sensitive HpaII restriction enzyme was used to differentiate the active and inactive X chromosomes. They found patterns of selective LOH at the AR locus in 5 (23%) of the 22 subjects, consistent with multifocal, polyclonal disease origin. Two patients with selective LOH also had alternating X-chromosome inactivation patterns. Patients with germline BRCA1 mutations were more likely to have evidence of multifocal disease. #### Prostate Cancer In Icelandic studies, Arason et al. (1993) suggested that male carriers of the BRCA1 gene may have an increased risk of prostate cancer. Langston et al. (1996) studied the BRCA1 gene in 61 men who met one or more of these criteria: (1) under 53 years of age at diagnosis of prostate cancer; (2) a family history of breast cancer in a first-degree female relative diagnosed under 51 years of age; or (3) a family history of prostate cancer in 2 or more male relatives, with at least 1 relative diagnosed at less than 56 years of age. They found 1 germline mutation, 185delAG (113705.0003), in 1 subject and 5 different rare sequence variants (1 of which was detected in 2 unrelated men). None of the rare variants were found in population-based controls. Isaacs et al. (1995) failed to identify a significantly increased risk of breast cancer among relatives of prostate cancer probands. The findings of Langston et al. (1996) are not necessarily in conflict, since the contribution of germline BRCA1 mutations to the overall incidence of prostate cancer appears to be small, at most, and may be limited to specific subgroups of patients. Nastiuk et al. (1999) set out to determine whether the common germline mutations of BRCA1 (113705.0003) or BRCA2 (600185.0009), which are frequent in the Ashkenazi Jewish population, predispose Ashkenazi Jewish men to prostate cancer. They found that each of these germline mutations occurred at an incidence in prostate cancer patients that closely matched that in the general Ashkenazi Jewish population. They suggested that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer. Vazina et al. (2000) also concluded that BRCA1 and BRCA2 germline mutations that are common in Jewish populations probably contribute little to the occurrence of cancer of the prostate, to inherited predisposition, or to early-onset disease in Jewish individuals. In 940 Ashkenazi Israelis with prostate cancer, Giusti et al. (2003) tested DNA obtained from paraffin sections for the 3 Jewish founder mutations: 185delAG (113705.0003) and 5382insC (113705.0018) in BRCA1 and 6174delT (600185.0009) in BRCA2. They estimated that there is a 2-fold increase in BRCA mutation-related prostate cancer among Ashkenazi Israelis. No differences were noted between the histopathologic features of cases with or without founder mutations, and no difference was found in the mean age at diagnosis between cases with or without a founder mutation. #### INHERITANCE The gene mapped by Hall et al. (1990) may be the same as that deduced by Claus et al. (1991). In a data-set based on 4,730 histologically confirmed breast cancer patients aged 20 to 54 years and on 4,688 controls, the latter group of workers presented evidence for the existence of a rare autosomal dominant allele (q = 0.0033) leading to increased susceptibility to breast cancer. The cumulative lifetime risk of breast cancer for women who carry the susceptibility allele was predicted to be approximately 92%, while the cumulative lifetime risk for noncarriers was estimated to be approximately 10%. Hall et al. (1992) indicated that the proportion of older-onset breast cancer attributable to BRCA1 was not yet determinable, because both inherited and sporadic cases occur in older-onset families. Rebbeck et al. (1996) performed specific studies of 23 families identified through 2 high-risk breast cancer research programs. In 14 (61%) it was possible to attribute the pattern of hereditary cancer to BRCA1 by a combination of linkage and mutation analyses. No families were attributed to BRCA2. In 5 families (22%), evidence against linkage to both BRCA1 and BRCA2 was found; no BRCA1 or BRCA2 mutations were detected in these 5 families. The BRCA1 or BRCA2 status of the 4 remaining families (17%) could not be determined. Ford et al. (1998) assessed the contribution of BRCA1 and BRCA2 to inherited breast cancer by linkage and mutation analysis in 237 families, each with at least 4 cases of breast cancer, collected by the Breast Cancer Linkage Consortium. Families were included without regard to the occurrence of ovarian or other cancers. Overall, disease was linked to BRCA1 in an estimated 52% of families, to BRCA2 in 32% of families, and to neither gene in 16%, suggesting other predisposition genes. The majority (81%) of the breast-ovarian cancer families were due to BRCA1, with most others (14%) due to BRCA2. Conversely, the majority (76%) of families with both male and female breast cancer were due to BRCA2. The largest proportion (67%) of families due to other genes were families with 4 or 5 cases of female breast cancer only. Among those families with disease due to BRCA1 that were tested by one of the standard screening methods, mutations were detected in the coding sequence or splice sites in an estimated 63%. The estimated sensitivity was identical for direct sequencing and other techniques. #### Genetic Counseling Lynch and Watson (1992) reported the first experience with genetic counseling and targeted management of patients demonstrated to be at risk for hereditary breast-ovarian cancer by use of multipoint linkage analysis in the largest and most informative of the kindreds studied to date. The single family provided a lod score of 3.03. In those persons shown by linkage to be at risk, they recommended completing their families before the age of 35 so that prophylactic oophorectomy could be performed at an early age. Cornelis et al. (1995) proposed that, during an interim period, BRCA1 mutation testing be offered only to families with a strong positive family history for early-onset breast and/or ovarian cancer. Friedman et al. (1998) suggested that identification of additional carriers of more than one mutation will increase our understanding between various mutations and will improve genetic counseling. Meijers-Heijboer et al. (2000) studied a large cohort of Dutch individuals at 50% or 25% risk of BRCA1 or BRCA2 mutation. Presymptomatic DNA testing was requested by 48% (198 of 411) of women and 22% (59 of 271) of men. In women, DNA testing was significantly more frequent at young age, in the presence of children, and at high pretest genetic risk for a mutation. Of the unaffected women with an identified mutation who were eligible for prophylactic surgery, 51% (35 of 68) opted for bilateral mastectomy and 64% (29 of 45) for oophorectomy. Age was significantly associated with prophylactic oophorectomy, but not with prophylactic mastectomy, although there was a tendency toward mastectomy at younger ages. Watson et al. (2003) studied the change in distribution of carrier risk status resulting from molecular testing in 75 families with hereditary breast-ovarian cancer and 47 families with hereditary nonpolyposis colorectal cancer (HNPCC; 120435). Carrier risk status changes from uncertainty to certainty (i.e., to carrier or to noncarrier) accounted for 89% of risk changes resulting from testing. These risk changes affect cancer prevention recommendations, most commonly reducing their burden. Watson et al. (2003) found that 60% of persons with a carrier risk status change were not themselves tested; their risk status changed because of a relative's test result. They noted that practices in use at the time did not ensure that untested family members were informed about changes in their carrier risk status resulting from mutation testing of their relatives. #### Loss of Heterozygosity If the gene predisposing to breast cancer (and ovarian cancer) mapped to 17q12-q21 is a tumor suppressor gene, one would expect, based on the Knudson hypothesis, that tumors from affected family members would show loss of heterozygosity (LOH) affecting the wildtype chromosome. In 4 multiple case breast-ovarian cancer families, Smith et al. (1992) indeed found that in each of 9 tumors that showed allele loss, the losses were from the wildtype chromosome. Kelsell et al. (1993) found the same for each of 7 breast tumors from a single multi-affected breast/ovarian cancer pedigree. In the same family, they generated linkage data which, in combination with previously published information, suggested that the BRCA1 gene is contained in a region estimated to be 1 to 1.5 Mb long. #### CLINICAL MANAGEMENT Meijers-Heijboer et al. (2001) conducted a prospective study of 139 women with pathogenic BRCA1 or BRCA2 mutations without a history of breast cancer; 76 underwent prophylactic mastectomy and 63 remained under regular surveillance. They found that prophylactic bilateral total mastectomy reduced the incidence of breast cancer at 3 years of follow-up. Eisen and Weber (2001) stated that prophylactic mastectomy is 'clearly the right choice for some women. For the remainder, oophorectomy and tamoxifen in conjunction with intensive screening that includes breast MRI is a viable alternative.' They noted the need for underlying and novel prospective studies to define the role of prophylactic surgery, new chemopreventive agents, and optimal screening strategies. Kauff et al. (2002) and Rebbeck et al. (2002) reported the results of studies indicating that prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer. In the study of Kauff et al. (2002), of 98 women who had salpingo-oophorectomy, 3 developed breast cancer and 1 developed peritoneal cancer. Among the 72 women who chose surveillance alone, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. In the study of Rebbeck et al. (2002), 6 of 259 women who underwent prophylactic oophorectomy (2.3%) received a diagnosis of stage I ovarian cancer at the time of the procedure; 2 women (0.8%) received a diagnosis of papillary serous peritoneal carcinoma 3.8 and 8.6 years after bilateral prophylactic oophorectomy. Among the controls, 58 women (19.9%) received a diagnosis of ovarian cancer, after a mean follow-up of 8.8 years. With the exclusion of the 6 women whose cancer was diagnosed at surgery, prophylactic oophorectomy significantly reduced the risk of coelomic epithelial cancer. #### POPULATION GENETICS In an editorial, Goldgar and Reilly (1995) raised the possibility that a high frequency of mortality from breast cancer in Nassau County, New York, in the previous 2 decades might be related to the high proportion of Ashkenazim (roughly 16%) in that population; the pathogenetic collaboration of exposure to an environmental pollutant was also raised. Ethical, legal, and social issues raised by these findings were also discussed by Goldgar and Reilly (1995). In a study of 37 families with 4 or more cases of breast cancer or breast and ovarian cancer, Friedman et al. (1995) found that 5 families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at 8 polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied from early-onset bilateral breast cancer and ovarian cancer to late-onset breast cancer without ovarian cancer. Overall, BRCA1 mutations were detected in 26 of the families: 16 with positive BRCA1 linkage lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Among 5,318 Jewish subjects, Struewing et al. (1997) found 120 carriers of a BRCA1 or BRCA2 mutation. The BRCA1 mutations studied were 185delAG (113705.0003) and 5382insC (113705.0018); the BRCA2 mutation studied was 6174delT (600185.0009). By the age of 70, the estimated risk of breast cancer among carriers was 56%; of ovarian cancer, 16%; and of prostate cancer, 16%. There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. They concluded that over 2% of Ashkenazi Jews carried mutations in BRCA1 or BRCA2 that conferred increased risks of breast, ovarian, and prostate cancer. Krainer et al. (1997) found definite BRCA2 mutations in 2 of 73 women with early onset (by age 32) breast cancer, suggesting that BRCA2 is associated with fewer cases than BRCA1 (P = 0.03). In a series of 268 Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset, Fodor et al. (1998) determined the frequency of the common BRCA1 and BRCA2 mutations: 185delAG (113705.0003), 5382insC (113705.0018), and 6174delT (600185.0009). DNA was analyzed for the 3 mutations by allele-specific oligonucleotide (ASO) hybridization. Eight patients (3%) were heterozygous for the 185delAG mutation, 2 (0.75%) for the 5382insC mutation, and 8 (3%) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was estimated to be 36%, approximately 3 times the overall risk for the general population (relative risk 2.9). The results differed markedly from previous estimates based on high-risk breast cancer families. In Australia, Bahar et al. (2001) found in Ashkenazi Jews the same high prevalence of 4 founder mutations as found in Ashkenazi Jews in the United States and Israel. The 4 mutations analyzed were 185delAG and 5382insC in BRCA1; 6174delT in BRCA2; and I1307K (175100.0029) in APC. In a population-based series of 54 breast cancer cases from southern California, Friedman et al. (1997) found no instance of germline mutation in the BRCA1 gene but found 2 male breast cancer patients who carried novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, namely, ovarian cancer in a first-degree relative. Hamann et al. (1997) studied 45 German breast/ovarian cancer families for germline mutations in the BRCA1 gene. They identified 4 germline mutations in 3 breast cancer families and in 1 breast/ovarian cancer family. One of these, a missense mutation, was also found in 2.8% of the general population, suggesting that this was not disease associated. Hamann et al. (1997) concluded that the low incidence of BRCA1 germline mutations in these families suggests the involvement of other susceptibility genes. In addition to the deletion mutations in BRCA1 and BRCA2 genes that appear to be highly penetrant in the causation of young onset breast cancer and ovarian cancer, there are several common polymorphisms in the BRCA1 gene that generate amino acid substitutions. Dunning et al. (1997) raised the question whether these common variants may confer more modest individual risks which might, however, be of significance. They examined the frequency of 4 of these polymorphisms in a large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, the 4 sites generated only 3 haplotypes with a frequency more than 1.3%. The 2 most common haplotypes had frequencies of 0.57 and 0.32, respectively, and these frequencies did not differ significantly between patient and control groups. Thus, Dunning et al. (1997) concluded that the most common polymorphisms of BRAC1 gene do not make a significant contribution to breast or ovarian cancer risk. However, the data suggested that the arg356 allele may have a different genotype distribution in breast cancer patients than that in controls; arg356 homozygotes were more frequent in the control group (P = 0.01), indicating that it may be protective against breast cancer. Szabo and King (1997) collated information on the population genetics of BRCA1 and BRCA2 in populations from many countries of Europe as well as the U.S., Canada, and Japan. Tonin et al. (1998) noted that 4 mutations in BRCA1 and 4 mutations in BRCA2 had been identified in French-Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, they examined independently ascertained French-Canadian cancer families for the distribution of these 8 mutations. Mutations were found in 41 of 97 families. Six of 8 mutations were observed at least twice. The 4446C-T mutation (arg1443 to ter; 113705.0016) was the most common mutation found, followed by the BRCA2 8765delAG mutation (600185.0012). Together, these mutations were found in 28 of 41 families identified as having the mutation. The odds of detection of any of the 4 BRCA1 mutations was 18.7 times greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the 4 BRCA2 mutations was 5.3 times greater if there were at least 5 cases of breast cancer in the family. Interestingly, the presence of a breast cancer case less than 36 years of age was strongly predictive of the presence of any of the 8 mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations could facilitate carrier detection in French-Canadian breast cancer and breast/ovarian cancer families. Using a comprehensive screen of the entire BRCA1 coding region, Janezic et al. (1999) determined the prevalence of BRCA1 alterations in a population-based series of 107 consecutive ovarian cancer cases diagnosed in Orange County, California, between March 1, 1994 and February 28, 1995. The participation rate was 82%. BRCA1 alterations were sought using the RNase mismatch cleavage assay followed by direct sequencing. Two truncating mutations, 962del4 (113705.0024) and 3600del11 (113705.0025), were identified. Both patients had a family history of breast or ovarian cancer. Several novel as well as previously reported uncharacterized variants were also identified, some of which were associated with a family history of cancer. Using allele-specific amplification, Janezic et al. (1999) determined the frequency distribution of common polymorphisms in the 91 Caucasian cancer cases in this series and 24 sister controls. The rare form of the Q356R polymorphism was significantly (P = 0.03) associated with a family history of ovarian cancer, suggesting that this polymorphism may influence ovarian cancer risk. Gorski et al. (2000) studied 66 Polish families in each of which at least 3 related females had breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50 years. A total of 26 families had both breast and ovarian cancers, 4 had ovarian cancers only, and 36 families had breast cancers only. Using SSCP followed by direct sequencing of observed variants, they screened the entire coding region of BRCA1 and BRCA2 for germline mutations. Mutations were found in 35 (53%) of the 66 families. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all 4 families with ovarian cancer only, and 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; 5 of these occurred in 2 or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Gorski et al. (2000) found that 3 BRCA1 abnormalities, 5382insC (113705.0018), cys61 to gly (113705.0002), and 4153delA (113705.0030), accounted for 51%, 20%, and 11% of the identified mutations, respectively. Sarantaus et al. (2001) studied 233 unselected Finnish ovarian carcinoma patients treated at the Helsinki University Central Hospital during the years 1989 to 1998. The patients were screened for 12 BRCA1 and 8 BRCA2 mutations identified previously in the Finnish population. Germline mutations of BRCA1/BRCA2 were detected in 13 of the patients (11 in BRCA1 and 2 in BRCA2) and 7 recurrent founder mutations accounted for 12 of the 13 mutations detected. All mutation-positive patients but one had serous or poorly differentiated carcinoma. The presence of breast and ovarian cancer in the same woman and/or early onset (under 50 years of age) breast cancer was characteristic of the majority (77%) of the mutation carriers. The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution of genetic factors to these high rates, Liede et al. (2002) conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from 2 major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7%, and that among case subjects with ovarian cancer was 15.8%. Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. Most of the detected mutations were unique to Pakistan. Five BRCA1 mutations and 1 BRCA2 mutation were found in multiple case subjects and may represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 was comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1 mutation-positive case subjects was 48%, and it was 37% for first-degree relatives of the BRCA2 mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio = 2.1). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age less than 40 years) (odds ratio = 2.7) and case subjects with ovarian cancer (odds ratio = 2.4). These results suggested that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan. King et al. (2003) determined the risks of breast and ovarian cancer for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. They selected 1,008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appeared to be increasing with time: breast cancer risk by age 50 years among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset. Easton et al. (2004) and Wacholder et al. (2004) disputed the conclusions of the report by King et al. (2003) estimating a breast cancer risk by age 70 to be 71%, irrespective of mutation. Both groups suggested bias of ascertainment. King (2004) rebutted these comments, suggesting that their penetrance estimates, at least to age 60, were comparable to those of other reported studies and that only the risk above age 70 was higher in their study, which may reflect a small sample size in that age group. #### MAPPING Albertsen et al. (1994) used simple sequence repeat (SSR) markers to construct a high-resolution genetic map of a 40-cM region around 17q21. For 5 of the markers, genotypes were 'captured' by using an ABI sequencing instrument and stored in a locally developed database as a step toward automated genotyping. In a second report, Albertsen et al. (1994) described construction of a physical map of a 4-cM region containing the BRCA1 gene. The map comprised a contig of 137 overlapping YACs and P1 clones, onto which they had placed 112 PCR markers. They localized more than 20 genes on the map, 10 of which had not been mapped to the region previously, and isolated 30 cDNA clones representing partial sequences of as yet unidentified genes. They failed to find any deleterious mutations on sequencing of 2 genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients. O'Connell et al. (1994) developed a radiation hybrid map of the BRCA1 region as the basis of YAC cloning and pulsed field gel electrophoretic mapping of the candidate region for the BRCA1 gene. Miki et al. (1994) identified a strong candidate for the BRCA1 gene by positional cloning methods. Probable predisposing mutations were detected in 5 of 8 kindreds thought to segregate BRCA1 susceptibility alleles. The mutations included an 11-bp deletion, a 1-bp insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1,863 amino acids. The protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Futreal et al. (1994) extended the observations to studies of primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all 4 mutations were germline alterations and occurred in cancers of early-onset type. These results were interpreted as indicating that mutation in the BRCA1 gene may not be critical to the development of most breast and ovarian cancers that arise in the absence of a mutant germline allele. This situation is unlike that in the APC gene (175100), which is involved in both hereditary polyposis coli and sporadic colorectal cancer, and that of some other genes involved in both familial and sporadic cancer. Bennett et al. (1995) found that the mouse Brca1 gene shares 75% identity of the coding region with the human sequence at the nucleotide level, whereas the predicted amino acid identity was only 58%. By an intersubspecific backcross using a DNA sequence variant in the Brca1 locus, they mapped the gene to distal mouse chromosome 11 in a region of extensive homology of synteny to human chromosome 17. Schrock et al. (1996) likewise mapped the Brca1 gene to mouse chromosome 11, specifically 11D. De Gregorio et al. (1996) also mapped the gene to mouse chromosome 11. #### Linkage Hall et al. (1990) studied 23 extended families with 146 cases of breast cancer. All were Caucasian and came from a variety of ancestries. The 329 participating relatives lived in 40 states of the United States, Puerto Rico, Canada, the United Kingdom, and Colombia. The families shared the epidemiologic features characteristic of familial, versus sporadic, breast cancer: younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men. Hall et al. (1990) found a lod score of 5.98 for linkage of breast cancer susceptibility in early-onset families to D17S74, which is located in band 17q21. Negative lod scores were found in families with late-onset disease. Likelihood ratios in favor of linkage heterogeneity among families ranged from 2000:1 to greater than 10(6):1 on the basis of multipoint analysis of 4 loci in the region of 17q21. Candidate genes in the region include HER2 (164870), which is thought to be identical to ERBB2; estradiol-17-beta-dehydrogenase (109684); a cluster of homeobox-2 genes (e.g., 142960); retinoic acid receptor alpha (180240); and INT4 (165330). Linkage analyses in studies of 103 women from 20 kindreds failed to show linkage with D17S74 in either early- or late-age onset Skolnick et al. (1990). Narod et al. (1991) investigated 5 large families with a hereditary predisposition to cancer of the breast and ovary. Three families showed linkage with the D17S74 marker used by Hall et al. (1990). For the largest family the lod score was 2.72 at a recombination fraction of 0.07. Narod et al. (1991) suggested that about 60% of breast cancer families have linkage of the susceptibility to the chromosome 17q locus. Lynch and Watson (1992) reported extension of the linkage work to 19 families, most of which showed the hereditary breast-ovarian cancer syndrome. In 70% of families, linkage to 17q was demonstrated. Hall et al. (1992) found that the most closely linked marker in their repertoire was D17S579, a highly informative CA repeat polymorphism located at 17q21. There were no recombinants with inherited breast or ovarian cancer in 79 informative meioses in the 7 families with early-onset disease; lod score = 9.12 at 0 recombination. Goldgar et al. (1992) identified a Utah kindred in which the BRCA1 locus was linked to 17q markers with odds in excess of a million to one. The kindred included 170 descendents of 2 Utah pioneers of 1847, containing a total of 24 cancer cases (16 breast, 8 ovarian). The median age of onset was 48 for breast cancer and 53 for ovarian cancer. The penetrance of the BRCA1 gene was estimated to be 0.92 by age 70. Easton et al. (1993) reported the results of genetic linkage analysis in 214 families. In 15 accompanying papers, confirmatory evidence on the linkage was reported from Icelandic, Scottish, Dutch, Swedish, and other families including one African-American family. Because of the finding of genetic recombination between the BRCA1 locus and the gene for retinoic acid receptor alpha (180240), Simard et al. (1993) was able to exclude that candidate gene. BRCA1 and the gene for estradiol 17-beta-hydroxysteroid dehydrogenase II (109685) map to a 6-cM interval (between THRA1 and D17S579) and no recombination was observed between the 2 genes; however, direct sequencing of overlapping PCR products containing the entire EDH17B2 gene in 4 unrelated affected woman did not uncover any sequence variation other than previously described polymorphisms. They concluded, therefore, that mutations in the EDH17B2 gene are probably not responsible for hereditary breast-ovarian cancer syndrome. Kelsell et al. (1993) sequenced the two 17-beta-estradiol dehydrogenase genes (EDH17B1, EDH17B2), which had been suggested as candidate genes for BRCA1, in 4 members of the same family; no germline mutations were detected. (Actually, the EDH17B1 and EDH17B2 genes appear to map proximal to the BRCA1 locus.) Cornelis et al. (1995) sought criteria that would identify breast cancer families with a high prior probability that the tumors were caused by a BRCA1 mutation. They performed a linkage study in 59 consecutively collected Dutch breast cancer families, including 16 families with at least 1 case of ovarian cancer. They used a family intake cutoff of at least 3 first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Tonin et al. (1995) studied 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking BRCA1. Of the 15 families that contained cases of ovarian cancer, 94% were estimated to be linked to BRCA1. In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer. Stratton et al. (1994) examined 22 families with at least 1 case of male breast cancer for linkage to the BRCA1 locus. They found strong evidence against linkage to BRCA1 (lod score, -16.63) and the best estimate of the proportion of linked families was 0% (95% confidence interval, 0-18%). Narod et al. (1995) reported the results of linkage analysis of 145 breast-ovarian families, each of which had 3 or more cases of early-onset breast cancer (age less than 60) or of ovarian cancer. All families had at least 1 case of ovarian cancer (there were 9 site-specific ovarian cancer families). Overall, they estimated that 76% of families were linked to the BRCA1 locus. At that time, the group stated that none of the 13 families with cases of male breast cancer appeared to be linked to BRCA1. In their letter, Narod et al. (1995) summarized their updated findings and reported a family with male breast cancer that showed a mutation (113705.0003) in BRCA1; Struewing et al. (1995) had also reported such a family. Their final results indicated that BRCA1 and BRCA2 account for the most breast-ovarian cancer families. Although a third breast cancer locus may be found, Narod et al. (1995) felt it unlikely that it would account for a significant proportion of breast-ovarian cancer families. Nathanson et al. (2002) used nonparametric linkage analysis to determine whether allele sharing of chromosomes 4p, 4q, and 5q was observed preferentially within 16 BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, the authors observed a significant linkage signal at D5S1471 on chromosome 5q (P = 0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P = 0.003). The authors suggested that 1 or more genes on chromosome 5q33-q34 modify breast cancer risk in BRCA1 mutation carriers. #### Linkage Heterogeneity Margaritte et al. (1992) found that when account is made for the higher relative probability of sporadic rather than inherited disease for late-onset cases of breast cancer, later-onset families are much less informative and linkage heterogeneity based on age at onset is no longer significant. Furthermore, for the sample of families as a whole, linkage is significant at a recombination fraction in the 17q21 region. Although there is probably more than one gene for inherited breast cancer, age at onset may not be a reflection of this heterogeneity. Sobol et al. (1992) also pointed to genetic heterogeneity of early-onset familial breast cancer; in an extensively affected family they found no evidence of linkage to markers on 17q. #### MOLECULAR GENETICS Using single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA in an analysis of 50 probands with a family history of breast and/or ovarian cancer, Castilla et al. (1994) found 8 putative disease-causing alterations: 4 frameshift mutations, 2 nonsense mutations, and 2 missense mutations. The data were considered consistent with a tumor suppressor model. The heterogeneity of mutations, coupled with the large size of the gene, indicated that clinical application of BRCA1 mutation testing would be technically challenging. Simard et al. (1994) identified mutations in the BRCA1 gene in 12 of 30 Canadian families. Six frameshift mutations accounted for all 12 mutant alleles, including nucleotide insertions (2 mutations) and deletions (4 mutations). The same 1-bp insertion mutation in codon 1,755 was found in 4 independent families, whereas 4 other families shared a 2-bp deletion mutation in codons 22 to 23. These families were not known to be related, but haplotype analysis suggested that the carriers of each of these mutations had common ancestors. Friedman et al. (1994) likewise used SSCP analysis and direct sequencing to identify 9 different mutations in 10 families. The mutations in 7 instances led to protein truncation at sites throughout the gene. A missense mutation, which occurred independently in 2 families, led to loss of a cysteine in the zinc-binding domain. An intronic single basepair substitution destroyed an acceptor site and activated a cryptic splice site, leading to a 59-bp insertion and chain termination. In 4 families with both breast and ovarian cancer, chain termination mutations were found in the N-terminal half of the protein. In 4 of 47 sporadic ovarian cancers, Merajver et al. (1995) examined tumor DNAs by SSCP and found 4 somatic mutations in the BRCA1 gene; all 4 had loss of heterozygosity at a BRCA1 intragenic marker. The findings supported a tumor-suppressor mechanism for BRCA1; somatic mutation on one chromosome and LOH on the other may result in inactivation of BRCA1 in some sporadic ovarian cancers. Since more than 75% of the reported mutations in the BRCA1 gene result in truncated proteins, Hogervorst et al. (1995) used the protein truncation test (PTT) to screen for mutations in exon 11 which encodes 61% of the BRCA1 protein. In 45 patients from breast and/or ovarian cancer families, they found 6 novel mutations: 2 single nucleotide insertions, 3 small deletions (of 1-5 bp), and a nonsense mutation identified in 2 unrelated families. Furthermore, they were able to amplify the remaining coding region by RT-PCR using lymphocyte RNA. Combined with the protein truncation test, they detected aberrantly spliced products affecting exons 5 and 6 in 1 of 2 BRCA1-linked families examined. Struewing et al. (1995) stated that more than 50 unique mutations had been detected in the BRCA1 gene in the germline of individuals with breast and ovarian cancer. In high-risk pedigrees, female carriers of a BRCA1 mutation had an 80 to 90% lifetime risk of breast cancer and a 40 to 50% risk of ovarian cancer. Not known, however, was the mutation status of women unselected for breast or ovarian cancer, and it was not known whether mutations in such women confer the same risk of cancer as in women from the high-risk families. Following the finding of a 185delAG frameshift mutation (113705.0003) in several Ashkenazi Jewish breast/ovarian families, Struewing et al. (1995) determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference persons not selected for ethnic origin. They found the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4%-1.8%) and in none of the reference samples. The results suggested that 1 in 100 women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer. Couch et al. (1997) identified BRCA1 mutations in 16% of women with a family history of breast cancer. Only 76% of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. They concluded that even in a referral clinic specializing in screening women from high risk families, most tests for BRCA1 mutations will be negative and, therefore, uninformative. Serova et al. (1996) analyzed 20 breast-ovarian cancer families, most of which showed evidence of linkage to 17q12, for germline mutations in BRCA1. Mutations in this gene cosegregating with breast and ovarian cancer susceptibility were identified in 16 of the 20 families, including 1 family with a case of male breast cancer. Nine of these mutations had not been reported previously. Most of them generated a premature stop codon leading to the formation of a truncated BRCA1 protein of 2 to 88% of the expected normal length. The RING-finger domain was altered by 2 of the mutations. A reduced quantity of BRCA1 transcript was associated with 8 of the mutations. Of the 4 families with no detectable BRCA1 mutation, only 1 was clearly linked to the BRCA1 locus. Lorick et al. (1999) showed that similar to other RING finger proteins, the N-terminal 788 amino acids of BRCA1 expressed as a GST fusion protein facilitated E2-dependent ubiquitination. The authors noted that RING mutations in BRCA1 are associated with familial carcinomas. Langston et al. (1996) found germline BRCA1 mutations in 6 of 80 women in whom breast cancer was diagnosed before the age of 35 and who were not selected on the basis of family history. Four additional rare sequence variants of unknown functional significance were also identified. Two of the mutations and 3 of the rare sequence variants were found among the 39 women who reported no family history of breast or ovarian cancer. None of the mutations and only 1 of the rare variants was identified in a reference population of 73 unrelated subjects. Similar results were found by FitzGerald et al., 1996 in a study of 30 women with breast cancer before the age of 30: 4 (13%) had chain-terminating mutations and 1 had a missense mutation. The 185delAG mutation (113705.0003) was found in 2 of the 4 Jewish women in this cohort. Among the 39 Jewish women with breast cancer before the age of 40, FitzGerald et al. (1996) found that 8 (21%) carried the 185delAG mutation (95% confidence interval, 9-36%). FitzGerald et al. (1996) concluded that germline BRCA1 mutations can be present in young women with breast cancer who do not belong to families with multiple affected members. Women who carry a mutation in the BRCA1 gene have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 years. Phelan et al. (1996) demonstrated that a modifier of this risk is the HRAS1 (190020) variable number of tandem repeats (VNTR) polymorphism, located 1 kb downstream of the HRAS1 oncogene. Individuals who have rare alleles of this VNTR had been found to have an increased risk of certain types of cancer, including breast cancer. Phelan et al. (1996) claimed that this was the first study to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome. Johannsson et al. (1996) identified 9 different germline mutations in the BRCA1 gene in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations were predicted to give rise to premature translation termination and included 7 frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation was a missense mutation (cys61-to-gly) in the zinc-binding motif. They also identified 4 novel Swedish founding mutations: deletion of 2595A in 5 families, the C-to-T nonsense mutation of nt1806 in 3 families, the insertion of TGAGA after nt3166 in 3 families, and the deletion of 11 nucleotides after nt1201 in 2 families. Analysis of the intragenic polymorphism D17S855 supported common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of which had a predominant ovarian cancer phenotype. Among the 32 families in which no BRCA1 alteration was detected, there was 1 breast-ovarian cancer kindred showing clear linkage to the BRCA1 region and loss of the wildtype chromosome in associated tumors. Other tumor types found in BRCA1 mutation or haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of the 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families. Gayther et al. (1996) stated that more than 65 distinct mutations scattered throughout the coding region of BRCA1 had been detected. Couch et al. (1996) reported a total of 254 BRCA1 mutations, 132 (52%) of which were unique. These represented mutations entered into a database established by the Breast Cancer Information Core (BIC). A total of 221 (87%) of all mutations or 107 (81%) of the unique mutations are small deletions, insertions, nonsense point mutations, splice variants, and regulatory mutations that result in truncation or absence of the BRCA1 protein. A total of 11 disease-associated missense mutations (5 unique) and 21 variants (19 unique) as yet unclassified as missense mutations or polymorphisms had been detected. Thirty-five independent benign polymorphisms had been described. The most common mutations were 185delAG (113705.0003) and 5382insC (113705.0018), which accounted for 30 (11.7%) and 26 (10.1%), respectively, of all the mutations. Stoppa-Lyonnet et al. (1996) described 2 independent BRCA1 mutations in a single family. A woman with breast cancer diagnosed at age 25 inherited a deleterious allele from her father. Her mother had ovarian and breast cancer caused by a separate mutation, which was the basis of breast cancer in 5 or more of her relatives. The authors pointed out that the segregation of 2 BRCA1 mutations resulted in the failure to demonstrate linkage to either chromosome 17 or chromosome 13 and could leads to the erroneous hypothesis of the involvement of a third locus in familial breast cancer. Narod et al. (1995) suggested that the fraction of familial breast cancer that is not accounted for by BRCA1 or BRCA2 may be small. Brown et al. (1996) determined the detailed structure of the BRCA1 genomic region. They showed that this region of chromosome 17 contains a tandem duplication of approximately 30 kb which results in 2 copies of BRCA1 exons 1 and 2, of exons 1 and 3 of the adjacent gene that Brown et al. (1994) designated 1A1-3B (M17S2; 166945), and of a previously reported 295-bp intergenic region. Sequence analysis of the duplicated exons of BRCA1, 1A1-3B, and flanking genomic DNA revealed to Brown et al. (1996) that there was maintenance of exon/intron structure and a high degree of nucleotide sequence identity, which suggested that these duplicated exons are nonprocessed pseudogenes. They noted that these findings could not only confound BRCA1 mutation analysis but have implications for the normal and abnormal regulation of BRCA1 transcription, translation, and function. Although many distinct mutations were identified in the breast-ovarian cancer susceptibility gene BRCA1 with loss of the wildtype allele in more than 90% of tumors from patients with inherited BRCA1 mutation, a very low incidence of somatic mutations were found in sporadic tumors, suggesting the BRCA1 inactivation occurs by alternative mechanisms, such as interstitial chromosomal deletion or reduced transcription. To identify possible features of the BRCA1 genomic region that may contribute to chromosomal instability, as well as potential transcriptional regulatory elements, Smith et al. (1996) sequenced 117,143 bp from human chromosome 17 encompassing BRCA1. The 24 exons of BRCA1 spanned an 81-kb region that had an unusually high density of Alu repetitive DNA (41.5%), but a relatively low density (4.8%) of other repetitive sequences. BRCA1 intron lengths ranged in size from 403 bp to 9.2 kb and contained 3 intragenic microsatellite markers located in introns 12, 19, and 20. In addition to BRCA1, the contig contained 2 complete genes which they called RHO7 (601555) and VAT1. RHO7 is a member of the RHO family of GTP binding proteins and VAT1 is an abundant membrane protein of cholinergic synaptic vesicles. The order of genes on the chromosome was found to be as follows: centromere-IFP35 (600735)-VAT1-RHO7-BRCA1-M17S2-telomere. In a screening of Hungarian breast/ovarian cancer families for germline mutations in BRCA1 and BRCA2, Ramus et al. (1997) found 1 individual who carried the 185delAG mutation (113705.0003) in BRCA1, as well as the 6174delT mutation (600185.0009) in BRCA2. Each mutation had been shown to have a frequency of approximately 1% in the Ashkenazi Jewish population. Although the patient was not recorded as having a Jewish origin, haplotype analysis suggested that both mutations were of the Ashkenazi type. There was a maternal family history of breast cancer and the paternal family history was unknown. The patient was found to have breast cancer at age 48 and ovarian cancer at age 50 years. The ages at diagnosis and the tumor types were not different from those of patients with either BRCA1 or BRCA2 mutations. Both mutations were present in 3 different samples from the patient: breast tumor, ovarian tumor, and lymphocyte DNA. There was no evidence of loss of heterozygosity on either chromosome 13 or chromosome 17. Liede et al. (1998) found mutations of both BRCA1 and BRCA2 in a breast cancer patient of Scottish descent. Grade II adenocarcinoma of the breast was diagnosed at the age of 35 years. Simultaneous screening by protein truncation tests of both BRCA genes detected a 2508G-T mutation of the BRCA1 gene (113705.0023) and a 3295insA mutation of BRCA2 (600185.0011). The patient had both a maternal and a paternal history of breast cancer. The maternal side contained cases of postmenopausal breast cancer; the paternal side contained cases of premenopausal breast cancer. The mother, however, did not have either mutation, suggesting that both BRCA1 and BRCA2 germline mutations originated from the father of the proband. Three Jewish founder mutations, 185delAG (113705.0003) and 5382insC (113705.0018) in BRCA1 and 6174delT (600185.0009) in BRCA2, have been identified in breast cancer and ovarian cancer Ashkenazi patients. Friedman et al. (1998) pooled results from 4 cancer/genetic centers in Israel to analyze approximately 1,500 breast-ovarian cancer Ashkenazi patients for the presence of double heterozygosity as well as homozygosity for any of these mutations. Although the small number of cases precluded definite conclusions, the results suggested that the phenotypic effects of double heterozygosity for BRCA1 and BRCA2 germline mutations were not cumulative. This was in agreement with the observation that the phenotype of mice that are homozygous knockouts for the BRCA1 and BRCA2 genes is similar to that of mice that were BRCA1 knockouts. This suggests that the BRCA1 mutation is epistatic over the BRCA2 mutation. Two of the double heterozygotes described had had reproductive problems: one with primary sterility and irregular menses and another with premature menopause at the age of 37 years. In a study of 515 women with invasive ovarian cancer in Ontario, Canada, Risch et al. (2001) found 39 mutations in the BRCA1 gene and 21 in the BRCA2 gene, for a total mutation frequency of 11.7%. Hereditary ovarian cancers diagnosed at less than 50 years of age were mostly (83%) due to BRCA1, whereas the majority (60%) of those diagnosed at more than 60 years of age were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5-prime fifth, but 8.8-fold increased risk for mutations in the 3-prime fifth, corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer-cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Risch et al. (2001) suggested that the trend in breast cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have an impact on management decisions for carriers of BRCA1 mutations. Vallon-Christersson et al. (2001) characterized the effect of C-terminal germline variants identified in Scandinavian breast and ovarian cancer families. Seven familial missense mutations, a truncating mutation, 4 missense variants, and 1 in-frame deletion were studied using 2 separate reporter genes. The authors concluded that transactivation activity may reflect a tumor-suppressing function of BRCA1 and further support the role of BRCA1 missense mutations in disease predisposition. A discrepancy was noted between results from yeast- and mammalian-based assays, indicating that it may not be possible to unambiguously characterize variants with the yeast assay alone. Perrin-Vidoz et al. (2002) assessed the relative amount of transcripts encoded by BRCA1 alleles harboring 30 different truncating mutations in lymphoblastoid cell lines established from carriers from breast/ovarian cancer families. The authors observed that nonsense-mediated decay (NMD) was triggered by 80% of alleles containing a premature termination codon (PTC) and resulted in a 1.5- to 5-fold reduction in mRNA abundance. All truncating mutations located in the 3.4-kb long central exon were subject to NMD, irrespective of their distance to the downstream exon-exon junction. PTCs not leading to NMD were either located in the last exon or very close to the translation initiation codon. Perrin-Vidoz et al. (2002) hypothesized that reinitiation could explain why transcripts carrying early PTCs escape NMD. #### Mutation Detection Methodology Hacia et al. (1996) noted that all of the current methods used to detect BRCA1 mutations begin with PCR amplification and require gel electrophoresis, which seriously complicates the challenge of scale-up, automation, and cost reduction. They demonstrated the feasibility of using oligonucleotide arrays in a DNA chip-based assay to screen for a wide range of heterozygous mutations in the 3.45-kb exon 11 of the BRCA1 gene. They concluded that DNA chip-based assays provided a valuable new technology for high throughput, cost-efficient detection of genetic alterations. The detection of inactivating mutations in tumor suppressor genes is critical to their characterization, as well as to the development of diagnostic testing. Most approaches for mutational screening of germline specimens are complicated by the fact that mutations are heterozygous and that missense mutations are difficult to interpret in the absence of information about protein function. Ishioka et al. (1997) described a novel method using Saccharomyces cerevisiae for detecting protein-truncating mutations in any gene of interest. In their procedure, the PCR-amplified coding sequence of the gene is inserted by homologous recombination into a yeast URA3 fusion protein, and transformants are assayed for growth in the absence of uracil. The high efficiency of homologous recombination in yeast ensures that both alleles are represented among transformants and achieves separation of alleles, which facilitates subsequent nucleotide sequencing of the mutated transcript. The specificity of translational initiation of the URA3 gene lead to minimal enzymatic activity in transformants harboring an inserted stop codon, and hence to reliable distinction between specimens with wildtype alleles and those with a heterozygous truncating mutation. This yeast-based codon assay accurately detected heterozygous truncating mutations in the BRCA1 gene in patients with early onset of breast cancer and in the APC gene (175100) in patients with familial adenomatous polyposis. Petrij-Bosch et al. (1997) reported that the mutation spectrum of BRCA1 available at that time had been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PPT), and direct sequencing, using genomic DNA as template. Three large genomic deletions that were not detectable by those approaches comprised 36% of all BRCA1 mutations found in Dutch breast cancer families up to that time. A 510-bp Alu-mediated deletion comprising exon 22 was found in 8 of 170 breast cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counseling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 6 of the 170 research families, while a deletion of approximately 14 kb was detected in a single family. Haplotype analyses indicated that each recurrent mutation had a single common ancestor. Using immunohistochemical staining of human breast specimens, Wilson et al. (1999) demonstrated discrete nuclear foci of BRCA1 proteins in benign breast, invasive lobular cancers, and low-grade ductal carcinomas. Conversely, BRCA1 expression was reduced or undetectable in the majority of high-grade, ductal carcinomas, suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers. Using x-ray diffraction studies with synchrotron radiation, James et al. (1999) found that hair from breast cancer patients had a different intermolecular structure than hair from healthy subjects. All 23 patients with breast cancer, including 8 without BRCA1 mutations, had altered hair structure. Of 5 women without breast cancer but carrying BRCA1 mutations, 3 had fully different structure and 2 had partial changes in hair structure. The authors proposed hair analysis to screen for breast cancer, but suggested additional study of the sensitivity and specificity of the test. Briki et al. (1999) repeated the studies of James et al. (1999), using scalp hair from 10 supposedly healthy people, 7 females and 3 males, and 10 breast cancer patients, all female. They irradiated a bundle of hair in a glass capillary with a 0.5-mm monochromatic x-ray beam. The diffraction patterns from healthy subjects displayed an intense ring at 4.48 +/- 0.05 nm. Eight of the 10 breast cancer patients had the same ring. These results were exactly the opposite of those observed by James et al. (1999). However, the study by Briki et al. (1999) used scalp hair rather than pubic hair. To identify downstream target genes of BRCA1, Harkin et al. (1999) established cell lines with tightly regulated inducible expression of the BRCA1 gene. High-density oligonucleotide arrays were used to analyze gene expression profiles at various times following BRCA1 induction. A major target of BRCA1 is the DNA damage-inducible gene GADD45 (126335). Induction of BRCA1 triggers apoptosis through activation of c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK; see 601158), a signaling pathway potentially linked to GADD45 gene family members. Van Orsouw et al. (1999) reported an inexpensive system for mutation analysis based on a combination of multiplex PCR amplification and 2-dimensional electrophoresis. In a panel of 60 samples, 14 mutations were confirmed, and an additional 5 mutations were found. Fifteen different polymorphic variants were also identified. Welcsh and King (2001) reviewed the mutagenicity of BRCA1 and BRCA2 and listed their interacting, modifying, and regulatory proteins, in order to explain why mutations in these 2 genes lead specifically to breast and ovarian cancer. To establish the role of missense changes in the BRCA1 gene in breast cancer susceptibility, Fleming et al. (2003) used comparative evolutionary methods to identify potential functionally important amino acid sites in exon 11. By aligning sequences from 57 eutherian mammals and categorizing amino acid sites by degree of conservation, they identified 41 missense mutations in exon 11 (38 in conserved and 3 in rapidly evolving regions) likely to influence gene function and thereby contribute to breast cancer susceptibility. They used Bayesian phylogenetic analyses to determine relationships among orthologs and identify codons evolving under positive selection. Most conserved residues occurred in a region with the highest concentration of protein-interacting domains. Rapidly evolving residues were concentrated in the RAD51-interacting domain, suggesting that selection is acting most strongly on the role of BRCA1 in DNA repair. The 5-prime end of the BRCA1 gene lies within a duplicated region of 17q21. This region contains BRCA1 exons 1A, 1B, and 2 and their surrounding introns; as a result, a BRCA1 pseudogene lies upstream of BRCA1. However, the sequence of this segment remained essentially unknown. Puget et al. (2002) found extensive homology between the tandemly situated BRCA1 and its pseudogene. Exon 1A of BRCA1 and of the pseudogene were 44.5 kb apart. Puget et al. (1999) described 2 families with breast and ovarian cancer who had different germline deletions that involved exons 1 and 2. Using newly available sequence data, Puget et al. (2002) characterized the breakpoints to discern that distinct homologous recombination events had occurred between intron 2 of BRCA1 and intron 2 of the BRCA1 pseudogene, leading to 37-kb deletions. Breakpoint junctions were found to be located at close but distinct sites within segments that are 98% identical. The mutant alleles lack the BRCA1 promoter and harbor a chimeric gene consisting of pseudogene exons 1A, 1B, and 2, which lacks the initiation codon, fused to BRCA1 exons 3-24. This represented a new mutational mechanism for the BRCA1 gene. The presence of a large region homologous to BRCA1 on the same chromosome appears to constitute a hotspot for recombination. Brown et al. (2002) likewise identified a deletion consistent with recombination between BRCA1 and the BRCA1 pseudogene. In germline BRCA1, a promoter deletion was found in 1 of 60 familial breast cancer patients from the Australian population. Montagna et al. (2003) applied multiplex ligation-dependent probe amplification (MLPA) methodology to 37 hereditary breast-ovarian cancer families. All had a high prior probability of BRCA1 mutation, and 15 were previously shown to carry a mutation in either the BRCA2 gene (5 families) or the BRCA1 gene (10 families, including 1 genomic rearrangement). The application of BRCA1 MLPA to the remaining 22 uninformative families allowed the identification of 5 additional genomic rearrangements. Loss of constitutive heterozygosity of polymorphic markers in linkage disequilibrium was predictive of such BRCA1 alterations. BRCA1 genomic deletions accounted for more than one-third (6 of 15) of the pathogenic BRCA1 mutations in this series. #### GENOTYPE/PHENOTYPE CORRELATIONS Gayther et al. (1995) analyzed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. In 32 families (53%), a total of 22 different mutations were detected, of which 14 were previously unreported. They observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within the family. The data suggested to the authors a transition in risk such that mutations in the 3-prime third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supported previous data suggesting that some BRCA1 mutation carriers have common ancestors; however, Gayther et al. (1995) found at least 2 examples where recurrent mutations appeared to have arisen independently, judging from the different haplotype background. Studies of a number of diseases have indicated that fine-structure haplotype analysis can provide insight into the 'genetic history' of a particular mutation (or presumed mutation for rare diseases where the disease gene is not yet identified). To address both the question of mutation origin and the relationship between mutation and phenotype, Neuhausen et al. (1996) constructed a haplotype of 9 polymorphic STR markers within or immediately flanking the BRCA1 locus in a set of 61 families (selected to contain 1 of 6 BRCA1 mutations that had been identified a minimum of 4 times). The mutation appeared to have an affect on the relative proportion of cases of breast and ovarian cancer: 57% of women presumed affected because of the 1294 del 40 mutation had ovarian cancer, compared with 14% of affected women with the splice site mutation in intron 5 of BRCA1. A high degree of haplotype conservation across the region was observed. Any haplotype differences found were most often due to mutations in the short-tandem-repeat markers, although some likely instances of recombination also were observed. One mutation, 4184 del 4, had the same ancestral haplotype in two-thirds of the families studied. Neuhausen et al. (1996) estimated that this mutation had arisen 170 generations ago. To determine whether hereditary ovarian cancers have distinct clinical and pathologic features compared with sporadic (nonhereditary) ovarian cancers, Boyd et al. (2000) performed a retrospective cohort study of a consecutive series of 933 ovarian cancers diagnosed and treated at the Sloan-Kettering Cancer Center. This study was restricted to patients of Jewish origin because of the ease of BRCA1 and BRCA2 genotyping in this ethnic group. Of the 189 patients who identified themselves as Jewish, 88 hereditary cases were identified with the presence of a germline founder mutation in BRCA1 or BRCA2. The remaining 101 cases from the same series not associated with a BRCA mutation, and 2 additional groups with ovarian cancer from clinical trials (for survival analysis), were included for comparison. Hereditary cancers were rarely diagnosed before age 40 years and were common after age 60 years, with mean age at diagnosis being significantly younger for BRCA1 versus BRCA2-linked patients (54 vs 62 years). Histology, grade, stage, and success of cytoreductive surgery were similar for hereditary and sporadic cases. The hereditary group had a longer disease-free interval following primary chemotherapy in comparison with the nonhereditary group, with a median time to recurrence of 14 months and 7 months, respectively (P less than 0.001). Those with hereditary cancers had improved survival compared with the nonhereditary group. Boyd et al. (2000) concluded that although BRCA-associated hereditary ovarian cancers in this population have surgical and pathologic characteristics similar to those of sporadic cancers, advanced-stage hereditary cancer patients survive longer than nonhereditary cancer patients. Age penetrance is greater for BRCA1-linked than for BRCA2-linked cancers in this population. #### GENE FUNCTION In sporadic breast cancer, Thompson et al. (1995) found that BRCA1 mRNA levels are markedly decreased during the transition from carcinoma in situ to invasive cancer. Thompson et al. (1995) found that experimental inhibition of BRCA1 expression with antisense oligonucleotides produced accelerated growth of normal and malignant mammary cells but had no effect on nonmammary epithelial cells. They interpreted these results as indicating that BRCA1 may normally serve as a negative regulator of mammary epithelial cell growth and that this function is compromised in breast cancer either by direct mutation or by alterations in gene expression. Chen et al. (1995) identified the BRCA1 gene product as a 220-kD nuclear phosphoprotein in normal cells, including breast ductal epithelial cells, and in 18 of 20 tumor cell lines derived from tissues other than breast and ovary. However, in 16 of 17 breast and ovarian cancer lines and in 17 of 17 samples of cells obtained from malignant effusions, BRCA1 localized mainly in the cytoplasm. Absence of BRCA1 or aberrant subcellular location was also observed to a variable extent in histologic sections of many breast cancer biopsies. The findings suggested to the authors that BRCA1 abnormalities may be involved in the pathogenesis of many breast cancers, sporadic as well as familial. Scully et al. (1996), however, reported results that did not support the hypothesis that wildtype BRCA1 is specifically excluded from the nucleus in sporadic breast and ovarian cancer. Coene et al. (1997) reported a well-defined localization of BRCA1 in the perinuclear compartment of the endoplasmic reticulum-Golgi complex and in tubes invaginating the nucleus. The nuclear detection was fixation dependent, which helped to explain the controversial findings previously reported. The nuclear tubes were not seen in every cell, and therefore the authors suggested that an involvement in the cell cycle was possible. These tubes probably enhance nuclear-cytoplasmic interactions by increasing the surface area. Chen et al. (1996) raised mouse polyclonal antibodies to 3 regions of the human BRCA1 protein and confirmed their earlier finding of a 220-kD nuclear phosphoprotein. They reported that expression and phosphorylation of the BRCA1 gene and protein are cell cycle dependent in a synchronized population of bladder carcinoma cells. The greatest levels of both expression and phosphorylation occurred in S and M phases. Chen et al. (1998) used mammalian expression vectors to transfect cells with BRCA1 and BRCA2 as well as with several antibodies to recognize these proteins in order to study their subcellular localizations. They showed that BRCA1 and BRCA2 coexist in a biochemical complex and colocalize in subnuclear foci in somatic cells and on the axial elements of developing synaptonemal complexes. Like BRCA1 and RAD51, BRCA2 relocates to replication sites following exposure of S phase cells to hydroxyurea or UV irradiation. Thus, BRCA1 and BRCA2 participate together in a pathway (or pathways) associated with the activation of double-strand break repair and/or homologous recombination. Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and/or ovarian cancer. Zhong et al. (1999) showed that BRCA1 interacts in vitro and in vivo with RAD50 (604040), which forms a complex with MRE11 (600814) and p95/nibrin (NBS1; 602667). Upon irradiation, BRCA1 was detected in the nucleus, in discrete foci which colocalize with RAD50. Formation of irradiation-induced foci positive for BRCA1, RAD50, MRE11, or p95 was dramatically reduced in HCC/1937 breast cancer cells carrying a homozygous mutation in BRCA1 but was restored by transfection of wildtype BRCA1. Ectopic expression of wildtype, but not mutated, BRCA1 in these cells rendered them less sensitive to the DNA damage agent methyl methanesulfonate. These data suggested to the authors that BRCA1 is important for the cellular responses to DNA damage that are mediated by the RAD50-MRE11-p95 complex. Holt et al. (1996) demonstrated that retroviral transfer of the wildtype BRCA1 gene inhibits growth in vitro of all breast cancer and ovarian cancer cell lines tested, but not colon or lung cancer cells or fibroblasts. Mutant BRCA1, however, had no effect on growth of breast cancer cells; ovarian cancer cell growth was not affected by BRCA1 mutations in the 5-prime portion of the gene but was inhibited by 3-prime BRCA1 mutations. Development of MCF-7 tumors in nude mice was inhibited when MCF-7 cells were transfected with wildtype, but not mutant, BRCA1. Among mice with established MCF-7 tumors, peritoneal treatment with a retroviral vector expressing wildtype BRCA1 significantly inhibited tumor growth and increased survival. The results of Holt et al. (1996) were consistent with the previous observation that the site of BRCA1 mutation is associated with relative susceptibility to ovarian versus breast cancer. Jensen et al. (1996) demonstrated that BRCA1 encodes a 190-kD protein with sequence homology and biochemical analogy to the granin protein family. BRCA2 also includes a motif similar to the granin consensus at the C terminus of the protein. Both BRCA1 and the granins localized to secretory vesicles, are secreted by a regulated pathway, are posttranslationally glycosylated, and are responsive to hormones. The authors stated that, as a regulated secretory protein, BRCA1 appears to function by a mechanism not previously described for tumor suppressor products. The granins with which BRCA1 and BRCA2 were compared included chromogranin A (118910), chromogranin B (118920), and secretogranin II, also known as chromogranin C (118930). As reviewed by Steeg (1996), granins are a family of acidic proteins that bind calcium and aggregate in its presence. Known members of the granin family have been solely neuroendocrine or endocrine in origin; if BRCA1 is a granin it will necessarily expand the families boundaries. In an effort to understand the function of BRCA1, Wu et al. (1996) used a yeast 2-hybrid system to identify proteins that associate with BRCA1 in vivo. This analysis led to the identification of a novel protein that interacts with the N-terminal region of BRCA1. Wu et al. (1996) designated this protein BARD1 (601593) and determined that it maps to chromosome 2q. By Western and immunofluorescence analyses in synchronized T24 bladder cancer cells, Jin et al. (1997) studied the expression patterns of the BARD1 and BRCA1 proteins. They found that the steady state levels of BARD1, unlike those of BRCA1, remain relatively constant during cell cycle progression. However, immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle, but not during the G1 phase. Nevertheless, BARD1 polypeptides are found exclusively in the nuclear fractions of both G1- and S-phase cells. Therefore, progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots. This cell cycle-dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1-mediated tumor suppression. Scully et al. (1997) found that the BRCA1 gene product is a component of the RNA polymerase II holoenzyme (polII) by several criteria. BRCA1 was found to copurify with the holoenzyme over multiple chromatographic steps. Other tested transcription activators that could potentially contact the holoenzyme were not stably associated with the holoenzyme as determined by copurification. Antibody specific for the holoenzyme component SRB7 specifically purified BRCA1. (SRB proteins are a key component of the holoenzyme and were discovered in a yeast genetic screen as suppressors of RNA polymerase B mutations; hence, the designation SRB. A benign difference is that SRB proteins bind to the C-terminal domain of yeast polII and are found only in the polII holoenzyme.) Immunopurification of BRCA1 complexes also specifically purified transcriptionally active RNA polII and transcription factors TFIIF (see 189968), TFIIE (see 189962), and TFIIH (see 189972), which are known components of the holoenzyme. Moreover, a BRCA1 domain, which is deleted in about 90% of clinically relevant mutations, participated in binding to the holoenzyme complex in cells. These data were considered consistent with other data identifying transcription activation domains in the BRCA1 protein, and link the BRCA1 tumor suppressor protein with the transcription process as a holoenzyme-bound protein. RNA helicase A, or RHA (140 kD), was identified by Lee and Hurwitz (1993) and Zhang and Grosse (1997) as a helicase of unknown function with homology to the Drosophila 'maleless' gene, which functions to increase expression of genes from the male X chromosome. Anderson et al. (1998) showed that RHA protein links BRCA1 to the holoenzyme complex. These results were the first to identify specific protein interaction with the BRCA1 C-terminal domain and were consistent with the model that BRCA1 functions as a transcriptional coactivator. Association of the BRCA1 protein with the DNA repair gene RAD51 (179617) and changes in the phosphorylation and cellular localization of the protein after exposure to DNA-damaging agents are consistent with a role for BRCA1 in DNA repair. Although Gowen et al. (1998) reported that mouse embryonic stem cells deficient in BRCA1 are defective in the ability to carry out transcription-coupled repair of oxidative DNA damage and are hypersensitive to ionizing radiation and hydrogen peroxide, this article was later retracted because of the possibility of 'fabricated and falsified research findings' (Gowen et al., 2003). Using transient transfection assays, Fan et al. (1999) demonstrated that BRCA1 inhibits signaling by the ligand-activated estrogen receptor ER-alpha (133430) through the estrogen-responsive enhancer element and blocks the C-terminal transcriptional activation function AF2 of ER-alpha. These results suggested that wildtype BRCA1 protein may function, in part, to suppress estrogen-dependent mammary epithelial proliferation by inhibiting ER-alpha mediated transcriptional pathways related to cell proliferation, and that loss of this ability may contribute to tumorigenesis. Scully et al. (1999) found that retrovirally expressed wildtype BRCA1 decreased the gamma irradiation (IR) sensitivity and increased the efficiency of double-strand DNA break repair of the BRCA1 -/- human breast cancer line, HCC1937. It also reduced the susceptibility of the cells to double-strand DNA break generation by IR. In contrast, multiple clinically validated BRCA1 products with missense mutations were nonfunctional in these assays. These data constituted the basis for a BRCA1 functional assay and suggested that efficient repair of double-strand DNA breaks is linked to BRCA1 tumor suppression. BRCA1 contains a C-terminal domain (BRCT) that is shared with several other proteins involved in maintaining genome integrity. In an effort to understand the function of BRCA1, Yarden and Brody (1999) sought to isolate proteins that interact with the BRCT domain. Purified BRCT polypeptide was used as a probe to screen a human placenta cDNA expression library by Far Western analysis. The authors reported that BRCA1 interacts in vivo and in vitro with the Rb-binding proteins RbAp46 (RBBP7; 602922) and RbAp48 (RBBP4; 602923), as well as with Rb (RB1; 180200). Moreover, the BRCT domain associated with the histone deacetylases HDAC1 (601241) and HDAC2 (605164). These results demonstrated that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRCA1 in multiple processes such as transcription, DNA repair, and recombination. Lee et al. (2000) reported that CHK2 (604373) regulates BRCA1 function after DNA damage by phosphorylating serine-988 of BRCA1. Lee et al. (2000) demonstrated that CHK2 and BRCA1 interact and colocalize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine-988 is required for the release of BRCA1 from CHK2. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937. However, BRCA1 phosphorylation may be complicated. For example, Cortez et al. (1999) demonstrated that ATM (607585) can phosphorylate serines at positions 1423 and 1524 of BRCA1 after a high dose of gamma radiation. In addition, Ruffner et al. (1999) demonstrated that CDK2 (116953) phosphorylated serine-1497 during the G1/S phase of cell cycle. Phosphorylation of the different serine residues is likely to have different effects on BRCA1 function. Maor et al. (2000) cotransfected a luciferase reporter gene under the control of the insulin-like growth factor-1 receptor (IGF1R; 147370) promoter with a wildtype BRCA1-encoding expression vector into multiple cell lines. They observed a significant reduction in luciferase activity in all 3 cell lines tested, demonstrating suppression of promoter activity by BRCA1 in a dose-dependent manner. Functional interaction between BRCA1 and SP1 (189906) in the regulation of the IGF1R gene was studied in Schneider cells, a Drosophila cell line which lacks endogenous SP1. In these cells, BRCA1 suppressed 45% of the SP1-induced trans-activation of the IGF1R promoter. Maor et al. (2000) concluded that BRCA1 is capable of suppressing the IGF1R promoter in a number of cell lines, resulting in low levels of receptor mRNA protein. Maor et al. (2000) hypothesized that mutant versions of BRCA1 lacking trans-activational activity can potentially derepress the IGF1R promoter. Activation of the overexpressed receptor by locally produced or circulating IGFs may elicit a myogenic event which may be a key mechanism in the etiology of breast and ovarian cancer. Li et al. (2000) demonstrated that the BRCA1-associated protein CTIP (604124) becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase ATM (see 607585). ATM phosphorylates CTIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CTIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. Li et al. (2000) concluded that ATM, by phosphorylating CTIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer. Huttley et al. (2000) used phylogeny-based maximum likelihood analysis of the BRCA1 sequences from primates and other animals and found that the ratios of replacement to silent nucleotide substitutions on the human and chimpanzee lineages were not different from one another but were different from those of other primate lineages, and were greater than 1. This is consistent with the historic occurrence of positive darwinian selection pressure on the BRCA1 protein in the human and chimpanzee lineages. Analysis of genetic variation in a sample of female Australians of northern European origin showed evidence for Hardy-Weinberg disequilibrium at polymorphic sites in BRCA1, consistent with the possibility that natural selection is affecting genotype frequencies in modern Europeans. The clustering of between-species variation in the region of the gene encoding the RAD51-interacting domain of BRCA1 suggests the maintenance of genomic integrity as a possible target of selection. Using a combination of affinity- and conventional chromatographic techniques, Bochar et al. (2000) isolated a predominant form of a multiprotein BRCA1-containing complex from human cells displaying chromatin-remodeling activity. Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex, and the authors showed that BRCA1 can directly interact with the BRG1 (SMARCA4; 603254) subunit of the SWI/SNF complex. Moreover, p53 (TP53; 191170)-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 (Khavari et al., 1993) or the cancer-causing deletion of exon 11 of BRCA1 (Xu et al., 1999). These findings revealed a direct function for BRCA1 in transcriptional control through modulation of chromatin structure. Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM, BLM (604610), MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50-MRE11-NBS1 complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. BRCA1 is implicated in the transcriptional regulation of DNA damage-inducible genes that function in cell cycle arrest. To explore the mechanistic basis for this regulation, Zheng et al. (2000) performed a yeast 2-hybrid screen for proteins associated with BRCA1 and isolated a cDNA encoding ZBRK1 (605422). ZBRK1 binds to a specific sequence, GGGxxxCAGxxxTTT, within GADD45 (126335) intron 3 that supports the assembly of a nuclear complex minimally containing both ZBRK1 and BRCA1. Through this recognition sequence, ZBRK1 represses transcription in a BRCA1-dependent manner. The results revealed a novel corepressor function for BRCA1 and provided a mechanistic basis for the biologic activity of BRCA1 through sequence-specific transcriptional regulation. The nonsense-mediated mRNA decay pathway minimizes the potential damage caused by nonsense mutations. In-frame nonsense codons located at a minimum distance upstream of the last exon-exon junction are recognized as premature termination codons, targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during pre-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediated altered splicing (NAS). By analyzing NAS in BRCA1, Liu et al. (2001) showed that inappropriate exon skipping can be reproduced in vitro and that it results from disruption of a splicing enhancer in the coding sequence. Enhancers can be disrupted by a single nonsense, missense, or translationally silent point mutation, without recognition of an open reading frame as such. These results argued against a nuclear reading-frame scanning mechanism for NAS. Coding region single-nucleotide polymorphisms within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenotypic variability and variable penetrance of mutations elsewhere in a gene. Hedenfalk et al. (2001) used microarray technology to determine gene-expression profiles in BRCA1-positive breast cancers as contrasted with BRCA2-positive breast cancers. The suspicion that a difference might be found came from the fact that the 2 types of tumors are often histologically distinctive. Furthermore, tumors with BRCA1 mutations are generally negative for both estrogen and progesterone receptors, whereas most tumors with BRCA2 mutations are positive for these hormone receptors. RNA from samples of primary tumors from 7 carriers of the BRCA1 mutation and 7 carriers of the BRCA2 mutation was compared with a microarray of 6,512 cDNA clones of 5,361 genes. The authors found that significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Garcia-Higuera et al. (2001) showed that a nuclear complex containing the FANCA (607139), FANCC (227645), FANCF (603467), and FANCG (602956) proteins is required for the activation of the FANCD2 protein (227646) to a monoubiquitinated isoform. In normal cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots). Activated FANCD2 protein colocalizes with BRCA1 in ionizing radiation-induced foci and in synaptonemal complexes of meiotic chromosomes. The authors concluded that the FANCD2 protein therefore provides the missing link between the FA protein complex and the cellular BRCA1 repair machinery. Disruption of this pathway results in the cellular and clinical phenotype common to all subtypes of Fanconi anemia. The Fanconi anemia (FA) nuclear complex (composed of the FA proteins A, C, G and F) is essential for protection against chromosome breakage. It activates the downstream protein FANCD2 by monoubiquitylation; this then forges an association with the BRCA1 protein at sites of DNA damage. Pace et al. (2002) showed that the FANCE (600901) protein is part of this nuclear complex, binding both FANCC and FANCD2. Indeed, FANCE is required for the nuclear accumulation of FANCC and provides a critical bridge between the FA complex and FANCD2. Disease-associated FANCC mutants do not bind to FANCE, cannot accumulate in the nucleus and are unable to prevent chromosome breakage. Paull et al. (2001) demonstrated that recombinant human BRCA1 protein binds strongly to DNA, an activity conferred by a domain in the center of the BRCA1 polypeptide. As a result of this binding, BRCA1 inhibits the nucleolytic activity of the MRE11/RAD50/NBS1 complex, an enzyme implicated in numerous aspects of double-strand break repair. BRCA1 displays a preference for branched DNA structures and forms protein-DNA complexes cooperatively between multiple DNA strands, but without DNA sequence specificity. Mutations in the TP53 tumor suppressor gene (191170) are found in 70 to 80% of BRCA1-mutated breast cancers but only 30% of those with wildtype BRCA1 (Schuyer and Berns, 1999). The p53 protein regulates nucleotide excision repair (NER) through transcriptional regulation of genes involved in the recognition of adducts in genomic DNA. Loss of p53 function, as in Li-Fraumeni syndrome (151623), results in deficient global genomic repair (GGR), a subset of NER that targets and removes lesions from the whole genome (51,50:Ford and Hanawalt, 1995, 1997). Hartman and Ford (2002) showed that BRCA1 specifically enhances the GGR pathway, independent of p53, and can induce p53-independent expression of the NER genes XPC (278720), DDB2 (600811), and GADD45. Defects in the NER pathway in BRCA1-associated breast cancers may be causal in tumor development, suggesting a multistep model of carcinogenesis. Yarden et al. (2002) showed that BRCA1 is essential for activating the Chk1 kinase (603078) that regulates DNA damage-induced G2/M arrest. BRCA1 controls the expression, phosphorylation, and cellular localization of Cdc25C (157680) and Cdc2/cyclin B kinase (116940)--proteins that are crucial for the G2/M transition. Since BRCA1 regulates key effectors that control the G2/M checkpoint, it is involved in regulating the onset of mitosis. Ganesan et al. (2002) found that BRCA1 colocalized with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associated with XIST (314670) RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 showed evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wildtype BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggested that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state. Folias et al. (2002) used yeast 2-hybrid analysis and coimmunoprecipitation methods to demonstrate a direct interaction between the FANCA and BRCA1 proteins. Direct interaction with other FANC proteins was not demonstrable. The amino terminal portion of FANCA and the central part (amino acids 740-1,083) of BRCA1 contained the sites of interaction. The interaction did not depend on DNA damage, suggesting that FANCA and BRCA1 may be constitutively interacting. To estimate the average magnitude of risks of breast and ovarian cancer associated with germline mutations in BRCA1 and BRCA2, Antoniou et al. (2003) pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% for breast cancer and 39% for ovarian cancer. The corresponding estimates for BRCA2 were 45% and 11%. Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed under the age of 35 years of age. They found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk according to mutation position for both genes. Rostagno et al. (2003) performed mutation analysis of the BRCA1 gene in 140 families from the southeast of France with a history of breast and/or ovarian cancer. As expected, BRCA1 gene alteration, including missense mutations of unknown biologic significance, were more frequent in families with a history of breast-ovarian cancer (32%) than in breast-cancer-only families (12%). Diez et al. (2003) screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germline mutations in the BRCA1 and BRCA2 genes. They identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 were novel and 12 had been reported only in Spanish families (41.5%); the prevalence of mutations in this set of families was 26.3%. The percentage was higher in families with breast and ovarian cancer (52.1%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. They found a higher frequency of ovarian cancer associated with mutations localized in the 5-prime end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the OCCR of exon 11 of the BRCA2 gene. Five mutations accounted for 46.6% of BRCA1 detected mutations, whereas 4 mutations accounted for 56.6% of the BRCA2 mutations. The BRCA1 330A-G substitution (113705.0034) had a Galician origin (northwest Spain). Yu et al. (2003) demonstrated that the BRCA1 BRCT domain directly interacts with phosphorylated BRCA1-associated carboxyl-terminal helicase (BACH1; 602751). The specific interaction between BRCA1 and phosphorylated BACH1 is cell cycle regulated and is required for DNA damage-induced checkpoint control during the transition from G2 to M phase of the cell cycle. Further, Yu et al. (2003) showed that 2 other BRCT domains interact with their respective physiologic partners in a phosphorylation-dependent manner. Thirteen additional BRCT domains also preferentially bind phosphopeptides rather than nonphosphorylated control peptides. Yu et al. (2003) concluded that their data implied that the BRCT domain is a phosphoprotein binding domain involved in cell cycle control. ElShamy and Livingston (2004) identified a splice variant of BRCA1 that incorporates a unique 40-nucleotide first exon, exon 1c, that is located 24 Mb upstream of BRCA1 exons 1a and 1b. The 3-prime end of this cDNA extends 335 nucleotides into intron 11, prompting ElShamy and Livingston (2004) to designate it IRIS for 'in-frame reading of BRCA1 intron 11 splice variant.' The deduced BRCA1-IRIS protein contains 1,399 amino acids. In vitro transcription-translation resulted in a protein with an apparent molecular mass of about 150 kD. Northern blot analysis of fibroblast mRNA detected BRCA1-IRIS at about 4.5 kb. Semiquantitative PCR detected variable and developmentally regulated expression of BRCA1-IRIS and full-length BRCA1 in several adult and fetal human tissues. Unlike full-length BRCA1, BRCA1-IRIS was exclusively chromatin associated, failed to interact with BARD1 in vivo or in vitro, exhibited unique nuclear immunostaining, and coimmunoprecipitated with core DNA replication initiation sites and with replication initiation proteins. Suppression of BRCA1-IRIS hindered DNA replication, whereas overexpression stimulated DNA replication. ElShamy and Livingston (2004) concluded that endogenous BRCA1-IRIS positively influences the DNA replication initiation machinery. Deng and Wang (2003) discussed the functions of BRCA1 in DNA damage repair and cellular responses that link development and cancer. #### ANIMAL MODEL Gowen et al. (1996) described homozygous mice lacking the mouse Brca1 gene. The mice, possessing a deletion of the large exon 11, died between days 10 and 13 of embryonic development, suffering from a variety of neuroepithelial defects. Hakem et al. (1996) described another strain of homozygous mice for a putative Brca1-null mutation produced by targeted deletion of exons 5 and 6. These mutant mice were more severely affected, dying at about embryonic day 7.5 with no signs of mesoderm formation and exhibiting reduced cell proliferation. There were also strong signs of disruptive cell cycle regulation via altered expression levels of cyclin E (123837), mdm2 (164785) and p21 (116899). Hakem et al. (1996) speculated that the death of mutant embryos was due to failure of the proliferative burst required for germ layer development. Hakem et al. (1996) reported that after about 1 year of age, Brca1 heterozygous female mice showed no evidence of cancer. Gowen et al. (1996) also had been unable to detect tumors in 1-year-old heterozygotes. To study mechanisms underlying BRCA1-related tumorigenesis, Xu et al. (1999) derived mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of the Brca1 gene. The mutant cells maintained an intact G1-S cell cycle checkpoint and proliferated poorly. However, a defective G2-M checkpoint in these cells was accompanied by extensive chromosomal abnormalities. Mutant fibroblasts contained multiple functional centrosomes, leading to unequal chromosome segregation, abnormal nuclear division, and aneuploidy. These data uncovered an essential role for BRCA1 in maintaining genetic stability through the regulation of centrosome duplication and the G2-M checkpoint. Moynahan et al. (1999) reported that Brca1-deficient mouse embryonic stem cells had impaired repair of chromosomal double-strand breaks by homologous recombination. The relative frequencies of homologous and nonhomologous DNA integration and double-strand break repair were also altered. The results demonstrated a caretaker role for BRCA1 in preserving genomic integrity by promoting homologous recombination and limiting mutagenic nonhomologous repair processes. Hakem et al. (1997) generated mice double mutant for Brca1(5-6) and p53, or Brca1(5-6) and p21. Mutation in either p53 or p21 prolonged the survival of Brca1(5-6) mutant embryos from embryonic day 7.5 to embryonic day 9.5. The development of most Brca1(5-6)/p21 double-mutant embryos was comparable to that of their wildtype littermates, although no mutant survived past embryonic day 10.5. Because mutation of neither p53 nor p21 completely rescued Brca1(5-6) embryos, the authors suggested that the lethality of the embryos is likely due to a multifactorial process. Ludwig et al. (1997) created mice deficient for Brca1 by targeted disruption, resulting in deletion of exon 2. They also disrupted Brca2 by replacing a segment of exon 11. Heterozygotes were indistinguishable from wildtype littermates. Nullizygous embryos became developmentally retarded and disorganized, and died early in development. In Brca1 mutants, the onset of abnormalities was earlier by 1 day and their phenotypic features and time of death were highly variable, whereas the phenotype of Brca2-null embryos was more uniform, and they survived for at least 8.5 embryonic days. Brca1/Brca2 double mutants were similar to Brca1-null mutants. Ludwig et al. (1997) reported that the impact of Brca1- or Brca2-null mutation was less severe in a p53-null background. Xu et al. (2001) found that mouse embryos homozygous for deletion of exon 11 of the Brca1 gene died late in gestation because of widespread apoptosis. Elimination of 1 p53 allele completely rescued this embryonic lethality and restored normal mammary gland development. However, most female mice homozygous for the Brca1 exon 11 deletion and heterozygous for loss of the p53 gene developed mammary tumors with loss of the remaining p53 allele within 6 to 12 months. Lymphomas and ovarian tumors also occurred at lower frequencies. Heterozygous mutation of the p53 gene decreased p53 and resulted in attenuated apoptosis and G1-S checkpoint control, allowing the homozygous Brca1 exon 11-deleted cells to proliferate. The p53 protein regulates Brca1 transcription both in vitro and in vivo, and Brca1 participates in p53 accumulation after gamma irradiation. These findings provided a mechanism for BRCA1-associated breast carcinogenesis. McCarthy et al. (2003) determined that mouse embryos with double mutant Bard1 -/- ; Brca1 -/- genotype were phenotypically indistinguishable from either single Bard1 or single Brca1 homozygous mutants. Embryos that carried at least 1 wildtype allele of both Bard1 and Brca1 were normal and had 20 to 25 somites, while each embryo that was null for either Bard1 or Brca1 exhibited the characteristic phenotype of severe growth retardation, degeneration, and embryonic lethality. The similarity of phenotypes indicated to McCarthy et al. (2003) that the developmental functions of Brca1 and Bard1 are mediated by the Brca1/Bard1 heterodimer. Mouse embryonic fibroblasts carrying targeted deletion of exon 11 of the Brca1 gene or a Gadd45a null mutation suffer centrosome amplification. Wang et al. (2004) found that mouse embryos carrying both mutations were exencephalic and exhibited a high incidence of apoptosis accompanied by altered levels of Bax (600040), Bcl2 (151430), and p53. They concluded that BRCA1 and GADD45A have a synergistic role in regulating centrosome duplication and maintaining genome integrity. ### ALLELIC VARIANTS (selected examples) #### .0001 BREAST-OVARIAN CANCER [BRCA1, CYS64GLY] In a kindred in which 8 members had breast cancer and 5 members ovarian cancer, Castilla et al. (1994) found a TGT-to-GGT transversion in codon 64 leading to substitution of glycine for cysteine. Analysis of tumor DNA in 2 affected members of this kindred showed that the wildtype allele had been lost and only the cys64-to-gly mutant allele remained, thus supporting the tumor suppressor model. #### .0002 OVARIAN CANCER, SPORADIC [BRCA1, CYS61GLY] Merajver et al. (1995) analyzed genomic DNA of tumor and normal fractions of 47 ovarian cancers for mutations in BRCA1 using the SSCP technique. In the DNA of 4 tumors, which also had loss of heterozygosity at a BRCA1 intragenic marker, they found somatic mutations. One of these, found in an endometrioid ovarian carcinoma in a 53-year-old woman, was a cys61-to-gly substitution in the zinc finger motif. The data supported a tumor-suppressor mechanism for BRCA1; a combination of somatic mutation on 1 allele and LOH on the other may result in inactivation of BRCA1 in at least a small number of ovarian cancers. Gorski et al. (2000) found C61G to be a founder mutation in Polish families with breast-ovarian cancer, accounting for 20% of identified mutations. They studied 66 families in which at least 3 related females were affected with breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50. Mutations were identified in 35 (53%) of the 66 families. #### .0003 BREAST-OVARIAN CANCER [BRCA1, 2-BP DEL, 185AG] PAPILLARY SEROUS CARCINOMA OF THE PERITONEUM, INCLUDED Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 2-bp (AG185) deletion in the normal sequence TTA GAG of codons 22-23 in exon 3. The AGAG presumably predisposed to the deletion. This mutation changes the reading frame of the mRNA and causes a premature termination codon at position 39. This mutation was detected in index cases from 4 families that were not known to be related and originated from different areas in Canada. In these 4 families there were a total of 12 cases of breast cancer and 11 cases of ovarian cancer. Struewing et al. (1995) pointed out that all 10 published families with the 185delAG mutation (also called 187delAG) were Ashkenazi Jewish (of Eastern European origin). They knew of an eleventh Ashkenazi breast/ovarian cancer family with the 185delAG mutation; furthermore, only 1 Ashkenazi Jewish family was known to have a BRCA1 mutation other than 185delAG. In addition, Ashkenazi families with the 185delAG mutation appeared to share a common haplotype. In a study of 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, they observed the 185delAG mutation in 0.9% (95% confidence limit, 0.4%-1.8%), and in 815 reference individuals not selected for ethnic origin, none had the mutation. Roa et al. (1996) found the 185delAG mutation in 1.09% of approximately 3,000 Ashkenazi Jewish individuals and found the 5382insC mutation (113705.0018) in 0.13%. BRCA2 analysis on 3,085 individuals from the same population showed a carrier frequency of 1.52% for the 6174delT mutation (600185.0009). The expanded population-based study confirmed that the BRCA1 185delAG mutation and the BRCA2 6174delT mutation constituted the 2 most frequent mutant alleles predisposing to hereditary breast cancer among Ashkenazim and suggested a relatively lower penetrance for the 6174delT mutation in BRCA2. Bar-Sade et al. (1997) examined 639 unrelated healthy Jews of Iraqi extraction, a presumed low-risk group for the 185delAG mutation which occurs predominantly in Ashkenazim. Three individuals were identified as 185delAG mutation carriers, and haplotype analysis of the Iraqi mutation carriers showed that 2 of the Iraqis shared a haplotype in common with 6 Ashkenazi mutation carriers, and a third had a haplotype that differed by a single marker. This suggested to Bar-Sade et al. (1997) that the BRCA1 185delAG mutation may have arisen before the dispersion of the Jewish people in the Diaspora, at least at the time of Christ. Bar-Sade et al. (1998) extended their analyses to other non-Ashkenazi subsets: 354 of Moroccan origin, 200 Yemenites, and 150 Iranian Jews. Four of Moroccan origin (1.1%) and none of the Yemenites or Iranians were carriers of the 185delAG mutation. BRCA1 allelic patterns (haplotypes) were determined for 4 of these individuals and for 12 additional non-Ashkenazi 185delAG mutation carriers who had breast/ovarian cancer. The common 'Ashkenazi haplotype' was shared by 6 non-Ashkenazi individuals; 4 had a closely related pattern, and the rest (n = 6) displayed a distinct BRCA1 allelic pattern. The authors concluded that the 185delAG BRCA1 mutation occurs in some non-Ashkenazi populations at rates comparable with that of Ashkenazim. The majority of Jewish 185delAG mutation carriers have the same haplotype, supporting the founder effect notion, but dating the mutation's origin to an earlier date than previously estimated. The different allelic pattern at the BRCA1 locus in some Jewish mutation carriers might suggest that the mutation arose independently. Bandera et al. (1998) demonstrated the 185delAG mutation in 2 women with papillary serous carcinoma of the peritoneum (PSCP). Schorge et al. (1998) demonstrated that the tumors were multifocal in these cases. Ah Mew et al. (2002) reported the 185delAG mutation in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. #### .0004 BREAST-OVARIAN CANCER [BRCA1, 59-BP INS] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. They identified a T-to-G transition at nucleotide 332 in exon 5, leading to a premature termination codon at position 75 and a truncated protein. #### .0005 BREAST-OVARIAN CANCER [BRCA1, 1-BP INS, FS345TER] Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (A) insertion in the normal sequence GAA AAA AAG of codons 337-339 in exon 11, changing the reading frame of the mRNA and causing a premature termination codon at position 345. This mutation was detected in the index case of a Canadian family with a total of 4 cases of breast cancer and 3 cases of ovarian cancer, bringing the probability of linkage to BRCA1 to 98.3%. #### .0006 BREAST-OVARIAN CANCER [BRCA1, 40-BP DEL, NT1294] Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They both identified a 40-bp deletion from position 1294 to 1333, which led to a premature termination codon that was 5 codons distal to the deletion and predicted a truncated BRCA1 protein of 396 amino acids. #### .0007 BREAST-OVARIAN CANCER [BRCA1, SER766TER ] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. They identified a 2-bp (AG) deletion at nucleotide 2415 in exon 11, leading to a premature termination codon in place of serine-766 and a truncated protein. #### .0008 BREAST-OVARIAN CANCER [BRCA1, 2-BP DEL, 2800AA] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. They identified a 2-bp (AA) deletion at nucleotide 2800 in exon 11, leading to a premature termination codon at position 901 and a truncated protein. #### .0009 BREAST-OVARIAN CANCER [BRCA1, SER915TER ] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. They identified a 2-bp (TC) deletion at nucleotide 2863 in exon 11, leading to a premature termination codon in place of serine-915 and a truncated protein. #### .0010 BREAST-OVARIAN CANCER [BRCA1, 1-BP DEL, FS1023TER] Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (A3121) deletion in the normal sequence GAA AAC of codons 1001-1002 in exon 11, changing the reading frame of the mRNA and causing a premature termination codon at position 1023. This mutation was detected in the index case of a Canadian family with a total of 5 cases of breast cancer and 1 case of ovarian cancer, bringing the probability of linkage to BRCA1 to 90%. #### .0011 BREAST-OVARIAN CANCER [BRCA1, SER1040ASN ] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. They identified a G-to-A transition at nucleotide 3238 in exon 11 of the BRCA1 gene, changing serine to asparagine at position 1040. #### .0012 BREAST-OVARIAN CANCER [BRCA1, ARG1203TER ] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. They identified a C-to-T substitution in exon 11 at position 3726, leading to a premature termination codon in place of arginine-1203 and a truncated protein. #### .0013 BREAST-OVARIAN CANCER [BRCA1, GLU1250TER ] Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a G-to-T substitution in exon 11 at position 3867, leading to a premature termination codon in place of glutamic acid-1250 and a truncated protein. #### .0014 BREAST-OVARIAN CANCER [BRCA1, 4-BP DEL, NT3875] Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 4-bp deletion at position 3875, leading to a premature termination codon at position 1252 and a truncated protein. #### .0015 BREAST-OVARIAN CANCER [BRCA1, 4-BP DEL, 4185TCAA] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They both identified a 4-bp (TCAA) deletion in exon 11 at position 4184, leading to a premature termination codon at position 1364 and a truncated protein. #### .0016 BREAST-OVARIAN CANCER [BRCA1, ARG1443TER ] Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a C-to-T substitution at position 4446 of the BRCA1 gene, leading to a premature termination codon in place of arginine-1443 and a truncated protein. #### .0017 BREAST-OVARIAN CANCER [BRCA1, ARG1443GLY ] Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a C-to-G transition at position 4446, changing arginine1443 to glycine. #### .0018 BREAST-OVARIAN CANCER [BRCA1, 1-BP INS, 5382C] Simard et al. (1994) studied 30 Canadian families with breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (C) insertion at position 5382 in exon 20, changing the reading frame of the mRNA and causing a premature termination codon at position 1829 in exon 24. This mutation was detected in the index case of 4 Canadian families. In 1 of these families, 10 cases of cancer appeared in a single large sibship, including 3 cases of breast cancer, 2 ovarian cancers, 2 leukemias, 2 pancreatic cancers, and 1 prostate cancer. A case of leukemia and a case of Hodgkin disease were seen in more recent generations. In the 4 families with the 5382insC mutation, there were 14 cases of breast cancer and 5 cases of ovarian cancer. Gayther et al. (1997) found that the 5382insC and 4153delA (113705.0030) mutations in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. Gorski et al. (2000) found that 5382insC is a founder mutation in Polish families with breast-ovarian cancer, accounting for 51% of identified mutations. They studied 66 families in which at least 3 related females were affected with breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50. Mutations were found in 35 (53%) of the 66 families; 18 of the families carried the 5382insC mutation. De Los Rios et al. (2001) reported findings in Canadian families suggesting that most of the mutation-carrying families of Polish ancestry have the BRCA1 5382insC mutation. #### .0019 BREAST-OVARIAN CANCER [BRCA1, TYR1853TER ] Friedman et al. (1994) studied 63 breast cancer patients and 10 ovarian cancer patients in 10 families with cancer linked to chromosome 17q21. They identified a 1-bp (A) insertion in exon 24 of the BRCA1 gene at position 5677, leading to a premature termination codon in place of tyrosine-1853 and a truncated protein. #### .0020 BREAST-OVARIAN CANCER [BRCA1, 19-BP DEL, NT5085] Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 19-bp deletion between basepairs 5085 and 5103, leading to a termination codon at position 1656 and a truncated protein. #### .0021 BREAST-OVARIAN CANCER [BRCA1, 1-BP INS, 5438C] Castilla et al. (1994) studied 50 probands with a family history of breast and/or ovarian cancer for germline mutations in the coding region of the BRCA1 candidate gene. They identified a 1-bp (C) insertion at nucleotide 5438, leading to a termination codon at position 1773 and a truncated protein. #### .0022 BREAST CANCER [BRCA1, ARG841TRP ] Barker et al. (1996) reported an arg841-to-trp mutation (R814W) in the BRCA1 gene as a common mutation with a moderate phenotype. #### .0023 BREAST CANCER [BRCA1, 2508G-T ] In a breast cancer patient of Scottish descent, Liede et al. (1998) found double heterozygosity for 2 high-penetrance mutations: 2508G-T resulting in a conversion of glutamic acid to a stop codon in BRCA1 and a 3295insA mutation (600185.0011) in BRCA2. Both mutations were thought to have come from the father. #### .0024 BREAST-OVARIAN CANCER [BRCA1, 4-BP DEL, 962CTCA] In a Caucasian patient with a positive family history of breast or ovarian cancer in a first-degree relative, Janezic et al. (1999) identified a 962delCTCA mutation in the BRCA1 gene. #### .0025 BREAST-OVARIAN CANCER [BRCA1, 11-BP DEL, NT3600] In a Caucasian patient with a positive family history of breast or ovarian cancer in a first-degree relative, Janezic et al. (1999) identified a 3600del11 mutation in the BRCA1 gene. #### .0026 BREAST-OVARIAN CANCER [BRCA1, 1675A DEL] Two BRCA1 founder mutations had been identified in the Norwegian population: 1675delA (Dorum et al., 1997) and 1135insA (Andersen et al., 1996). Both result in a frameshift and a stop in exon 11. Dorum et al. (1999) ascertained 20 patients with the BRCA1 1675delA mutation and 10 with the 1135insA mutation. Their relatives were described with respect to absence/presence of breast and/or ovarian cancer. Of 133 living female relatives, 83 (62%) were tested for the presence of a mutation. No difference in penetrance or expression between the 2 mutations was found, whereas differences according to method of ascertainment were seen. The overall findings were that disease started to occur at age 30 years and that by age 50 years 48% of the mutation-carrying women had experienced breast and/or ovarian cancer. More ovarian cancers than breast cancers were recorded. Both penetrance and expression (breast cancer vs ovarian cancer) were different from those in reports of the Ashkenazi founder mutations. #### .0027 BREAST-OVARIAN CANCER [BRCA1, 1135A INS] See 113705.0026 and Dorum et al. (1999). #### .0028 BREAST CANCER [BRCA1, 2-BP DEL, 3888GA] Individuals with an inherited mutation in both BRCA1 and BRCA2 (600185) had been rarely described. Furthermore, despite the large number of variants identified in these genes, there appeared to be no published reports of de novo mutations. Tesoriero et al. (1999) identified a woman who developed high-grade breast cancer with axillary nodal metastases before the age of 40 years. Her father developed prostate cancer during his early fifties. Her mother had no cancer. The patient was found to have a de novo 2-bp deletion (GA) at nucleotide 3888 in exon 11 of the BRCA1 gene (3888delGA), and a 1-bp deletion (T) at nucleotide 6174 in exon 11 of the BRCA2 gene (600185.0009), which had been inherited from the father. Studies of a heterozygous polymorphism indicated that the 3888delGA mutation of BRCA1 originated from the father. #### .0029 BREAST-OVARIAN CANCER [BRCA1, 10-BP INS, NT943] Mefford et al. (1999) suggested that a 10-bp insertion at nucleotide 943 of the BRCA1 gene represents a founder mutation of African origin. #### .0030 BREAST-OVARIAN CANCER [BRCA1, 1-BP DEL, 4153A ] By mutation analysis of the BRCA1 gene in families with breast-ovarian cancer in Russia, Gayther et al. (1997) identified a novel 4153delA mutation. They stated that this mutation and the 5382insC (113705.0018) mutation in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. #### .0031 BREAST-OVARIAN CANCER [BRCA1, 16-KB INS, EX13 ] Puget et al. (1999) described a 6-kb duplication of exon 13 that created a frameshift in the coding sequence in 3 unrelated U.S. families of European ancestry and in 1 Portuguese family. To estimate the frequency and geographic diversity of carriers of this duplication, the BRCA1 Exon 13 Duplication Screening Group (2000) studied 3,580 unrelated individuals with a family history of breast cancer and 934 early-onset breast and/or ovarian cancer cases ascertained through 39 institutions in 19 countries. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they were likely to have derived from a common ancestor, possibly of northern British origin. The screening group suggested that BRCA1 screening protocols, either in English-speaking countries or in countries with historic links with Great Britain, should include the PCR-based assay described in their report. #### .0032 BREAST-OVARIAN CANCER [BRCA1, 1-BP DEL, 3744T] Sarantaus et al. (2000) performed haplotype analysis of 26 Finnish patients carrying a 3744delT mutation in exon 11 of the BRCA1 gene. They estimated that the mutation could be traced back 23 to 36 generations (500-700 years). The mutation was observed in Swedish families also. Most of the Finnish families had lived in Central Ostrobothnia for at least 300 years, whereas the Swedish families came from the opposite side of the Gulf of Bothnia. Thus, the mutation could have been brought across the sea from Sweden to Finland with Swedish settlers. #### .0033 BREAST-OVARIAN CANCER [BRCA1, 5-BP INS, NT3171 ] The 3171ins5 mutation in the BRCA1 gene is the most recurrent germline BRCA1/BRCA2 mutation in Sweden (Johannsson et al., 1996). Bergman et al. (2001) constructed haplotypes with polymorphic microsatellite markers within and flanking the BRCA1 gene in 18 apparently unrelated families with hereditary breast and/or ovarian cancer with confirmed 3171ins5 mutation. All affected families originated from the same geographic area along the west coast of Sweden. The microsatellite markers spanned a region of 17.3 cM, and all of the analyzed families shared a common 3.7 cM haplotype in the 3171ins5 carriers spanning over 4 markers located within or very close to the BRCA1 gene. This haplotype was not present in any of the 116 control chromosomes, and the 3171ins5 mutation was likely to be identical by descent, i.e., a true founder. The estimated age of the mutation was calculated to be approximately 50 generations, or a first appearance some time around the 6th century (Bergman et al., 2001). No obvious correlation between the geographic origin and genotype was observed. This is probably a reflection of how the population of western Sweden historically has been a migrating people along the west coast, with limited migration beyond this distinct geographic area. #### .0034 BREAST-OVARIAN CANCER [BRCA1, ARG71GLY] Vega et al. (2002) studied 30 Spanish breast and breast/ovarian cancer families for mutations in the BRCA1 and BRCA2 genes. Mutations were found in 8 of the 30 families (26.66%). All mutations were in the BRCA1 gene. The 330A-G transition in the BRCA1 gene, which resulted in an arg71-to-gly (R71G) substitution, was found in 4 unrelated families and accounted for 50% of all identified mutations. It had been described as a founder Spanish mutation, leading to aberrant splicing (Vega et al., 2001). The proband in 1 family had bilateral breast cancer at 27 and 30 years of age. Her mother, who also had the mutation, was diagnosed as having ovarian cancer at the age of 50. Diez et al. (2003) stated that the 330A-G mutation affected the splice donor site in intron 5; it caused aberrant splicing which resulted in a deletion of 22 nucleotides in exon 5 and a stop at codon 64 (C64X). Diez et al. (2003) observed this mutation in 7 families, most of them of known Galician origin. As reported in the BRCA1 database, the 330A-G mutation had been observed in families with probable Spanish origin in diverse geographic locations in Europe other than Spain (France and the United Kingdom), and in Caribbean and South American families. #### .0035 BREAST-OVARIAN CANCER [BRCA1, MET1775ARG ] In the germline of patients with breast or ovarian cancer, Monteiro et al. (1996) identified a met1775-to-arg (M1775R) mutation in the BRCA1 gene. This mutation has impaired transcriptional activity on BRCA1. Williams and Glover (2003) performed structural studies on the effect of this mutation. The mutated side chain is extruded from the protein hydrophobic core, thereby altering the protein surface. Charge-charge repulsion, rearrangement of the hydrophobic core, and disruption of the native hydrogen bonding network at the interface between the 2 BRCT repeats contribute to the conformational instability of the mutant protein. Williams and Glover (2003) concluded that destabilization and global unfolding of the mutated BRCT domain at physiologic temperatures explained the pleiotropic molecular and genetic defects associated with the mutant protein. ### SEE ALSO Albertsen et al. (1994); Langston et al. (1996); Narod et al. (1991); Narod et al. (1995); Struewing et al. (1995) ### REFERENCES 1. Ah Mew, N.; Hamel, N.; Galvez, M.; Al-Saffar, M.; Foulkes, W. D. : Haplotype analysis of a BRCA1:185delAG mutation in a Chilean family supports its Ashkenazi origins. Clin. Genet. 62: 151-156, 2002. PubMed ID : 12220453 2. Albertsen, H.; Plaetke, R.; Ballard, L.; Fujimoto, E.; Connolly, J.; Lawrence, E.; Rodriguez, P.; Robertson, M.; Bradley, P.; Milner, B.; Fuhrman, D.; Marks, A.; Sargent, R.; Cartwright, P.; Matsunami, N.; White, R. : Genetic mapping of the BRCA1 region on chromosome 17q21. Am. J. Hum. Genet. 54: 516-525, 1994. PubMed ID : 8116621 3. Albertsen, H. M.; Smith, S. A.; Mazoyer, S.; Fujimoto, E.; Stevens, J.; Williams, B.; Rodriguez, P.; Cropp, C. S.; Slijepcevic, P.; Carlson, M.; Robertson, M.; Bradley, P.; Lawrence, E.; Harrington, T.; Mei Sheng, Z.; Hoopes, R.; Sternberg, N.; Brothman, A.; Callahan, R.; Ponder, B. A. J.; White, R. : A physical map and candidate genes in the BRCA1 region on chromosome 17q12-21. Nature Genet. 7: 472-479, 1994. PubMed ID : 7951316 4. Andersen, T. I.; Borresen, A.-L.; Moller, P. : A common BRCA1 mutation in Norwegian breast and ovarian cancer families? Am. J. Hum. Genet. 59: 486-487, 1996. PubMed ID : 8755943 5. Anderson, S. F.; Schlegel, B. P.; Nakajima, T.; Wolpin, E. S.; Parvin, J. D. : BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nature Genet. 19: 254-256, 1998. PubMed ID : 9662397 6. Antoniou, A.; Pharoah, P. D. P.; Narod, S.; Risch, H. A.; Eyfjord, J. E.; Hopper, J. L.; Loman, N.; Olsson, H.; Johannsson, O.; Borg, A.; Pasini, B.; Radice, P.; and 21 others : Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am. J. Hum. Genet. 72: 1117-1130, 2003. Note: Erratum: Am. J. Hum. Genet. 73: 709 only, 2003. PubMed ID : 12677558 7. Arason, A.; Barkardottir, R. B.; Egilsson, V. : Linkage analysis of chromosome 17q markers and breast-ovarian cancer in Icelandic families, and possible relationship to prostatic cancer. Am. J. Hum. Genet. 52: 711-717, 1993. PubMed ID : 8460636 8. Bahar, A. Y.; Taylor, P. J.; Andrews, L.; Proos, A.; Burnett, L.; Tucker, K.; Friedlander, M.; Buckley, M. F. : The frequency of founder mutations in the BRCA1, BRCA2, and APC genes in Australian Ashkenazi Jews: implications for the generality of U.S. population data. Cancer 92: 440-445, 2001. PubMed ID : 11466700 9. Bandera, C. A.; Muto, M. G.; Schorge, J. O.; Berkowitz, R. S.; Rubin, S. C.; Mok, S. C. : BRCA1 gene mutations in women with papillary serous carcinoma of the peritoneum. Obstet. Gynec. 92: 596-600, 1998. PubMed ID : 9764635 10. Bar-Sade, R. B.; Kruglikova, A.; Modan, B.; Gak, E.; Hirsh-Yechezkel, G.; Theodor, L.; Novikov, I.; Gershoni-Baruch, R.; Risel, S.; Papa, M. Z.; Ben-Baruch, G.; Friedman, E. : The 185delAG BRCA1 mutation originated before the dispersion of Jews in the Diaspora and is not limited to Ashkenazim. Hum. Molec. Genet. 7: 801-805, 1998. PubMed ID : 9536083 11. Bar-Sade, R. B.; Theodor, L.; Gak, E.; Kruglikova, A.; Hirsch-Yechezkel, G.; Modan, B.; Kuperstein, G.; Seligsohn, U.; Rechavi, G.; Friedman, E. : Could the 185delAG BRCA1 mutation be an ancient Jewish mutation? Europ. J. Hum. Genet. 5: 413-416, 1997. PubMed ID : 9450187 12. Barker, D. F.; Almeida, E. R. A.; Casey, G.; Fain, P. R.; Liao, S. Y.; Masunaka, I.; Noble, B.; Kurosaki, T.; Anton-Culver, H. : BRCA1 R841W: a strong candidate for a common mutation with moderate phenotype. Genet. Epidemiol. 13: 595-604, 1996. PubMed ID : 8968716 13. Bennett, L. M.; Haugen-Strano, A.; Cochran, C.; Brownlee, H. A.; Fiedorek, F. T., Jr.; Wiseman, R. W. : Isolation of the mouse homologue of BRCA1 and genetic mapping to mouse chromosome 11. Genomics 29: 576-581, 1995. PubMed ID : 8575748 14. Bergman, A.; Einbeigi, Z.; Olofsson, U.; Taib, Z.; Wallgren, A.; Karlsson, P.; Wahlstrom, J.; Martinsson, T.; Nordling, M. : The western Swedish BRCA1 founder mutation 3171ins5; a 3.7 cM conserved haplotype of today is a reminiscence of a 1500-year-old mutation. Europ. J. Hum. Genet. 9: 787-793, 2001. PubMed ID : 11781691 15. Bochar, D. A.; Wang, L.; Beniya, H.; Kinev, A.; Xue, Y.; Lane, W. S.; Wang, W.; Kashanchi, F.; Shiekhattar, R. : BRCA1 is associated with a human SWI/SNF-related complex: linking chromatin remodeling to breast cancer. Cell 102: 257-265, 2000. PubMed ID : 10943845 16. Boyd, J.; Sonoda, Y.; Federici, M. G.; Bogomolniy, F.; Rhei, E.; Maresco, D. L.; Saigo, P. E.; Almadrones, L. A.; Barakat, R. R.; Brown, C. L.; Chi, D. S.; Curtin, J. P.; Poynor, E. A.; Hoskins, W. J. : Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. J.A.M.A. 283: 2260-2265, 2000. PubMed ID : 10807385 17. BRCA1 Exon 13 Duplication Screening Group : The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. Am. J. Hum. Genet. 67: 207-212, 2000. PubMed ID : 10827109 18. Breast Cancer Linkage Consortium : Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 and BRCA2 mutations and sporadic cases. Lancet 349: 1505-1510, 1997. PubMed ID : 9167459 19. Briki, F.; Busson, B.; Salicru, B.; Esteve, F.; Doucet, J. : Breast-cancer diagnosis using hair. (Letter) Nature 400: 220 only, 1999. 20. Brown, M. A.; Lo, L.-J.; Catteau, A.; Xu, C.-F.; Lindeman, G. J.; Hodgson, S.; Solomon, E. : Germline BRCA1 promoter deletions in UK and Australian familial breast cancer patients: identification of a novel deletion consistent with BRCA1:psi-BRCA1 recombination. Hum. Mutat. 19: 435-442, 2002. PubMed ID : 11933198 21. Brown, M. A.; Nicolai, H.; Xu, C.-F.; Griffiths, B. L.; Jones, K. A.; Solomon, E.; Hosking, L.; Trowsdale, J.; Black, D. M.; McFarlane, R. : Regulation of BRCA1. (Letter) Nature 372: 733 only, 1994. PubMed ID : 7997258 22. Brown, M. A.; Xu, C.-F.; Nicolai, H.; Griffiths, B.; Chambers, J. A.; Black, D.; Solomon, E. : The 5-prime end of the BRCA1 gene lies within a duplicated region of human chromosome 17q21. Oncogene 12: 2507-2513, 1996. PubMed ID : 8700509 23. Castilla, L. H.; Couch, F. J.; Erdos, M. R.; Hoskins, K. F.; Calzone, K.; Garber, J. E.; Boyd, J.; Lubin, M. B.; Deshano, M. L.; Brody, L. C.; Collins, F. S.; Weber, B. L. : Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nature Genet. 8: 387-391, 1994. PubMed ID : 7894491 24. Chen, J.; Silver, D. P.; Walpita, D.; Cantor, S. B.; Gazdar, A. F.; Tomlinson, G.; Couch, F. J.; Weber, B. L.; Ashley, T.; Livingston, D. M.; Scully, R. : Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Molec. Cell 2: 317-328, 1998. PubMed ID : 9774970 25. Chen, Y.; Chen, C.-F.; Riley, D. J.; Allred, D. C.; Chen, P.-L.; Von Hoff, D.; Osborne, C. K.; Lee, W.-H. : Aberrant subcellular localization of BRCA1 in breast cancer. Science 270: 789-791, 1995. PubMed ID : 7481765 26. Chen, Y.; Farmer, A. A.; Chen, C.-F.; Jones, D. C.; Chen, P.-L.; Lee, W.-H. : BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res. 56: 3168-3172, 1996. PubMed ID : 8764100 27. Claus, E. B.; Risch, N.; Thompson, W. D. : Genetic analysis of breast cancer in the cancer and steroid hormone study. Am. J. Hum. Genet. 48: 232-242, 1991. PubMed ID : 1990835 28. Coene, E.; Van Oostveldt, P.; Willems, K.; van Emmelo, J.; De Potter, C. R. : BRCA1 is localized in cytoplasmic tube-like invaginations in the nucleus. (Letter) Nature Genet. 116: 122-124, 1997. 29. Cornelis, R. S.; Vasen, H. F. A.; Meijers-Heijboer, H.; Ford, D.; van Vliet, M.; van Tilborg, A. A. G.; Cleton, F. J.; Klijn, J. G. M.; Menko, F. H.; Khan, P. M.; Cornelisse, C. J.; Devilee, P. : Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer. Hum. Genet. 95: 539-544, 1995. PubMed ID : 7759075 30. Cortez, D.; Wang, Y.; Qin, J.; Elledge, S. J. : Requirement of ATM-dependent phosphorylation of Brca1 in the DNA damage response to double-strand breaks. Science 286: 1162-1166, 1999. PubMed ID : 10550055 31. Couch, F. J.; DeShano, M. L.; Blackwood, M. A.; Calzone, K.; Stopfer, J.; Campeau, L.; Ganguly, A.; Rebbeck, T.; Weber, B. L. : BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. New Eng. J. Med. 336: 1409-1415, 1997. PubMed ID : 9145677 32. Couch, F. J.; Weber, B. L.; Breast Cancer Information Core : Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Hum. Mutat. 8: 8-18, 1996. PubMed ID : 8807330 33. De Gregorio, L.; Harshman, K.; Rosenthal, J.; Dragani, T. A.; Pierotti, M. A. : Genetic mapping of the Brca1 gene on mouse chromosome 11. Mammalian Genome 7: 242, 1996. PubMed ID : 8833256 34. De Los Rios, P.; Jack, E.; Kuperstein, G.; Lynch, H.; Lubinski, J.; Narod, S. A. : Founder mutations in BRCA1 and BRCA2 in North American families of Polish origin that are affected with breast cancer. (Letter) Am. J. Hum. Genet. 68: 546 only, 2001. PubMed ID : 11170903 35. Deng, C.-X.; Wang, R.-H. : Roles of BRCA1 in DNA damage repair: a link between development and cancer. Hum. Molec. Genet. 12(R1): R113-R123, 2003. PubMed ID : 12668603 36. Diez, O.; Osorio, A.; Duran, M.; Martinez-Ferrandis, J. I.; de la Hoya, M.; Salazar, R.; Vega, A.; Campos, B.; Rodriguez-Lopez, R.; Velasco, E.; Chaves, J.; Diaz-Rubio, E.; and 13 others : Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum. Mutat. 22: 301-312, 2003. PubMed ID : 12955716 37. Dorum, A.; Heimdal, K.; Hovig, E.; Inganas, M.; Moller, P. : Penetrances of BRCA1 1675delA and 1135insA with respect to breast cancer and ovarian cancer. Am. J. Hum. Genet. 65: 671-679, 1999. PubMed ID : 10441573 38. Dorum, A.; Moller, P.; Kamsteeg, E. J.; Scheffer, H.; Burton, M.; Heimdal, K. R.; Maehle, L. O.; Hovig, E.; Trope, C. G.; van der Hout, A. H.; van der Meulen, M. A.; Buys, C. H. C. M.; te Meerman, G. J. : A BRCA1 founder mutation, identified with haplotype analysis, allowing genotype/phenotype determination and predictive testing. Europ. J. Cancer 33: 2390-2392, 1997. 39. Dunning, A. M.; Chiano, M.; Smith, N. R.; Dearden, J.; Gore, M.; Oakes, S.; Wilson, C.; Stratton, M.; Peto, J.; Easton, D.; Clayton, D.; Ponder, B. A. J. : Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. Hum. Molec. Genet. 6: 285-289, 1997. PubMed ID : 9063749 40. Easton, D. F.; Bishop, D. T.; Ford, D.; Crockford, G. P.; Breast Cancer Linkage Consortium : Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. Am. J. Hum. Genet. 52: 678-701, 1993. PubMed ID : 8460634 41. Easton, D. F.; Hopper, J. L.; Thomas, D. C.; Antoniou, A.; Pharoah, P. D. P.; Whittemore, A. S.; Haile, R. W. : Breast cancer risks for BRCA1/2 carriers. (Letter) Science 306: 2187-2188, 2004. PubMed ID : 15622557 42. Eisen, A.; Weber, B. L. : Prophylactic mastectomy for women with BRCA1 and BRCA2 mutations--facts and controversy. (Editorial) New Eng. J. Med. 345: 207-208, 2001. PubMed ID : 11463017 43. ElShamy, W. M.; Livingston, D. M. : Identification of BRCA1-IRIS, a BRCA1 locus product. Nature Cell Biol. 6: 954-967, 2004. PubMed ID : 15448696 44. Fan, S.; Wang, J.-A.; Yuan, R.; Ma, Y.; Meng, Q.; Erdos, M. R.; Pestell, R. G.; Yuan, F.; Auborn, K. J.; Goldberg, I. D.; Rosen, E. M. : BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science 284: 1354-1356, 1999. PubMed ID : 10334989 45. FitzGerald, M. G.; MacDonald, D. J.; Krainer, M.; Hoover, I.; O'Neil, E.; Unsal, H.; Silva-Arrieto, S.; Finkelstein, D. M.; Beer-Romero, P.; Englert, C.; Sgroi, D. C.; Smith, B. L.; Younger, J. W.; Garber, J. E.; Duda, R. B.; Mayzel, K. A.; Isselbacher, K. J.; Friend, S. H.; Haber, D. A. : Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. New Eng. J. Med. 334: 143-149, 1996. PubMed ID : 8531968 46. Fleming, M. A.; Potter, J. D.; Ramirez, C. J.; Ostrander, G. K.; Ostrander, E. A. : Understanding missense mutations in the BRCA1 gene: an evolutionary approach. Proc. Nat. Acad. Sci. 100: 1151-1156, 2003. PubMed ID : 12531920 47. Fodor, F. H.; Weston, A.; Bleiweiss, I. J.; McCurdy, L. D.; Walsh, M. M.; Tartter, P. I.; Brower, S. T.; Eng, C. M. : Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients. Am. J. Hum. Genet. 63: 45-51, 1998. PubMed ID : 9634504 48. Folias, A.; Matkovic, M.; Bruun, D,; Reid, S.; Hejna, J.; Grompe, M.; D'Andrea, A.; Moses, R. : BRCA1 interacts directly with the Fanconi anemia protein FANCA. Hum. Molec.Genet. 11: 2591-2597, 2002. PubMed ID : 12354784 49. Ford, D.; Easton, D. F.; Stratton, M.; Narod, S.; Goldgar, D.; Devilee, P.; Bishop, D. T.; Weber, B.; Lenoir, G.; Chang-Claude, J.; Sobol, H.; Teare, M. D.; and 27 others : Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am. J. Hum. Genet. 62: 676-689, 1998. PubMed ID : 9497246 50. Ford, J. M.; Hanawalt, P. C. : Expression of wild-type p53 is required for efficient global genomic nucleotide excision repair in UV-irradiated human fibroblasts. J. Biol. Chem. 272: 28073-28080, 1997. PubMed ID : 9346961 51. Ford, J. M.; Hanawalt, P. C. : Li-Fraumeni syndrome fibroblasts homozygous for p53 mutations are deficient in global DNA repair but exhibit normal transcription-coupled repair and enhanced UV resistance. Proc. Nat. Acad. Sci. 92: 8876-8880, 1995. PubMed ID : 7568035 52. Franceschi, S.; Parazzini, F.; Negri, E.; Booth, M.; La Vecchia, C.; Beral, V.; Tzonov, A.; Trichopoulos, D. : Pooled analysis of 3 European case-control studies of epithelial ovarian cancer. III. Oral contraceptive use. Int. J. Cancer 49: 61-65, 1991. PubMed ID : 1874572 53. Friedman, E.; Bar-Sade, R. B.; Kruglikova, A.; Risel, S.; Levy-Lahad, E.; Halle, D.; Bar-On, E.; Gershoni-Baruch, R.; Dagan, E.; Kepten, I.; Peretz, T.; Lerer, I.; Wienberg, N.; Shushan, A.; Abeliovich, D. : Double heterozygotes for the Ashkenazi founder mutations in BRCA1 and BRCA2 genes. (Letter) Am. J. Hum. Genet. 63: 1224-1227, 1998. PubMed ID : 9758598 54. Friedman, L. S.; Gayther, S. A.; Kurosaki, T.; Gordon, D.; Noble, B.; Casey, G.; Ponder, B. A. J.; Anton-Culver, H. : Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population. Am. J. Hum. Genet. 60: 313-319, 1997. PubMed ID : 9012404 55. Friedman, L. S.; Ostermeyer, E. A.; Szabo, C. I.; Dowd, P.; Lynch, E. D.; Rowell, S. E.; King, M.-C. : Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nature Genet. 8: 399-404, 1994. PubMed ID : 7894493 56. Friedman, L. S.; Szabo, C. I.; Ostermeyer, E. A.; Dowd, P.; Butler, L.; Park, T.; Lee, M. K.; Goode, E. L.; Rowell, S. E.; King, M.-C. : Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. Am. J. Hum. Genet. 57: 1284-1297, 1995. PubMed ID : 8533757 57. Futreal, P. A.; Liu, Q.; Shattuck-Eidens, D.; Cochran, C.; Harshman, K.; Tavtigian, S.; Bennett, L. M.; Haugen-Strano, A.; Swensen, J.; Miki, Y.; Eddington, K.; McClure, M.; and 15 others : BRCA1 mutation in primary breast and ovarian carcinomas. Science 266: 120-122, 1994. PubMed ID : 7939630 58. Ganesan, S.; Silver, D. P.; Greenberg, R. A.; Avni, D.; Drapkin, R.; Miron, A.; Mok, S. C.; Randrianarison, V.; Brodie, S.; Salstrom, J.; Rasmussen, T. P.; Klimke, A.; Marrese, C.; Marahrens, Y.; Deng, C.-X.; Feunteun, J.; Livingston, D. M. : BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell 111: 393-405, 2002. PubMed ID : 12419249 59. Garcia-Higuera, I.; Taniguchi, T.; Ganesan, S.; Meyn, M. S.; Timmers, C.; Hejna, J.; Grompe, M.; D'Andrea, A. D. : Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Molec. Cell 7: 249-262, 2001. PubMed ID : 11239454 60. Gayther, S. A.; Harrington, P.; Russell, P.; Kharkevich, G.; Garkavtseva, R. F.; Ponder, B. A. J. : Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia. (Letter) Am. J. Hum. Genet. 60: 1239-1242, 1997. PubMed ID : 9150173 61. Gayther, S. A.; Harrington, P.; Russell, P.; Kharkevich, G.; Garkavtseva, R. F.; Ponder, B. A. J.; UKCCCR Familial Ovarian Cancer Study Group : Rapid detection of regionally clustered germ-line BRCA1 mutations by multiplex heteroduplex analysis. Am. J. Hum. Genet. 58: 451-456, 1996. PubMed ID : 8644703 62. Gayther, S. A.; Warren, W.; Mazoyer, S.; Russell, P. A.; Harrington, P. A.; Chiano, M.; Seal, S.; Hamoudi, R.; van Rensburg, E. J.; Dunning, A. M.; Love, R.; Evans, G.; Easton, D.; Clayton, D.; Stratton, M. R.; Ponder, B. A. J. : Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nature Genet. 11: 428-433, 1995. PubMed ID : 7493024 63. Giusti, R. M.; Rutter, J. L.; Duray, P. H.; Freedman, L. S.; Konichezky, M.; Fisher-Fischbein, J.; Greene, M. H.; Maslansky, B.; Fischbein, A.; Gruber, S. B.; Rennert, G.; Ronchetti, R. D.; Hewitt, S. M.; Struewing, J. P.; Iscovich, J. : A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J. Med. Genet. 40: 787-792, 2003. PubMed ID : 14569130 64. Goldgar, D. E.; Fields, P.; Lewis, C. M.; Cannon-Albright, L. A.; Linker, G.; Tran, T.; Skolnick, M. : A large kindred with 17q-linked susceptibility to breast and ovarian cancer: relationship between genotype and phenotype. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A27, 1992. 65. Goldgar, D. E.; Reilly, P. R. : A common BRCA1 mutation in the Ashkenazim. Nature Genet. 11: 113-114, 1995. PubMed ID : 7550331 66. Gorski, B.; Byrski, T.; Huzarski, T.; Jakubowska, A.; Menkiszak, J.; Gronwald, J.; Pluzanska, A.; Bebenek, M.; Fischer-Maliszewska, L.; Grzybowska, E.; Narod, S. A.; Lubinski, J. : Founder mutations in the BRCA1 gene in Polish families with breast-ovarian cancer. Am. J. Hum. Genet. 66: 1963-1968, 2000. PubMed ID : 10788334 67. Gowen, L. C.; Avrutskaya, A. V.; Latour, A. M.; Koller, B. H.; Leadon, S. A. : Retraction. (Letter) Science 300: 1657 only, 2003. PubMed ID : 12805518 68. Gowen, L. C.; Avrutskaya, A. V.; Latour, A. M.; Koller, B. H.; Leadon, S. A. : BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science 281: 1009-1012, 1998. Note: Retracted. PubMed ID : 9703501 69. Gowen, L. C.; Johnson, B. L.; Latour, A. M.; Sulik, K. K.; Koller, B. H. : Brca1 deficiency results in early embryonic lethality characterized by neuroepithelial abnormalities. Nature Genet. 12: 191-194, 1996. PubMed ID : 8563759 70. Hacia, J. G.; Brody, L. C.; Chee, M. S.; Fodor, S. P. A.; Collins, F. S. : Detection of heterozygous mutations in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence analysis. Nature Genet. 14: 441-447, 1996. PubMed ID : 8944024 71. Hakem, R.; de la Pompa, J. L.; Elia, A.; Potter, J.; Mak, T. W. : Partial rescue of Brca1(5-6) early embryonic lethality by p53 or p21 null mutation. Nature Genet. 16: 298-302, 1997. PubMed ID : 9207798 72. Hakem, R.; de la Pompa, J. L.; Sirard, C.; Mo, R.; Woo, M.; Hakem, A.; Wakeham, A.; Potter, J.; Reitmair, A.; Billia, F.; Firpo, E.; Hui, C. C.; Roberts, J.; Rossant, J.; Mak, T. W. : The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell 85: 1009-1023, 1996. PubMed ID : 8674108 73. Hall, J. M.; Friedman, L.; Guenther, C.; Lee, M. K.; Weber, J. L.; Black, D. M.; King, M.-C. : Closing in on a breast cancer gene on chromosome 17q. Am. J. Hum. Genet. 50: 1235-1242, 1992. PubMed ID : 1598904 74. Hall, J. M.; Lee, M. K.; Newman, B.; Morrow, J. E.; Anderson, L. A.; Huey, B.; King, M.-C. : Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250: 1684-1689, 1990. PubMed ID : 2270482 75. Hamann, U.; Haner, M.; Stosiek, U.; Bastert, G.; Scott, R. J. : Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families. J. Med. Genet. 34: 884-888, 1997. PubMed ID : 9391879 76. Harkin, D. P.; Bean, J. M.; Miklos, D.; Song, Y.-H.; Truong, V. B.; Englert, C.; Christians, F. C.; Ellisen, L. W.; Maheswaran, S.; Oliner, J. D.; Haber, D. A. : Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97: 575-586, 1999. PubMed ID : 10367887 77. Hartman, A.-R.; Ford, J. M. : BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nature Genet. 32: 180-184, 2002. PubMed ID : 12195423 78. Hedenfalk, I.; Duggan, D.; Chen, Y.; Radmacher, M.; Bittner, M.; Simon, R.; Meltzer, P.; Gusterson, B.; Esteller, M.; Kallioniemi, O.-P.; Wilfond, B.; Borg, A.; Trent, J. : Gene-expression profiles in hereditary breast cancer. New Eng. J. Med. 344: 539-548, 2001. PubMed ID : 11207349 79. Hogervorst, F. B. L.; Cornelis, R. S.; Bout, M.; van Vliet, M.; Oosterwijk, J. C.; Olmer, R.; Bakker, B.; Klijn, J. G. M.; Vasen, H. F. A.; Meijers-Heijboer, H.; Menko, F. H.; Cornelisse, C. J.; den Dunnen, J. T.; Devilee, P.; van Ommen, G.-J. B. : Rapid detection of BRCA1 mutations by the protein truncation test. Nature Genet. 10: 208-212, 1995. PubMed ID : 7663517 80. Holt, J. T.; Thompson, M. E.; Szabo, C.; Robinson-Benion, C.; Arteaga, C. L.; King, M.-C.; Jensen, R. A. : Growth retardation and tumour inhibition by BRCA1. Nature Genet. 12: 298-302, 1996. PubMed ID : 8589721 81. Huttley, G. A.; Easteal, S.; Southey, M. C.; Tesoriero, A.; Giles, G. G.; McCredie, M. R. E.; Hopper, J. L.; Venter, D. J.; Australian Breast Cancer Family Study : Adaptive evolution of the tumour suppressor BRCA1 in humans and chimpanzees. Nature Genet. 25: 410-413, 2000. PubMed ID : 10932184 82. Isaacs, S. D.; Kiemeney, L. A. L. M.; Baffoe-Bonnie, A.; Beaty, T. H.; Walsh, P. C. : Risk of cancer in relatives of prostate cancer probands. J. Nat. Cancer Inst. 87: 991-996, 1995. PubMed ID : 7629886 83. Ishioka, C.; Suzuki, T.; Fitzgerald, M.; Krainer, M.; Shimodaira, H.; Shimada, A.; Nomizu, T.; Isselbacher, K. J.; Haber, D.; Kanamaru, R. : Detection of heterozygous truncating mutations in the BRCA1 and APC genes by using a rapid screening assay in yeast. Proc. Nat. Acad. Sci. 94: 2449-2453, 1997. PubMed ID : 9122215 84. James, V.; Kearsley, J.; Irving, T.; Amemiya, Y.; Cookson, D. : Using hair to screen for breast cancer. Nature 398: 33-34, 1999. PubMed ID : 10078527 85. Janezic, S. A.; Ziogas, A.; Krumroy, L. M.; Krasner, M.; Plummer, S. J.; Cohen, P.; Gildea, M.; Barker, D.; Haile, R.; Casey, G.; Anton-Culver, H. : Germline BRCA1 alterations in a population-based series of ovarian cancer cases. Hum. Molec. Genet. 8: 889-897, 1999. PubMed ID : 10196379 86. Jensen, R. A.; Thompson, M. E.; Jetton, T. L.; Szabo, C. I.; van der Meer, R.; Helou, B.; Tronick, S. R.; Page, D. L.; King, M.-C.; Holt, J. T. : BRCA1 is secreted and exhibits properties of a granin. Nature Genet. 12: 303-308, 1996. PubMed ID : 8589722 87. Jin, Y.; Xu, X. L.; Yang, M.-C. W.; Wei, F.; Ayi, T.-C.; Bowcock, A. M.; Baer, R. : Cell cycle-dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains. Proc. Nat. Acad. Sci. 94: 12075-12080, 1997. PubMed ID : 9342365 88. Johannsson, O.; Ostermeyer, E. A.; Hakansson, S.; Friedman, L. S.; Johansson, U.; Sellberg, G.; Brondum-Nielsen, K.; Sele, V.; Olsson, H.; King, M.-C.; Borg, A. : Founding BRCA1 mutations in hereditary breast and ovarian cancer in Southern Sweden. Am. J. Hum. Genet. 58: 441-450, 1996. PubMed ID : 8644702 89. Kauff, N. D.; Satagopan, J. M.; Robson, M. E.; Scheuer, L.; Hensley, M.; Hudis, C. A.; Ellis, N. A.; Boyd, J.; Borgen, P. I.; Barakat, R. R.; Norton, L.; Offit, K. : Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. New Eng. J. Med. 346: 1609-1615, 2002. PubMed ID : 12023992 90. Kelsell, D. P.; Black, D. M.; Bishop, D. T.; Spurr, N. K. : Genetic analysis of the BRCA1 region in a large breast/ovarian family: refinement of the minimal region containing BRCA1. Hum. Molec. Genet. 2: 1823-1828, 1993. PubMed ID : 8281142 91. Khavari, P. A.; Peterson, C. L.; Tamkun, J. W.; Mendel, D. B.; Crabtree, G. R. : BRG1 contains a conserved domain of the SWI2/SNF2 family necessary for normal mitotic growth and transcription. Nature 366: 170-174, 1993. PubMed ID : 8232556 92. King, M.-C. : Response to Breast cancer risks for BRCA1/2 carriers. (Letter) Science 306: 2188-2191, 2004. 93. King, M.-C.; Marks, J. H.; Mandell, J. B. : Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302: 643-646, 2003. PubMed ID : 14576434 94. Krainer, M.; Silva-Arrieta, S.; Fitzgerald, M. G.; Shimada, A.; Ishioka, C.; Kanamaru, R.; MacDonald, D. J.; Unsal, H.; Finkelstein, D. M.; Bowcock, A.; Isselbacher, K. J.; Haber, D. A. : Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. New Eng. J. Med. 336: 1416-1421, 1997. PubMed ID : 9145678 95. Langston, A. A.; Malone, K. E.; Thompson, J. D.; Daling, J. R.; Ostrander, E. A. : BRCA1 mutations in a population-based sample of young women with breast cancer. New Eng. J. Med. 334: 137-142, 1996. PubMed ID : 8531967 96. Langston, A. A.; Stanford, J. L.; Wicklund, K. G.; Thompson, J. D.; Blazej, R. G.; Ostrander, E. A. : Germ-line BRCA1 mutations in selected men with prostate cancer. (Letter) Am. J. Hum. Genet. 58: 881-885, 1996. PubMed ID : 8644752 97. Lee, C. G.; Hurwitz, J. : Human RNA helicase A is homologous to the maleless protein of Drosophila. J. Biol. Chem. 268: 16822-16830, 1993. PubMed ID : 8344961 98. Lee, J.-S.; Collins, K. M.; Brown, A. L.; Lee, C.-H.; Chung, J. H. : hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404: 201-204, 2000. PubMed ID : 10724175 99. Li, S.; Ting, N. S. Y.; Zheng, L.; Chen, P.-L.; Ziv, Y.; Shiloh, Y.; Lee, E. Y.-H. P.; Lee, W.-H. : Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406: 210-215, 2000. PubMed ID : 10910365 100. Liede, A.; Malik, I. A.; Aziz, Z.; de los Rios, P.; Kwan, E.; Narod, S. A. : Contribution of BRCA1 and BRCA2 mutations to breast and ovarian cancer in Pakistan. Am. J. Hum. Genet. 71: 595-606, 2002. PubMed ID : 12181777 101. Liede, A.; Rehal, P.; Vesprini, D.; Jack, E.; Abrahamson, J.; Narod, S. A. : A breast cancer patient of Scottish descent with germ-line mutations in BRCA1 and BRCA2. (Letter) Am. J. Hum. Genet. 62: 1543-1544, 1998. PubMed ID : 9585617 102. Liu, H.-X.; Cartegni, L.; Zhang, M. Q.; Krainer, A. R. : A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes. Nature Genet. 27: 55-58, 2001. PubMed ID : 11137998 103. Lorick, K. L.; Jensen, J. P.; Fang, S.; Ong, A. M.; Hatakeyama, S.; Weissman, A. M. : RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc. Nat. Acad. Sci. 96: 11364-11369, 1999. PubMed ID : 10500182 104. Ludwig, T.; Chapman, D. L.; Papaioannou, V. E.; Efstratiadis, A. : Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 11: 1226-1241, 1997. PubMed ID : 9171368 105. Lynch, H. T.; Watson, P. : Genetic counselling and hereditary breast/ovarian cancer. (Letter) Lancet 339: 1181 only, 1992. PubMed ID : 1349410 106. Maor, S. B.; Abramovitch, S.; Erdos, M. R.; Brody, L. C.; Werner, H. : BRCA1 suppresses insulin-like growth factor-I receptor promoter activity: potential interaction between BRCA1 and Sp1. Molec. Genet. Metab. 69: 130-136, 2000. 107. Margaritte, P.; Bonaiti-Pellie, C.; King, M.-C.; Clerget-Darpoux, F. : Linkage of familial breast cancer to chromosome 17q21 may not be restricted to early-onset disease. Am. J. Hum. Genet. 50: 1231-1234, 1992. PubMed ID : 1598903 108. McCarthy, E. E.; Celebi, J. T.; Baer, R.; Ludwig, T. : Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Molec. Cell. Biol. 23: 5056-5063, 2003. PubMed ID : 12832489 109. Mefford, H. C.; Baumbach, L.; Panguluri, R. C. K.; Whitfield-Broome, C.; Szabo, C.; Smith, S.; King, M.-C.; Dunston, G.; Stoppa-Lyonnet, D.; Arena, F. : Evidence for a BRCA1 founder mutation in families of West African ancestry. (Letter) Am. J. Hum. Genet. 65: 575-578, 1999. PubMed ID : 10417303 110. Meijers-Heijboer, E. J.; Verhoog, L. C.; Brekelmans, C. T. M.; Seynaeve, C.; Tilanus-Linthorst, M. M. A.; Wagner, A.; Dukel, L.; Devilee, P.; van den Ouweland, A. M. W.; van Geel, A. N.; Klijn, J. G. M. : Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355: 2015-2020, 2000. PubMed ID : 10885351 111. Meijers-Heijboer, H.; van Geel, B.; van Putten, W. L. J.; Henzen-Logmans, S. C.; Seynaeve, C.; Menke-Pluymers, M. B. E.; Bartels, C. C. M.; Verhoog, L. C.; van den Ouweland, A. M. W.; Niermeijer, M. F.; Brekelmans, C. T. M.; Klijn, J. G. M. : Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. New Eng. J. Med. 345: 159-164, 2001. PubMed ID : 11463009 112. Merajver, S. D.; Pham, T. M.; Caduff, R. F.; Chen, M.; Poy, E. L.; Cooney, K. A.; Weber, B. L.; Collins, F. S.; Johnston, C.; Frank, T. S. : Somatic mutations in the BRCA1 gene in sporadic ovarian tumours. Nature Genet. 9: 439-443, 1995. PubMed ID : 7795652 113. Miki, Y.; Swensen, J.; Shattuck-Eidens, D.; Futreal, P. A.; Harshman, K.; Tavtigian, S.; Liu, Q.; Cochran, C.; Bennett, L. M.; Ding, W.; Bell, R.; Rosenthal, J.; and 33 others : A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66-71, 1994. PubMed ID : 7545954 114. Montagna, M.; Dalla Palma, M.; Menin, C.; Agata, S.; De Nicolo, A.; Chieco-Bianchi, L.; D'Andrea, E. : Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum. Molec. Genet. 12: 1055-1061, 2003. PubMed ID : 12700174 115. Monteiro, A. N. A.; August, A.; Hanafusa, H. : Evidence for a transcriptional activation function of BRCA1 C-terminal region. Proc. Nat. Acad. Sci. 93: 13595-13599, 1996. PubMed ID : 8942979 116. Moynahan, M. E.; Chiu, J. W.; Koller, B. H.; Jasin, M. : Brca1 controls homology-directed DNA repair. Molec. Cell 4: 511-518, 1999. PubMed ID : 10549283 117. Narod, S.; Feunteun, J.; Lynch, H.; Watson, P.; Conway, T.; Lynch, J.; Lenoir, G. : A breast-ovarian cancer locus on chromosome 17. (Abstract) Am. J. Hum. Genet. 49 (suppl.): 352, 1991. 118. Narod, S.; Ford, D.; Devilee, P.; Barkardottir, R. B.; Eyfjord, J.; Lenoir, G.; Serova, O.; Easton, D.; Goldgar, D.; Breast Cancer Linkage Consortium : Genetic heterogeneity of breast-ovarian cancer revisited. (Letter) Am. J. Hum. Genet. 57: 957-958, 1995. PubMed ID : 7573057 119. Narod, S.; Tonin, P.; Lynch, H.; Watson, P.; Feunteun, J.; Lenoir, G. : Histology of BRCA1-associated ovarian tumours. (Letter) Lancet 343: 236 only, 1994. PubMed ID : 7904689 120. Narod, S. A.; Feunteun, J.; Lynch, H. T.; Watson, P.; Conway, T.; Lynch, J.; Lenoir, G. M. : Familial breast-ovarian cancer locus on chromosome 17q12-q23. Lancet 338: 82-83, 1991. PubMed ID : 1676470 121. Narod, S. A.; Ford, D.; Devilee, P.; Barkardottir, R. B.; Lynch, H. T.; Smith, S. A.; Ponder, B. A. J.; Weber, B. L.; Garber, J. E.; Birch, J. M.; Cornelis, R. S.; Kelsell, D. P.; and 17 others : An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Am. J. Hum. Genet. 56: 254-264, 1995. PubMed ID : 7825586 122. Narod, S. A.; Risch, H.; Moslehi, R.; Dorum, A.; Neuhausen, S.; Olsson, H.; Provencher, D.; Radice, P.; Evans, G.; Bishop, S.; Brunet, J.-S.; Ponder, B. A. J.; Hereditary Ovarian Cancer Clinical Study Group : Oral contraceptives and the risk of hereditary ovarian cancer. New Eng. J. Med. 339: 424-428, 1998. PubMed ID : 9700175 123. Nastiuk, K. L.; Mansukhani, M.; Terry, M. B.; Kularatne, P.; Rubin, M. A.; Melamed, J.; Gammon, M. D.; Ittmann, M.; Krolewski, J. J. : Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40: 172-177, 1999. PubMed ID : 10398279 124. Nathanson, K. L.; Shugart, Y. Y.; Omaruddin, R.; Szabo, C.; Goldgar, D.; Rebbeck, T. R.; Weber, B. L. : CGH-targeted linkage analysis reveals a possible BRCA1 modifier locus on chromosome 5q. Hum. Molec. Genet. 11: 1327-1332, 2002. PubMed ID : 12019214 125. Neuhausen, S. L.; Mazoyer, S.; Friedman, L.; Stratton, M.; Offit, K.; Caligo, A.; Tomlinson, G.; Cannon-Albright, L.; Bishop, T.; Kelsell, D.; Solomon, E.; Weber, B.; Couch, F.; Struewing, J.; Tonin, P.; Durocher, F.; Narod, S.; Skolnick, M. H.; Lenoir, G.; Serova, O.; Ponder, B.; Stoppa-Lyonnet, D.; Easton, D.; King, M.-C.; Goldgar, D. E. : Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am. J. Hum. Genet. 58: 271-280, 1996. PubMed ID : 8571953 126. O'Connell, P.; Albertsen, H.; Matsunami, N.; Taylor, T.; Hundley, J. E.; Johnson-Pais, T. L.; Reus, B.; Lawrence, E.; Ballard, L.; White, R.; Leach, R. J. : A radiation hybrid map of the BRCA1 region. Am. J. Hum. Genet. 54: 526-534, 1994. PubMed ID : 8116622 127. Pace, P.; Johnson, M.; Tan, W. M.; Mosedale, G.; Sng, C.; Hoatlin, M.; de Winter, J.; Joenje, H.; Gergely, F.; Patel, K. J. : FANCE: the link between Fanconi anaemia complex assembly and activity. EMBO J. 21: 3414-3423, 2002. PubMed ID : 12093742 128. Paull, T. T.; Cortez, D.; Bowers, B.; Elledge, S. J.; Gellert, M. : Direct DNA binding by Brca1. Proc. Nat. Acad. Sci. 98: 6086-6091, 2001. PubMed ID : 11353843 129. Perrin-Vidoz, L.; Sinilnikova, O. M.; Stoppa-Lyonnet, D.; Lenoir, G. M.; Mazoyer, S. : The nonsense-mediated mRNA decay pathway triggers degradation of most BRCA1 mRNAs bearing premature termination codons. Hum. Molec. Genet. 11: 2805-2814, 2002. PubMed ID : 12393792 130. Petrij-Bosch, A.; Peelen, T.; van Vliet, M.; van Eijk, R.; Olmer, R.; Drusedau, M.; Hogervorst, F. B. L.; Hageman, S.; Arts, P. J. W.; Ligtenberg, M. J. L.; Meijers-Heijboer, H.; Klijn, J. G. M.; Vasen, H. F. A.; Cornelisse, C. J.; van't Veer, L. J.; Bakker, E.; van Ommen, G.-J. B.; Devilee, P. : BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nature Genet. 17: 341-345, 1997. PubMed ID : 9354803 131. Phelan, C. M.; Rebbeck, T. R.; Weber, B. L.; Devilee, P.; Ruttledge, M. H.; Lynch, H. T.; Lenoir, G. M.; Stratton, M. R.; Easton, D. F.; Ponder, B. A. J.; Cannon-Albright, L.; Larsson, C.; Goldgar, D. E.; Narod, S. A. : Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nature Genet. 12: 309-311, 1996. PubMed ID : 8589723 132. Piver, M. S.; Baker, T. R.; Jishi, M. F.; Sandecki, A. M.; Tsukada, Y.; Natarajan, N.; Mettlin, C. J.; Blake, C. A. : Familial ovarian cancer: a report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 71: 582-588, 1993. PubMed ID : 8420680 133. Puget, N.; Gad, S.; Perrin-Vidoz, L.; Sinilnikova, O. M.; Stoppa-Lyonnet, D.; Lenoir, G. M.; Mazoyer, S. : Distinct BRCA1 rearrangements involving the BRCA1 pseudogene suggest the existence of a recombination hot spot. Am. J. Hum. Genet. 70: 858-865, 2002. PubMed ID : 11880951 134. Puget, N.; Sinilnikova, O. M.; Stoppa-Lyonnet, D.; Audoynaud, C.; Pages, S.; Lynch, H. T.; Goldgar, D.; Lenoir, G. M.; Mazoyer, S. : An Alu-mediated 6-kb duplication in the BRCA1 gene: a new founder mutation? Am. J. Hum. Genet. 64: 300-302, 1999. PubMed ID : 9915971 135. Puget, N.; Stoppa-Lyonnet, D.; Sinilnikova, O. M.; Pages, S.; Lynch, H. T.; Lenoir, G. M.; Mazoyer, S. : Screening for germline rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Res. 59: 455-461, 1999. PubMed ID : 9927062 136. Ramus, S. J.; Friedman, L. S.; Gayther, S. A.; Ponder, B. A. J.; Bobrow, L. G.; van der Looji, M.; Papp, J.; Olah, E. : A breast/ovarian cancer patient with germline mutations in both BRCA1 and BRCA2. (Letter) Nature Genet. 15: 14-15, 1997. PubMed ID : 8988162 137. Rebbeck, T. R.; Couch, F. J.; Kant, J.; Calzone, K.; DeShano, M.; Peng, Y.; Chen, K.; Garber, J. E.; Weber, B. L. : Genetic heterogeneity in hereditary breast cancer: role of BRCA1 and BRCA2. Am. J. Hum. Genet. 59: 547-553, 1996. PubMed ID : 8751855 138. Rebbeck, T. R.; Lynch, H. T.; Neuhausen, S. L.; Narod, S. A.; van't Veer, L.; Garber, J. E.; Evans, G.; Isaacs, C.; Daly, M. B.; Matloff, E.; Olopade, O. I.; Weber, B. L. : :Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. New Eng. J. Med. 346: 1616-1622, 2002. PubMed ID : 12023993 139. Risch, H. A.; McLaughlin, J. R.; Cole, D. E. C.; Rosen, B.; Bradley, L.; Kwan, E.; Jack, E.; Vesprini, D. J.; Kuperstein, G.; Abrahamson, J. L. A.; Fan, I.; Wong, B.; Narod, S. A. : Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am. J. Hum. Genet. 68: 700-710, 2001. PubMed ID : 11179017 140. Roa, B. B.; Boyd, A. A.; Volcik, K.; Richards, C. S. : Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nature Genet. 14: 185-187, 1996. PubMed ID : 8841191 141. Rostagno, P.; Gioanni, J.; Garino, E.; Vallino, P.; Namer, M.; Frenay, M. : A mutation analysis of the BRCA1 gene in 140 families from southeast France with a history of breast and/or ovarian cancer. J. Hum. Genet. 48: 362-366, 2003. PubMed ID : 12827452 142. Ruffner, H.; Jiang, W.; Craig, A. G.; Hunter, T.; Verma, I. M. : BRCA1 is phosphorylated at serine 1497 in vivo at a cyclin-dependent kinase 2 phosphorylation site. Molec. Cell. Biol. 19: 4843-4854, 1999. PubMed ID : 10373534 143. Sarantaus, L.; Huusko, P.; Eerola, H.; Launonen, V.; Vehmanen, P.; Rapakko, K.; Gillanders, E.; Syrjakoski, K.; Kainu, T.; Vahteristo, P.; Krahe, R.; Paakkonen, K.; and 14 others : Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Europ. J. Hum. Genet. 8: 757-763, 2000. PubMed ID : 11039575 144. Sarantaus, L.; Vahteristo, P.; Bloom, E.; Tamminen, A.; Unkila-Kallio, L.; Butzow, R.; Nevanlinna, H. : :BRCA1 and BRCA2 mutations among 233 unselected Finnish ovarian carcinoma patients. Europ. J. Hum. Genet. 9: 424-430, 2001. PubMed ID : 11436123 145. Schorge, J. O.; Muto, M. G.; Welch, W. R.; Bandera, C. A.; Rubin, S. C.; Bell, D. A.; Berkowitz, R. S.; Mok, S. C. : Molecular evidence for multifocal papillary serous carcinoma of the peritoneum in patients with germline BRCA1 mutations. J. Nat. Cancer Inst. 90: 841-845, 1998. PubMed ID : 9625172 146. Schrock, E.; Badger, P.; Larson, D.; Erdos, M.; Wynshaw-Boris, A.; Ried, T.; Brody, L. : The murine homolog of the human breast and ovarian cancer susceptibility gene Brca1 maps to mouse chromosome 11D. Hum. Genet. 97: 256-259, 1996. PubMed ID : 8566965 147. Schuyer, M.; Berns, E. M. : Is TP53 dysfunction required for BRCA1-associated carcinogenesis? Molec. Cell. Endocrin. 155: 143-152, 1999. 148. Scully, R.; Anderson, S. F.; Chao, D. M.; Wei, W.; Ye, L.; Young, R. A.; Livingston, D. M.; Parvin, J. D. : BRCA1 is a component of the RNA polymerase II holoenzyme. Proc. Nat. Acad. Sci. 94: 5605-5610, 1997. PubMed ID : 9159119 149. Scully, R.; Ganesan, S.; Brown, M.; De Caprio, J. A.; Cannistra, S. A.; Feunteun, J.; Schnitt, S.; Livingston, D. M. : Location of BRCA1 in human breast and ovarian cancer cells. Science 272: 123-125, 1996. PubMed ID : 8600523 150. Scully, R.; Ganesan, S.; Vlasakova, K.; Chen, J.; Socolovsky, M.; Livingston, D. M. : Genetic analysis of BRCA1 function in a defined tumor cell line. Molec. Cell 4: 1093-1099, 1999. PubMed ID : 10635334 151. Serova, O.; Montagna, M.; Torchard, D.; Narod, S. A.; Tonin, P.; Sylla, B.; Lynch, H. T.; Feunteun, J.; Lenoir, G. M. : A high incidence of BRCA1 mutations in 20 breast-ovarian cancer families. Am. J. Hum. Genet. 58: 42-51, 1996. PubMed ID : 8554067 152. Simard, J.; Feunteun, J.; Lenoir, G.; Tonin, P.; Normand, T.; The, V. L.; Vivier, A.; Lasko, D.; Morgan, K.; Rouleau, G. A.; Lynch, H.; Labrie, F.; Narod, S. A. : Genetic mapping of the breast-ovarian cancer syndrome to a small interval on chromosome 17q12-21: exclusion of candidate genes EDH17B2 and RARA. Hum. Molec. Genet. 2: 1193-1199, 1993. PubMed ID : 8401501 153. Simard, J.; Tonin, P.; Durocher, F.; Morgan, K.; Rommens, J.; Gingras, S.; Samson, C.; Leblanc, J.-F.; Belanger, C.; Dion, F.; Liu, Q.; Skolnick, M.; Goldgar, D.; Shattuck-Eidens, D.; Labrie, F.; Narod, S. A. : Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nature Genet. 8: 392-398, 1994. PubMed ID : 7894492 154. Skolnick, M. H.; Cannon-Albright, L. A.; Goldgar, D. E.; Ward, J. H.; Marshall, C. J.; Schumann, G. B.; Hogle, H.; McWhorter, W. P.; Wright, E. C.; Tran, T. D.; Bishop, D. T.; Kushner, J. P.; Eyre, H. J. : Inheritance of proliferative breast disease in breast cancer kindreds. Science 250: 1715-1720, 1990. PubMed ID : 2270486 155. Smith, S. A.; Easton, D. F.; Evans, D. G. R.; Ponder, B. A. J. : Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nature Genet. 2: 128-131, 1992. PubMed ID : 1303261 156. Smith, T. M.; Lee, M. K.; Szabo, C. I.; Jerome, N.; McEuen, M.; Taylor, M.; Hood, L.; King, M.-C. : Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1. Genome Res. 6: 1029-1049, 1996. PubMed ID : 8938427 157. Sobol, H.; Mazoyer, S.; Narod, S. A.; Smith, S. A.; Black, D. M.; Kerbrat, P.; Jamot, B.; Solomon, E.; Ponder, B. A. J.; Guerin, D. : Genetic heterogeneity of early-onset familial breast cancer. Hum. Genet. 89: 381-383, 1992. PubMed ID : 1352270 158. Steeg, P. S. : Granin expectations in breast cancer? Nature Genet. 12: 223-225, 1996. PubMed ID : 8589705 159. Stoppa-Lyonnet, D.; Fricker, J. P.; Essioux, L.; Pages, S.; Limacher, J. M.; Sobol, H.; Laurent-Puig, P.; Thomas, G. : Segregation of two BRCA1 mutations in a single family. (Letter) Am. J. Hum. Genet. 59: 479-481, 1996. PubMed ID : 8755940 160. Stratton, M. R.; Ford, D.; Neuhasen, S.; Seal, S.; Wooster, R.; Friedman, L. S.; King, M.-C.; Egilsson, V.; Devilee, P.; McManus, R.; Daly, P. A.; Smyth, E.; Ponder, B. A. J.; Peto, J.; Cannon-Albright, L.; Easton, D. F.; Goldgar, D. E. : Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nature Genet. 7: 103-107, 1994. PubMed ID : 8075631 161. Struewing, J. P.; Abeliovich, D.; Peretz, T.; Avishai, N.; Kaback, M. M.; Collins, F. S.; Brody, L. C. : The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nature Genet. 11: 198-200, 1995. PubMed ID : 7550349 162. Struewing, J. P.; Brody, L. C.; Erdos, M. R.; Kase, R. G.; Giambarresi, T. R.; Smith, S. A.; Collins, F. S.; Tucker, M.A. : Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer. Am. J. Hum. Genet. 57: 1-7, 1995. PubMed ID : 7611277 163. Struewing, J. P.; Hartge, P.; Wacholder, S.; Baker, S. M.; Berlin, M.; McAdams, M.; Timmerman, M. M.; Brody, L. C.; Tucker, M. A. : The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. New Eng. J. Med. 336: 1401-1408, 1997. PubMed ID : 9145676 164. Szabo, C. I.; King, M.-C. : Population genetics of BRCA1 and BRCA2. (Editorial) Am. J. Hum. Genet. 60: 1013-1020, 1997. PubMed ID : 9150148 165. Tesoriero, A.; Andersen, C.; Southey, M.; Somers, G.; McKay, M.; Armes, J.; McCredie, M.; Giles, G.; Hopper, J. L.; Venter, D. : De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. (Letter) Am. J. Hum. Genet. 65: 567-569, 1999. PubMed ID : 10417300 166. Thompson, M. E.; Jensen, R. A.; Obermiller, P. S.; Page, D. L.; Holt, J. T. : Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nature Genet. 9: 444-450, 1995. PubMed ID : 7795653 167. Tonin, P.; Moslehi, R.; Green, R.; Rosen, B.; Cole, D.; Boyd, N.; Cutler, C.; Margolese, R.; Carter, R.; McGillivray, B.; Ives, E.; Labrie, F.; Gilchrist, D.; Morgan, K.; Simard, J.; Narod, S. A. : Linkage analysis of 26 Canadian breast and breast-ovarian cancer families. Hum. Genet. 95: 545-550, 1995. PubMed ID : 7759076 168. Tonin, P. N.; Mes-Masson, A.-M.; Futreal, P. A.; Morgan, K.; Mahon, M.; Foulkes, W. D.; Cole, D. E. C.; Provencher, D.; Ghadirian, P.; Narod, S. A. : Founder BRCA1 and BRCA2 mutations in French Canadian breast ovarian cancer families. Am. J. Hum. Genet. 63: 1341-1351, 1998. PubMed ID : 9792861 169. Vallon-Christersson, J.; Cayanan, C.; Haraldsson, K.; Loman, N.; Bergthorsson, J. T.; Brondum-Nielsen, K.; Gerdes, A.-M.; Moller, P.; Kristoffersson, U.; Olsson, H.; Borg, A.; Monteiro, A. N. A. : Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families. Hum. Molec. Genet. 10: 353-360, 2001. PubMed ID : 11157798 170. van Orsouw, N. J.; Dhanda, R. K.; Elhaji, Y.; Narod, S. A.; Li, F. P.; Eng, C.; Vijg, J. : A highly accurate, low cost test for BRCA1 mutations. J. Med. Genet. 36: 747-753, 1999. PubMed ID : 10528853 171. Vazina, A.; Baniel, J.; Yaacobi, Y.; Shtriker, A.; Engelstein, D.; Leibovitz, I.; Zehavi, M.; Sidi, A. A.; Ramon, Y.; Tischler, T.; Livne, P. M.; Friedman, E. : The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Brit. J. Cancer 83: 463-466, 2000. PubMed ID : 10945492 172. Vega, A.; Campos, B.; Bressac-de-Paillerets, B.; Bond, P. M.; Janin, N.; Douglas, F. S.; Domenech, M.; Baena, M.; Pericay, C.; Alonso, C.; Carracedo, A.; Baiget, M.; Diez, O. : The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum. Mutat. 17: 520-521, 2001. PubMed ID : 11385711 173. Vega, A.; Torres, M.; Martinez, J. I.; Ruiz-Ponte, C.; Barros, F.; Carracedo, A. : Analysis of BRCA1 and BRCA2 in breast and breast/ovarian cancer families shows population substructure in the Iberian peninsula. Ann. Hum. Genet. 66: 29-36, 2002. PubMed ID : 12014998 174. Wacholder, S.; Struewing, J. P.; Hartge, P.; Greene, M. H.; Tucker, M. A. : Breast cancer risks for BRCA1/2 carriers. (Letter) Science 306: 2188 only, 2004. 175. Wang, X.; Wang, R.-H.; Li, W.; Xu, X.; Hollander, M. C.; Fornace, A. J., Jr.; Deng, C.-X. : Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. J. Biol. Chem. 279: 29606-29614, 2004. PubMed ID : 15123655 176. Wang, Y.; Cortez, D.; Yazdi, P.; Neff, N.; Elledge, S. J.; Qin, J. : BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14: 927-939, 2000. PubMed ID : 10783165 177. Watson, P.; Narod, S. A.; Fodde, R.; Wagner, A.; Lynch, J. F.; Tinley, S. T.; Snyder, C. L.; Coronel, S. A.; Riley, B.; Kinarsky, Y.; Lynch, H. T. : Carrier risk status changes resulting from mutation testing in hereditary non-polyposis colorectal cancer and hereditary breast-ovarian cancer. J. Med. Genet. 40: 591-596, 2003. PubMed ID : 12920070 178. Welcsh, P. L.; King, M.-C. : BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum. Molec. Genet. 10: 705-713, 2001. PubMed ID : 11257103 179. Whittemore, A. S.; Harris, R.; Itnyre, J.; Collaborative Ovarian Cancer Group : Characteristics relating to ovarian cancer risk: collaborative analysis of 12 U.S. case-control studies. II. Invasive epithelial ovarian cancers in white women. Am. J. Epidemiol. 136: 1184-1203, 1992. PubMed ID : 1476141 180. Williams, R. S.; Glover, J. N. : Structural consequences of a cancer-causing BRCA1-BRCT missense mutation. J. Biol. Chem. 278: 2630-2635, 2003. PubMed ID : 12427738 181. Wilson, C. A.; Ramos, L.; Villasenor, M. R.; Anders, K. H.; Press, M. F.; Clarke, K.; Karlan, B.; Chen, J.-J.; Scully, R.; Livingston, D.; Zuch, R. H.; Kanter, M. H.; Cohen, S.; Calzone, F. J.; Slamon, D. J. : Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nature Genet. 21: 236-240, 1999. PubMed ID : 9988281 182. Wu, L. C.; Wang, Z. W.; Tsan, J. T.; Spillman, M. A.; Phung, A.; Xu, X. L.; Yang, M.-C. W.; Hwang, L.-Y.; Bowcock, A. M.; Baer, R. : Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nature Genet. 14: 430-440, 1996. PubMed ID : 8944023 183. Xu, X.; Qiao, W.; Linke, S. P.; Cao, L.; Li, W.-M.; Furth, P. A.; Harris, C. C.; Deng, C.-X. : Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nature Genet. 28: 266-271, 2001. PubMed ID : 11431698 184. Xu, X.; Weaver, Z.; Linke, S. P.; Li, C.; Gotay, J.; Wang, X.-W.; Harris, C. C.; Ried, T.; Deng, C.-X. : Centrosome amplification and a defective G(2)-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Molec. Cell 3: 389-395, 1999. PubMed ID : 10198641 185. Yarden, R. I.; Brody, L. C. : BRCA1 interacts with components of the histone deacetylase complex. Proc. Nat. Acad. Sci. 96: 4983-4988, 1999. PubMed ID : 10220405 186. Yarden, R. I.; Pardo-Reoyo, S.; Sgagias, M.; Cowan, K. H.; Brody, L. C. : BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Nature Genet. 30: 265-269, 2002. 187. Yu, X.; Chini, C. C. S.; He, M.; Mer, G.; Chen, J. : The BRCT domain is a phospho-protein binding domain. Science 302: 639-642, 2003. PubMed ID : 14576433 188. Zhang, S.; Grosse, F. : Domain structure of human nuclear DNA helicase II (RNA helicase A). J. Biol. Chem. 272: 11487-11494, 1997. PubMed ID : 9111062 189. Zheng, L.; Pan, H.; Li, S.; Flesken-Nikitin, A.; Chen, P.-L.; Boyer, T. G.; Lee, W.-H. : Sequence-specific transcriptional corepressor function for BRCA1 through a novel zinc finger protein, ZBRK1. Molec. Cell 6: 757-768, 2000. PubMed ID : 11090615 190. Zhong, Q.; Chen, C.-F.; Li, S.; Chen, Y.; Wang, C.-C.; Xiao, J.; Chen, P.-L.; Sharp, Z. D.; Lee, W.-H. : Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285: 747-750, 1999. PubMed ID : 10426999 ### CONTRIBUTORS George E. Tiller - updated : 3/3/2005 Patricia A. Hartz - updated : 2/11/2005 Ada Hamosh - updated : 1/14/2005 George E. Tiller - updated : 12/17/2004 Patricia A. Hartz - updated : 9/9/2004 George E. Tiller - updated : 4/1/2004 Victor A. McKusick - updated : 2/6/2004 George E. Tiller - updated : 2/3/2004 Ada Hamosh - updated : 11/11/2003 Patricia A. Hartz - updated : 10/27/2003 Victor A. McKusick - updated : 10/23/2003 Victor A. McKusick - updated : 10/1/2003 Victor A. McKusick - updated : 8/27/2003 Victor A. McKusick - updated : 6/4/2003 Victor A. McKusick - updated : 3/12/2003 George E. Tiller - updated : 2/20/2003 Stylianos E. Antonarakis - updated : 11/26/2002 Victor A. McKusick - updated : 11/25/2002 Victor A. McKusick - updated : 9/27/2002 Victor A. McKusick - updated : 9/17/2002 Victor A. McKusick - updated : 8/29/2002 Victor A. McKusick - updated : 7/1/2002 Victor A. McKusick - updated : 6/12/2002 Michael B. Petersen - updated : 4/29/2002 Victor A. McKusick - updated : 4/12/2002 Victor A. McKusick - updated : 4/12/2002 Victor A. McKusick - updated : 2/11/2002 Michael B. Petersen - updated : 11/19/2001 Victor A. McKusick - updated : 10/9/2001 Victor A. McKusick - updated : 8/3/2001 Victor A. McKusick - updated : 6/27/2001 Victor A. McKusick - updated : 6/25/2001 George E. Tiller - updated : 4/24/2001 Victor A. McKusick - updated : 3/16/2001 Victor A. McKusick - updated : 3/15/2001 Stylianos E. Antonarakis - updated : 3/9/2001 Victor A. McKusick - updated : 3/8/2001 Victor A. McKusick - updated : 3/2/2001 Victor A. McKusick - updated : 1/2/2001 Victor A. McKusick - updated : 12/19/2000 Stylianos E. Antonarakis - updated : 11/27/2000 Paul J. Converse - updated : 11/16/2000 Paul J. Converse - updated : 11/14/2000 Ada Hamosh - updated : 10/19/2000 Carol A. Bocchini - updated : 10/3/2000 Victor A. McKusick - updated : 9/11/2000 Ada Hamosh - updated : 8/18/2000 Stylianos E. Antonarakis - updated : 8/8/2000 Ada Hamosh - updated : 8/1/2000 Victor A. McKusick - updated : 7/26/2000 Ada Hamosh - updated : 7/20/2000 Ada Hamosh - updated : 7/12/2000 Ada Hamosh - updated : 5/31/2000 Ada Hamosh - updated : 4/18/2000 Michael J. Wright - updated : 3/22/2000 Victor A. McKusick - updated : 2/18/2000 Victor A. McKusick - updated : 1/11/2000 Stylianos E. Antonarakis - updated : 1/7/2000 Stylianos E. Antonarakis - updated : 11/19/1999 Victor A. McKusick - updated : 11/1/1999 Victor A. McKusick - updated : 9/24/1999 Ada Hamosh - updated : 9/15/1999 John F. Jackson - reorganized : 9/14/1999 Wilson H. Y. Lo - updated : 7/16/1999 Ada Hamosh - updated : 7/14/1999 Stylianos E. Antonarakis - updated : 6/24/1999 Stylianos E. Antonarakis - updated : 5/21/1999 Ada Hamosh - updated : 5/20/1999 Victor A. McKusick - updated : 5/17/1999 Ada Hamosh - updated : 3/5/1999 Victor A. McKusick - updated : 3/2/1999 Victor A. McKusick - updated : 12/7/1998 Stylianos E. Antonarakis - updated : 11/10/1998 Victor A. McKusick - updated : 10/23/1998 Victor A. McKusick - updated : 10/1/1998 Victor A. McKusick - updated : 8/21/1998 Victor A. McKusick - updated : 8/17/1998 Victor A. McKusick - updated : 7/20/1998 Victor A. McKusick - updated : 6/23/1998 Michael J. Wright - updated : 6/16/1998 Victor A. McKusick - updated : 5/22/1998 Victor A. McKusick - updated : 5/8/1998 Victor A. McKusick - updated : 2/17/1998 Victor A. McKusick - updated : 12/18/1997 Victor A. McKusick - updated : 10/28/1997 Victor A. McKusick - updated : 6/23/1997 Victor A. McKusick - updated : 6/16/1997 Victor A. McKusick - updated : 6/2/1997 Victor A. McKusick - updated : 4/21/1997 Victor A. McKusick - updated : 4/15/1997 Victor A. McKusick - updated : 4/8/1997 Moyra Smith - updated : 3/3/1997 Moyra Smith - updated : 12/20/1996 Moyra Smith - updated : 12/11/1996 Lori M. Kelman - updated : 11/8/1996 Moyra Smith - updated : 10/4/1996 Stylianos E. Antonarakis - updated : 7/15/1996 ### CREATION DATE Victor A. McKusick : 12/20/1990 ### EDIT HISTORY mgross : 4/14/2005 terry : 3/16/2005 alopez : 3/3/2005 mgross : 2/11/2005 alopez : 1/18/2005 alopez : 1/18/2005 terry : 1/14/2005 tkritzer : 12/17/2004 mgross : 9/9/2004 terry : 4/1/2004 terry : 3/18/2004 carol : 3/17/2004 tkritzer : 2/6/2004 cwells : 2/3/2004 tkritzer : 1/13/2004 tkritzer : 11/13/2003 terry : 11/11/2003 carol : 11/7/2003 cwells : 10/31/2003 terry : 10/27/2003 carol : 10/24/2003 cwells : 10/24/2003 terry : 10/23/2003 tkritzer : 10/3/2003 tkritzer : 10/1/2003 carol : 10/1/2003 carol : 9/12/2003 cwells : 9/12/2003 terry : 8/27/2003 carol : 6/26/2003 cwells : 6/9/2003 terry : 6/4/2003 carol : 4/1/2003 tkritzer : 3/25/2003 terry : 3/12/2003 ckniffin : 3/11/2003 cwells : 2/20/2003 ckniffin : 1/24/2003 terry : 1/6/2003 mgross : 11/26/2002 mgross : 11/26/2002 cwells : 11/25/2002 terry : 11/20/2002 alopez : 10/1/2002 alopez : 9/27/2002 mgross : 9/17/2002 carol : 9/17/2002 tkritzer : 9/6/2002 tkritzer : 9/4/2002 terry : 8/29/2002 carol : 8/5/2002 terry : 8/2/2002 cwells : 7/23/2002 terry : 7/1/2002 terry : 6/26/2002 cwells : 6/24/2002 terry : 6/12/2002 cwells : 5/2/2002 cwells : 4/29/2002 alopez : 4/25/2002 cwells : 4/18/2002 terry : 4/12/2002 terry : 4/12/2002 mgross : 4/8/2002 alopez : 3/21/2002 alopez : 3/12/2002 alopez : 2/12/2002 terry : 2/12/2002 terry : 2/11/2002 alopez : 1/16/2002 cwells : 11/29/2001 cwells : 11/19/2001 carol : 11/13/2001 mcapotos : 10/24/2001 terry : 10/9/2001 carol : 9/10/2001 cwells : 8/10/2001 cwells : 8/7/2001 terry : 8/3/2001 mgross : 6/27/2001 terry : 6/27/2001 terry : 6/27/2001 terry : 6/25/2001 cwells : 6/20/2001 cwells : 5/1/2001 cwells : 4/24/2001 cwells : 4/24/2001 mcapotos : 3/27/2001 mcapotos : 3/26/2001 mcapotos : 3/23/2001 mcapotos : 3/23/2001 terry : 3/16/2001 terry : 3/15/2001 carol : 3/12/2001 mgross : 3/9/2001 cwells : 3/8/2001 cwells : 3/8/2001 terry : 3/8/2001 terry : 3/2/2001 mcapotos : 1/22/2001 joanna : 1/17/2001 carol : 1/2/2001 carol : 12/19/2000 terry : 12/19/2000 mgross : 11/27/2000 mgross : 11/16/2000 mgross : 11/14/2000 mgross : 11/14/2000 alopez : 10/19/2000 mcapotos : 10/3/2000 carol : 10/3/2000 mcapotos : 9/27/2000 mcapotos : 9/20/2000 terry : 9/11/2000 alopez : 8/18/2000 mgross : 8/8/2000 carol : 8/3/2000 alopez : 8/1/2000 mcapotos : 8/1/2000 mcapotos : 7/28/2000 mcapotos : 7/28/2000 terry : 7/26/2000 alopez : 7/24/2000 terry : 7/20/2000 alopez : 7/12/2000 alopez : 5/31/2000 alopez : 4/18/2000 alopez : 3/22/2000 mgross : 3/15/2000 terry : 2/18/2000 mgross : 2/15/2000 terry : 1/11/2000 mgross : 1/7/2000 terry : 12/2/1999 mgross : 11/19/1999 alopez : 11/15/1999 carol : 11/9/1999 terry : 11/1/1999 alopez : 10/26/1999 terry : 9/24/1999 carol : 9/15/1999 carol : 9/15/1999 carol : 9/14/1999 carol : 7/16/1999 carol : 7/14/1999 carol : 7/14/1999 mgross : 6/24/1999 mgross : 6/4/1999 mgross : 5/25/1999 mgross : 5/21/1999 mgross : 5/21/1999 alopez : 5/20/1999 terry : 5/17/1999 alopez : 3/5/1999 alopez : 3/5/1999 terry : 3/2/1999 alopez : 2/17/1999 carol : 12/11/1998 terry : 12/7/1998 carol : 11/10/1998 dkim : 11/6/1998 terry : 10/29/1998 terry : 10/29/1998 carol : 10/27/1998 terry : 10/27/1998 terry : 10/23/1998 dkim : 10/12/1998 carol : 10/6/1998 terry : 10/1/1998 alopez : 8/21/1998 carol : 8/20/1998 terry : 8/17/1998 dholmes : 7/22/1998 dholmes : 7/22/1998 terry : 7/20/1998 terry : 7/16/1998 terry : 7/9/1998 alopez : 6/29/1998 carol : 6/25/1998 terry : 6/23/1998 terry : 6/17/1998 terry : 6/16/1998 terry : 6/3/1998 terry : 5/22/1998 alopez : 5/14/1998 terry : 5/8/1998 mark : 3/2/1998 terry : 2/17/1998 mark : 2/11/1998 terry : 2/4/1998 mark : 1/10/1998 terry : 12/18/1997 alopez : 11/17/1997 jenny : 10/28/1997 terry : 10/28/1997 alopez : 8/8/1997 mark : 7/16/1997 mark : 7/16/1997 alopez : 7/10/1997 alopez : 7/8/1997 mark : 7/8/1997 alopez : 7/3/1997 alopez : 7/3/1997 mark : 7/2/1997 jenny : 6/23/1997 jenny : 6/23/1997 mark : 6/18/1997 terry : 6/16/1997 terry : 6/5/1997 mark : 6/2/1997 terry : 6/2/1997 mark : 5/16/1997 mark : 5/16/1997 mark : 4/21/1997 jenny : 4/15/1997 terry : 4/9/1997 jenny : 4/8/1997 terry : 4/4/1997 mark : 3/3/1997 terry : 1/17/1997 mark : 12/20/1996 terry : 12/16/1996 terry : 11/20/1996 jamie : 11/20/1996 jamie : 11/8/1996 mark : 11/7/1996 mark : 11/7/1996 mark : 10/24/1996 mark : 10/5/1996 mark : 10/4/1996 mark : 9/18/1996 mark : 9/10/1996 terry : 9/3/1996 terry : 8/22/1996 mark : 8/10/1996 terry : 8/9/1996 terry : 8/5/1996 carol : 7/15/1996 terry : 7/12/1996 terry : 7/12/1996 mark : 4/27/1996 mark : 4/25/1996 terry : 4/22/1996 mark : 4/19/1996 terry : 4/15/1996 mark : 3/6/1996 terry : 3/4/1996 mark : 2/29/1996 mark : 2/29/1996 terry : 2/26/1996 mark : 2/23/1996 mark : 2/23/1996 terry : 2/19/1996 mark : 2/16/1996 mark : 2/13/1996 mark : 1/25/1996 terry : 1/23/1996 mark : 12/15/1995 terry : 12/13/1995 mark : 12/7/1995 terry : 12/7/1995 terry : 12/7/1995 terry : 12/7/1995 mark : 11/17/1995 terry : 11/16/1995 jason : 6/7/1994 mimadm : 4/12/1994 pfoster : 3/25/1994 warfield : 3/23/1994 Copyright © 1966-2005 Johns Hopkins University
5: | *609309 | Links
| MutS, E. COLI, HOMOLOG OF, 2; MSH2
### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE FUNCTION BIOCHEMICAL FEATURES GENE STRUCTURE MAPPING MOLECULAR GENETICS CYTOGENETICS ANIMAL MODEL ALLELIC VARIANTS View List REFERENCES CREATION DATE EDIT HISTORY ### TEXT #### DESCRIPTION MSH2 is homologous to the E. coli MutS gene and is involved in DNA mismatch repair. Mutations in the MSH2 gene result in hereditary nonpolyposis colorectal cancer-1 (HNPCC1; 120435) #### CLONING Fishel et al. (1993) studied human homologs of the mismatch repair system in Escherichia coli referred to as the MutHLS pathway. The pathway promotes a long patch (approximately 2 kb) excision repair reaction that is dependent on the products of the MutH, MutL, MutS, and MutU genes. Genetic analysis suggested that Saccharomyces cerevisiae has a mismatch repair system similar to the bacterial MutHLS system. The S. cerevisiae pathway has a MutS homolog, MSH2. In both bacteria and S. cerevisiae, mismatch repair plays a role in maintaining the genetic stability of DNA. In S. cerevisiae, Msh2 mutants exhibit increased rates of expansion and contraction of dinucleotide repeat sequences. Fishel et al. (1993) cloned and characterized a human MutS homolog, MSH2. Leach et al. (1993) identified the MSH2 gene within the 0.8-Mb interval on chromosome 2p containing theh HNPCC1 locus. MSH2 is homologous to a prokaryotic gene, MutS, that participates in mismatch repair. The highest homology is to the yeast Msh2 gene in the helix-turn-helix domain, perhaps responsible for MutS binding to DNA. The yeast and human Msh2 proteins are 77% identical between codons 615 and 788. There are 10 other blocks of similar amino acids distributed throughout the length of the 2 proteins. Genuardi et al. (1998) reported the existence of alternative splicing in the MSH2 gene. Coupled RT-PCR of various tissue samples from normal individuals and hereditary nonpolyposis colon cancer patients identified MSH2 gene products lacking exons 5, 13, 2-7, and 2-8. The levels of expression varied among different samples. All isoforms were found in 43 to 100% of the mononuclear blood samples, as well as in other tissues. The authors cautioned that knowledge of the existence of multiple alternative splicing events not caused by genomic DNA changes is important for the evaluation of the results of molecular diagnostic tests based on RNA analysis. #### GENE FUNCTION The microsatellite DNA instability that is associated with alteration in the MSH2 gene in hereditary nonpolyposis colon cancer and several forms of sporadic cancer is thought to arise from defective repair of DNA replication errors that create insertion-deletion loop-type (IDL) mismatched nucleotides. Fishel et al. (1994) showed that purified MSH2 protein efficiently and specifically binds DNA containing IDL mismatches of up to 14 nucleotides. The findings supported a direct role for MSH2 in mutation avoidance and microsatellite stability in human cells. Lishanski et al. (1994) developed an experimental strategy for detecting heterozygosity in genomic DNA based on preferential binding of E. coli MutS protein to DNA molecules containing mismatched bases. The binding was detected by a gel mobility-shift assay. The approach was tested by using as a model the most commonly occurring mutations within the cystic fibrosis gene (CFTR; 602421). Pearson et al. (1997) studied the interaction of the human mismatch repair protein MSH2 with slipped-strand structures formed from a triplet repeat sequence in order to address the possible role of MSH2 in trinucleotide expansion, which is associated with several neurodegenerative diseases such as myotonic dystrophy (DM; 160900). Genomic clones of the myotonic dystrophy locus containing disease-relevant lengths of (CTG)n(CAG)n triplet repeats were examined. They found that the affinity of MSH2 increased with the length of the repeat sequence. Furthermore, MHS bound preferentially to looped-out CAG repeat sequences, implicating a strand asymmetry in MSH2 recognition. Pearson et al. (1997) suggested that MSH2 may participate in trinucleotide repeat expansion via its role in repair and/or recombination. All homologs of the MutS proteins contain a highly conserved region of approximately 150 amino acids that encompasses a helix-turn-helix domain associated with an adenine nucleotide and magnesium binding motif, termed Walker-A motif. This part of the molecule has ATPase activity. Gradia et al. (1997) found that this ATPase activity and the associated adenine nucleotide-binding domain functions to regulate mismatch binding as a molecular switch. The MSH2-MSH6 (600678) complex is 'on' (binds mismatched nucleotides) in the ADP-bound form and 'off' in the ATP-bound form. Hydrolysis of ATP results in the recovery of mismatch binding, while ADP-to-ATP exchange results in mismatch dissociation. These results suggested to Gradia et al. (1997) a new model for the function of MutS proteins during mismatch repair in which the switch determines the timing of downstream events. Gradia et al. (1999) showed that ATP-induced release of MSH2-MSH6 from mismatched DNA is prevented if the ends are blocked or if the DNA is circular. The authors demonstrated that mismatched DNA provokes ADP-to-ATP exchange, resulting in a conformational transition that converts MSH2-MSH6 into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. These results suggested to Gradia et al. (1999) a model for bidirectional mismatch repair in which stochastic loading of multiple ATP-bound MSH2-MSH6 sliding clamps onto mismatch-containing DNA leads to activation of the repair machinery and/or other signaling effectors similar to G protein switches. Oxidation of G in DNA yields 8-oxo-G (GO), a mutagenic lesion that leads to misincorporation of A opposite GO. In S. cerevisiae, Ni et al. (1999) found that mutations in the MSH2 or MSH6 genes caused a synergistic increase in mutation rate when in combination with mutations in the OGG1 gene (601982), resulting in a 140- to 218-fold increase in the G:C-to-T:A transversion rate. Consistent with this, MSH2-MSH6 complex bound with high affinity and specificity to GO:A mispairs and GO:C basepairs. These data indicated that in S. cerevisiae, MSH2-MSH6-dependent mismatch repair is the major mechanism by which misincorporation of A opposite GO is corrected. Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (113705)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM (604610), MSH2, MSH6, MLH1 (120436), the RAD50 (604040)-MRE1 1 (600814)-NBS1 (602667) complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. Defective S-phase checkpoint activation results in an inability to downregulate DNA replication following genotoxic insult such as exposure to ionizing radiation. This 'radioresistant DNA synthesis' (RDS) is a phenotypic hallmark of ataxia-telangiectasia, a cancer-predisposing disorder caused by mutations in the ATM gene. The mismatch repair system principally corrects nucleotide mismatches that arise during replication. By studies in cultured cells, Brown et al. (2003) showed that the mismatch repair system is required for activation of the S-phase checkpoint in response to ionizing radiation. Cells deficient in mismatch repair proteins showed RDS, and restoration of mismatch repair function restored normal S-phase checkpoint function. Catalytic activation of ATM and ATM-mediated phosphorylation of the protein nibrin (NBS1; 602667), which is mutant in the Nijmegen breakage syndrome (251260), occurred independently of mismatch repair. However, ATM-dependent phosphorylation and activation of the checkpoint kinase CHK2 (604373) and subsequent degradation of its downstream target, CDC25A (116947), was abrogated in cells lacking mismatch repair. Both in vitro and in vivo approaches showed that MSH2 binds CHK2 and that MLH1 associates with ATM. These findings indicated that the mismatch repair complex formed at the sites of DNA damage facilitates the phosphorylation of CHK2 by ATM, and that defects in this mechanism form the molecular basis for the RDS observed in cells deficient in mismatch repair. #### BIOCHEMICAL FEATURES Lamers et al. (2000) and Obmolova et al. (2000) independently determined the crystal structure of bacterial MutS binding with substrate DNA. Lamers et al. (2000) presented the crystal structure at a 2.2-angstrom resolution of MutS from E. coli bound to a G/T mismatch. The 2 MutS monomers have different conformations and form a heterodimer at the structural level. Only one monomer recognizes the mismatch specifically and has ADP bound. Mismatch recognition occurs by extensive minor groove interactions causing unusual basepairing and kinking of the DNA. Lamers et al. (2000) stated that mutations in human MSH2 that lead to hereditary predisposition for HNPCC can be mapped to this crystal structure. #### GENE STRUCTURE Kolodner et al. (1994) found that the genomic MSH2 locus covers approximately 73 kb and contains 16 exons. #### MAPPING Fishel et al. (1993) demonstrated that the MSH2 gene maps to chromosome 2p22-p21 by study of a mapping panel of somatic cell hybrid DNAs using PCR. #### MOLECULAR GENETICS Fishel et al. (1993) identified a T-to-C transition in the -6 position of a splice acceptor site in sporadic colon tumors and as a constitutional change in affected members of 2 small families with HNPCC. Leach et al. (1993) demonstrated the existence of MSH2 germline mutations that substantially altered the predicted gene product and cosegregated with disease in the HNPCC kindreds. Furthermore, they identified specific germline mutations in each of the 2 kindreds that originally established linkage of HNPCC to chromosome 2 (e.g., 609309.0001) (Peltomaki et al., 1993). Kolodner et al. (1994) analyzed 2 large HNPCC kindreds exhibiting features of the Muir-Torre syndrome (158320) and demonstrated that cancer susceptibility was due to the inheritance of a frameshift mutation in the MSH2 gene in one family and a nonsense mutation in the MSH2 gene in the other family. Linkage of the cancer phenotype to chromosome 2p had been described in these families by Hall et al. (1994). Aquilina et al. (1994) detected a mismatch binding defect leading to a mutator phenotype in LoVo, a human colorectal carcinoma cell line. Umar et al. (1994) described a deletion in the MSH2 gene in LoVo cells together with a defect in mismatch repair by LoVo cell extracts. Using denaturing gradient gel electrophoresis (DGGE) to screen for mutations in all 16 exons of the MSH2 gene in 34 unrelated HNPCC kindreds, Wijnen et al. (1995) found 7 novel pathogenic germline mutations resulting in stop codons, either directly or through frameshifts. Four nonpathogenic variations, including 1 useful polymorphism, were also identified. MSH2 mutations were found in 21% of the families. They could not establish any correlation between the site of the individual mutations and the spectrum of tumor types. Maliaka et al. (1996) identified 6 different new mutations in the MLH1 (120436) and MSH2 genes in Russian and Moldavian HNPCC families. Three of these mutations occurred in CpG dinucleotides and led to a premature stop codon, splicing defect, or an amino acid substitution in evolutionarily conserved residues. Analysis of a compilation of published mutations including the new data suggested to the authors that CpG dinucleotides within the coding regions of the MSH2 and MLH1 genes are hotspots for single basepair substitutions. Ellison et al. (2001) performed quantitative in vivo DNA mismatch repair (MMR) assays in the yeast S. cerevisiae to determine the functional significance of amino acid replacements in MLH1 and MSH2 genes observed in the human population. Missense codons previously observed in human genes were introduced at the homologous residue in the yeast MLH1 or MSH2 genes. Three classes of missense codons were found: (i) complete loss of function, i.e., mutations; (ii) variants indistinguishable from wildtype protein, i.e., silent polymorphisms; and (iii) functional variants which supported MMR at reduced efficiency, i.e., efficiency polymorphisms. There was a good correlation between the functional results in yeast and available human clinical data regarding penetrance of the missense codon. The authors suggested that differences in the efficiency of DNA MMR may exist between individuals in the human population due to common polymorphisms. Wang et al. (2002) described a modified multiplex PCR assay effective in detecting large deletions in either the MSH2 or MLH1 gene in HNPCC. Mangold et al. (2004) screened for mutations in the MSH2 and MLH1 genes in 41 unrelated index patients diagnosed with Muir-Torre syndrome (MTS), most of whom were preselected for mismatch repair deficiency in their tumor tissue. Germline mutations were identified in 27 patients (mutation detection rate of 66%). Mangold et al. (2004) noted that 25 (93%) of the mutations were located in MSH2, in contrast to HNPCC patients without the MTS phenotype, in whom the proportions of MLH1 and MSH2 mutations are almost equal (p less than 0.001). Mangold et al. (2004) further noted that 6 (22%) of the mutation carriers did not meet the Bethesda criteria for HNPCC and suggested that sebaceous neoplasm be added to the HNPCC-specific malignancies in the Bethesda guidelines. Orth et al. (1994) found that 5 of 10 ovarian tumor cell lines were genetically unstable at most microsatellite loci analyzed. In clones and subclones derived serially from 1 of these cell lines (serous cystadenocarcinoma), a very high proportion of microsatellites distributed in many different regions of the genome changed their size in a mercurial fashion. In 1 ovarian tumor, they identified the source of the genetic instability as a point mutation (arg524 to pro; 609309.0007) in the MSH2 gene. The patient was a 38-year-old heterozygote for this mutation and her normal tissue carried both mutant and wildtype alleles of the MSH2 gene. However, the wildtype allele was lost at some point early during tumorigenesis so that DNA isolated either from the patients ovarian tumor or from the cell line carried only the mutant MSH2 allele. The genetic instability observed in the tumor and cell line DNA, together with the germline mutation in a mismatch repair gene, suggested that MSH2 is involved in the onset and/or progression in a subset of ovarian cancer. Whiteside et al. (2002) described a 2-year-old infant with T-cell acute lymphoblastic leukemia and, from birth, multiple cafe-au-lait spots, suggesting neurofibromatosis type I (NF1; 162200). The child was found to be homozygous for a splice site mutation in the MSH2 gene (120435.0014). Both parents were heterozygous for the mutation. Other than cafe-au-lait spots, the infant had no other signs of NF1. There was no family history of either NF1 or cancers indicative of HNPCC. Homozygosity for another DNA mismatch repair gene, MLH1, had been reported in 3 families (Wang et al., 1999; Ricciardone et al., 1999; Vilkki et al., 2001). The homozygous offspring in all of these families were diagnosed with NF1 with no family history of the disorder. Five homozygous children in 2 of the families developed leukemia or lymphoma. Whiteside et al. (2002) pointed out that more than two-thirds of Msh2 -/- knockout mice succumb to thymic lymphomas. Using specific markers of the mutator phenotype, Duval et al. (2004) screened a series of 603 human non-Hodgkin lymphomas (NHLs; 605027) and found 12 microsatellite instability-high (MSI-H) cases (2%). This phenotype was specifically associated with immunodeficiency-related lymphomas being observed in both posttransplant lymphoproliferative disorders and in HIV infection-related lymphomas but not in a large series of NHL arising in the general population. The MSI pathway is known to lead to the production of hundreds of abnormal protein neoantigens that are generated in MSI-H neoplasms by frameshift mutations of a number of genes containing coding microsatellite sequences. As expected, Duval et al. (2004) found that MSI-H immunodeficiency-related lymphomas harbored such genetic alterations in 12 target genes with a putative role in lymphomagenesis. #### CYTOGENETICS Wagner et al. (2002) identified a paracentric inversion of chromosome 2p that inactivated the MSH2 locus and caused HNPCC. They showed that the centromeric and telomeric breakpoints of the paracentric inversion mapped within intron 7 of the MSH2 gene and to a contig 10 Mb 3-prime of MSH2, respectively. Northern and Western blot analysis showed that expression of MSH2 was abolished. #### ANIMAL MODEL To investigate the role of the MSH2 gene in genome stability and tumorigenesis, de Wind et al. (1995) generated cells and mice deficient for the gene. Msh2-deficient mouse embryonic stem cell lines were found to have lost mismatch binding and acquired microsatellite instability, a mutator phenotype, and tolerance to methylation agents. Moreover, in these cells, homologous recombination had lost dependence on complete identity between interacting DNA sequences, suggesting that Msh2 is involved in safeguarding the genome from promiscuous recombination. MSH2-deficient mice displayed no major abnormalities, but a significant fraction developed lymphomas at an early age. Reitmair et al. (1995) described a mouse strain homozygous for a 'knockout' mutation at the MSH2 locus. Surprisingly, these mice were found to be viable, produced offspring in a mendelian ratio, and bred through at least 2 generations. Starting at 2 months of age, homozygous MSH2-deficient mice began to develop lymphoid tumors with high frequency that contained microsatellite instabilities. These data established a direct link between MSH2 deficiency and the pathogenesis of cancer. Mice carrying a targeted germline disruption of the MSH2 gene are viable and susceptible to lymphoid tumors; however, defects in this gene had not been identified in human lymphomas. To determine if the lymphomas these mice develop are related to a particular subtype of human lymphoma, Lowsky et al. (1997) evaluated 20 clinically ill homozygous MSH2 -/- mice ranging in age from 2 to 13 months. The murine tumors comprised a single histopathologic entity representing the malignant counterpart of precursor thymic T cells and closely resembling human precursor T-cell lymphoblastic lymphoma (LBL). Evaluation of the expression of 3 T-cell malignancy-associated genes showed that rhombotin-2 (RBTN2; 180385), TAL1 (187040), and HOX11 (186770) were expressed in 100, 40, and 0% of the murine tumors, respectively. The MSH2 -/- murine model of precursor T-cell LBL was substantiated by the finding of a newly identical expression pattern of RBTM2, TAL1, and HOX11 in 10 well-characterized cases of human LBL. Direct evidence for MSH2 abnormalities in human LBL was established by sequence analysis of exon 13 of human MSH2, which revealed coding region mutations in 2 of 10 cases. The findings of Lowsky et al. (1997) implicated defects in the mismatch repair system with the aberrant expression of T-cell specific protooncogenes and defined a new pathway of human lymphomagenesis. Chronic oxidative stress may play a critical role in the pathogenesis of many human cancers. DeWeese et al. (1998) reported that mouse embryonic stem (ES) cells from mice carrying either 1 or 2 disrupted Msh2 alleles displayed an increased survival following protracted exposures to low-level ionizing radiation as compared with wildtype ES cells. The increases in survival exhibited by ES cells deficient in DNA mismatch repair appeared to have resulted from a failure to execute cell death (apoptosis) efficiently in response to radiation exposure. For each of the ES cell types, prolonged low-level radiation treatment generated oxidative genome damage that manifested as an accumulation of oxidized bases in genomic DNA. However, ES cells from Msh2 +/- and Msh2 -/- mice accumulated more oxidized bases as a consequence of low-level radiation exposure than did ES cells from Msh2 +/+ mice. The propensity for normal cells with mismatch repair enzyme deficiencies, including cells heterozygous for inactivating mismatch repair enzyme gene mutations, to survive promutagenic genome insults accompanying stresses may contribute to the increased cancer risk characteristic of the hereditary nonpolyposis colorectal cancer syndrome. Most errors that arise during DNA replication can be corrected by DNA polymerase proofreading or by postreplication mismatch repair (MMR). Inactivation of both mutation-avoidance systems resulting in high mutability and the likelihood of cancer can be caused by mutations (e.g., in the MSH2 gene) and by epigenetic changes that reduce MMR. Hypermutability can also be caused by external factors that directly inhibit MMR. Jin et al. (2003) found that chronic exposure of yeast to environmentally relevant concentrations of cadmium, a known human carcinogen, can result in extreme hypermutability. The mutation specificity along with responses in proofreading-deficient and MMR-deficient mutants indicated that cadmium reduces the capacity for MMR of small misalignments and base-base mismatches. In extracts of human cells, Jin et al. (2003) found that cadmium inhibited at least 1 step leading to mismatch removal. Thus, the data showed that a high level of genetic instability can result from environmental impediment of a mutation-avoidance system. McMurray and Tainer (2003) commented on the direct inhibition of DNA mismatch repair as a molecular mechanism for cadmium toxicity. Somatic instability of expanded huntingtin (HD; 143100) CAG repeats that encode the polyglutamine tract in mutant huntingtin has been implicated in the striatal selectivity of Huntington disease pathology. Wheeler et al. (2003) tested whether a genetic background deficient in Msh2 would eliminate the unstable behavior of the CAG array in Hdh(Q111) mice. Analyses of Hdh(Q111/+):Msh2(+/+) and Hdh(Q111/+):Msh2(-/-) progeny revealed that, while inherited instability involved Msh2-dependent and -independent mechanisms, lack of Msh2 was sufficient to abrogate progressive HD CAG repeat expansion in striatum. The absence of Msh2 also eliminated striatal mutant huntingtin with somatically expanded glutamine tracts and caused an approxixmately 5-month delay in nuclear mutant protein accumulation, but did not alter the striatal specificity of this early phenotype. ### ALLELIC VARIANTS (selected examples) #### .0001 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, PRO622LEU] In family J living in New Zealand and studied by Peltomaki et al. (1993) for demonstration of linkage of colorectal cancer (HNPCC1; 120435) to chromosome 2, Leach et al. (1993) demonstrated a CCA-to-CTA transition in codon 622, resulting in substitution of leucine for proline. The mutation was present in 1 allele of individual J-42, who was afflicted with colon and endometrial cancer at ages 42 and 44, respectively. All 11 affected individuals in the family had the mutation, while all 10 unaffected members and 20 unrelated individuals had proline at codon 622. #### .0002 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, DEL 50 CODONS] In studies of DNA from family C, a North American family with HNPCC1 (120435) studied by Peltomaki et al. (1993), Leach et al. (1993) found no mutations of the conserved region of MSH2. A presumptive splicing defect was found that removed codons 265 to 314 from the MSH2 transcript. #### .0003 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, ARG406TER] In a kindred with hereditary nonpolyposis colorectal cancer and linkage to 2p (HNPCC1; 120435), Leach et al. (1993) demonstrated a CGA-to-TGA transition in codon 406, resulting in change of arginine to a stop. #### .0004 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, HIS639TYR] In a family with hereditary nonpolyposis colorectal cancer linked to 2p (HNPCC1; 120435), Leach et al. (1993) demonstrated a CAT-to-TAT transition in codon 639, resulting in substitution of tyrosine for histidine. Of interest was the finding that, in addition to the germline mutation, an RER(+) tumor had a somatic mutation: substitution of TG for A in codon 663 (ATG), resulting in a frameshift. #### .0005 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, 3-BP DEL, ASN596DEL] In a family in which 3 first-degree relatives developed colon cancer (HNPCC1; 120435) under the age of 45 years, with all neoplasms being mucinous adenocarcinomas, Mary et al. (1994) found deletion of codon 596 (AAT) resulting in the deletion of an asparagine residue from the protein. #### .0006 MUIR-TORRE FAMILY CANCER SYNDROME [MSH2, GLN601TER] In a kindred with characteristics of the Muir-Torre syndrome (158320), Kolodner et al. (1994) found a C-to-T transition at nucleotide 1801 converting codon 601 from gln to stop. Thus, a truncated MSH2 protein was predicted. The affected members were heterozygous. This was 1 of 2 families in which all individuals in whom colorectal or endometrial cancers occurred were found to carry the mutant allele. Many of those carrying MSH2 mutations had tumors outside the colorectum, e.g., stomach cancer and small bowel cancer, and there were skin lesions characteristic of Muir-Torre syndrome. #### .0007 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, ARG524PRO] In a 38-year-old woman with serous cystadenocarcinoma of the ovary, Orth et al. (1994) found constitutional heterozygosity for an arg524-to-pro mutation of the MSH2 gene. Whereas normal tissue carried both mutant and wildtype alleles, the DNA isolated either from the patient's ovarian tumor or from the derived cell line carried only the mutant allele of the MSH2 gene. Orth et al. (1994) concluded that the woman probably had hereditary nonpolyposis colorectal cancer (HNPCC1; 120435), of which ovarian cancer is an integral lesion. #### .0008 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, 1-BP DEL] In 2 apparently unrelated families with familial nonpolyposis colon cancer type 1 (HNPCC1; 120435), Jeon et al. (1996) found the same mutation in exon 13 of the MSH2 gene: deletion of a single nucleotide from codon 705, changing TGT to TT. Exon 13 of the MSH2 gene was chosen for screening because it is in the middle of the most conserved region of the gene. The 2 families did not fulfill the strict Amsterdam criteria for HNPCC because each had an unaffected individual over the age of 50 with the mutation. #### .0009 MUIR-TORRE FAMILY CANCER SYNDROME [MSH2, 22-BP INS] Esche et al. (1997) described the case of a 62-year-old man with rectal cancer, 2 keratoacanthomas, and multiple sebaceous adenomas, epitheliomas, and sebaceous hyperplasia (MTS; 158320). His brother and father died of colorectal cancer. A frameshift mutation leading to a truncated protein was demonstrated in the mismatch repair gene MSH2. One allele contained an insertion of 22 bp at codon 97 (after nucleotide 289) leading to a frameshift with a stop after 9 further codons. Presymptomatic molecular diagnosis could be offered to the children of the patient. #### .0010 MSH2 POLYMORPHISM [MSH2, GLY322ASP] Liu et al. (1998) concluded that gly322 to asp is a common polymorphism of the MSH2 gene and not a disease-causing mutation. They found this exon 6 mutation in 9 of 170 colorectal cancer (see 114500) patients (5.3%) from high-risk families, and in 6 of those families this alteration was shown not to segregate with disease. They also found this alteration in 12 of 192 normal controls (6.3%) and in none of 104 sporadic colorectal cancer cases. #### .0011 COLORECTAL CANCER, HEREDITARY, NONPOLYPOSIS, TYPE 1 [MSH2, DEL EXON 5] Froggatt et al. (1999) reported an A-to-T transversion at nucleotide 943+3 of the MSH2 gene disrupting the 3-prime splice site of exon 5 and leading to deletion of this exon from the MSH2 mRNA. This mutation was originally identified in 3 of 29 North American HNPCC (HNPCC1; 120435) families (Liu et al., 1994) and had also been found in 4 of 52 English families and in 10 of 20 families from Newfoundland. Froggatt et al. (1999) stated that this was the most common MSH2 mutation reported to that time. To investigate the origin of this mutation in these families, Froggatt et al. (1999) performed haplotype analysis using microsatellite markers linked to MSH2. A common haplotype was identified in 8 of the Newfoundland families, suggesting a founder effect. Froggatt et al. (1999) calculated age-related risks of all, colorectal, endometrial, and ovarian cancers in 76 carriers of the nucleotide 943+3 A-to-T MSH2 mutation for all patients and for men and women separately. For both sexes combined, the penetrance at age 60 years for all cancers and colorectal cancers was 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (P = less than 0.01) in males than in females. For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). In a note added in proof, Froggatt et al. (1999) reported that another 21 HNPCC families had been identified in Newfoundland, 1 of which carried the 943+3A-T mutation, raising the proportion of Newfoundland families with this mutation to 11 of 41 (27%). Three of these families were shown to have a common ancestor, and another common ancestor was found for an additional 2 families. Desai et al. (2000) studied 10 families from England, Italy, Hong Kong, and Japan with this mutation. Haplotype sharing was not apparent even within the European and the Asian kindreds. The authors concluded that the 943+3A-T mutation occurs de novo with relatively high frequency and hypothesized that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenine residues, of which the mutated A is the first. #### .0012 COLORECTAL CANCER, HEREDITARY, NONPOLYPOSIS, TYPE 1 [MSH2, ALA636PRO] In an Ashkenazi kindred with HNPCC (120435), Yuan et al. (1999) found a G-to-C transversion in the MSH2 gene that resulted in an ala636-to-pro missense mutation segregating with the disease. In addition, they found a missense mutation in the APC gene (I1307K; 175100.0029) in 2 unaffected members of the kindred. Yuan et al. (1999) concluded that clinical surveillance for CRC should not be discontinued in Ashkenazi families with HNPCC where an MSH2 mutation had been found until the APC gene had also been analyzed, and that the APC I1307K mutation should be sought in Ashkenazi families with multiple cases of CRC. Yuan et al. (1999) also recognized that the relationship between the presence of that mutation and CRC was not fully resolved. Foulkes et al. (2002) stated that the 1906G-C mutation (ala636 to pro) had been found in 25 apparently unrelated Ashkenazi Jewish families. It was estimated to account for 2 to 3% of colorectal cancer in those whose age at diagnosis was less than 60 years. The mutation was highly penetrant and accounted for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfilled the Amsterdam criteria. #### .0013 COLORECTAL CANCER, HEREDITARY, NONPOLYPOSIS, TYPE 1 [MSH2, 24-BP INS] In the historic family G with HNPCC (120435) of Warthin (1913), Yan et al. (2000) identified a 24-bp insertion in the MSH2 gene by use of a method that converted cells from diploidy to haploidy. The insertion occurred between codons 215 and 216 of the cDNA resulting in a change in the splice acceptor of exon 4. #### .0014 NEUROFIBROMATOSIS, TYPE I, WITH LEUKEMIA [MSH2, IVS10, G-A, -1] Whiteside et al. (2002) reported a male infant who presented at 24 months of age with failure to thrive and a gastrointestinal infection that led to the diagnosis of T-cell acute lymphoblastic leukemia and IgA deficiency. He was also noted to have multiple cafe-au-lait spots, present from birth, of a size and number sufficient to satisfy one of the criteria for the diagnosis of NF1 (162200). However, he had no neurofibromas, axillary or inguinal freckling, Lisch nodules, optic glioma, sphenoid wing dysplasia, pseudoarthrosis, or previous history of malignancy. There was no family history of NF1 or cancers indicative of HNPCC. His parents were nonconsanguineous but were from the same ethnic, religious, and geographic background. A homozygous G-to-A transition was found in the proband in the invariant G of the intron 10 acceptor site of the MSH2 gene. This mutation at position 1662-1 bp (relative to the ATG translational start site) was predicted to result in skipping of exon 11 to exon 12, with out-of-frame translation of the mutant mRNA resulting in a truncated, nonfunctional protein. The parents, who were both heterozygous for the mutation, did not have HNPCC, but the authors noted that their young age may explain the lack of observed cancer at that time. Andrew (2002) stated that the family reported by Whiteside et al. (2002) was of East Indian descent and lived in Alberta; they had moved to Canada from Fiji. #### .0015 GLIOBLASTOMA, EARLY-ONSET [MSH2, EX1-6 DEL] LYMPHOMA, T-CELL, INCLUDED Bougeard et al. (2003) described 2 sibs, a female who died of mediastinal T-cell lymphoma at the age of 15 months and her brother who died at age 4 years from a temporal glioblastoma (see 137800). The parents were healthy. The unaffected father was heterozygous for a genomic deletion removing exons 1-6 of the MSH2 gene; the unaffected mother was heterozygous for a 1-bp deletion at codon 153 within exon 3 of the MSH2 gene (120435.0016). Study of glioblastoma DNA from the boy indicated compound heterozygosity for the 2 parental mutations. In this family, endometrial carcinoma was the cause of death at age 43 years in an aunt of the mother and at age 59 years in the grandmother of the father. Furthermore, an uncle of the father had died of astrocytoma at age 27 years. #### .0016 GLIOBLASTOMA, EARLY-ONSET [MSH2, 1-BP DEL] LYMPHOMA, T-CELL, INCLUDED See 120435.0015 and Bougeard et al. (2003). #### .0017 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, 11.4-KB DEL] In affected members of 2 generations of an Ohio family with HNPCC (120435), Pyatt et al. (2003) identified a genomic deletion of approximately 11.4 kb encompassing the first 2 exons of the MSH2 gene. By Southern blot analysis, using a cDNA probe spanning the first 7 exons of MSH2, an alteration in each of 3 different enzyme digests was observed (including a unique 13-kb band on Hind III digests), which suggested the presence of a large alteration in the 5-prime region of the gene. The authors then generated mouse-human cell hybrids from a mutation carrier which contained a single copy each of human chromosome 2, upon which the MSH2 gene resides. Southern blots of DNA from the cell hybrids demonstrated the same unique 13-kb band from 1 MSH2 allele, as seen in the diploid DNA. DNA from this same monosomal cell hybrid failed to amplify in PCR using primers to exons 1 and 2, demonstrating the deletion of these sequences in 1 MSH2 allele, and the breakpoints involving Alu repeats were identified by PCR amplification and sequence analysis. #### .0018 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, EX1-6 DEL] In about 10% of North American families with HNPCC (120435), Wagner et al. (2003) found deletion of exons 1-6 of the MSH2 gene. In most of the families the haplotype of the deleted allele was shared. By genealogic studies, a common ancestor could be traced for 5 of the 9 families found to have the MSH2 exon 1-6 founder deletion. The alleged ancestor was born around 1814 in Alabama and was presumably of German origin. He married and became a Mormon and had many children distributed over a rather wide geographic area after the ancestor was excommunicated from the Mormon church. #### .0019 COLORECTAL CANCER, HEREDITARY NONPOLYPOSIS, TYPE 1 [MSH2, 4-BP DEL, 1452AATG] Chan et al. (2004) reported that in the southern Chinese population, a germline 4-bp deletion in the MSH2 gene, 1452delAATG, constitutes 21% of all germline mismatch repair (MMR) gene mutations and 36% of all MSH2 germline mutations identified. In 10 families with HNPCC (120435) caused by the 4-bp deletion, haplotype analysis demonstrated the same disease haplotype, suggesting a founder effect. The 10 families all originated from the Chinese province of Guangdong, which historically included Hong Kong. It is the most populous of the Chinese provinces, with a population of more than 93 million. Chan et al. (2004) estimated that the founder mutation occurred 22 to 103 generations ago. The mutation had not been identified in other ethnic groups. Since there were major emigrations from Hong Kong and Guangdong province during the 19th and 20th centuries, this finding is also significant for Chinese communities worldwide. ### REFERENCES 1. Andrew, S. : Personal Communication. Edmonton, Alberta, Canada, 4/11/2002. 2. Aquilina, G.; Hess, P.; Branch, P.; MacGeoch, C.; Casciano, I.; Karran, P.; Bignami, M. : A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype. Proc. Nat. Acad. Sci. 91: 8905-8909, 1994. PubMed ID : 8090742 3. Bougeard, G.; Charbonnier, F.; Moerman, A.; Martin, C.; Ruchoux, M. M.; Drouot, N.; Frebourg, T. : Early-onset brain tumor and lymphoma in MSH2-deficient children. (Letter) Am. J. Hum. Genet. 72: 213-216, 2003. PubMed ID : 12549480 4. Brown, K. D.; Rathi, A.; Kamath, R.; Beardsley, D. I.; Zhan, Q.; Mannino, J. L.; Baskaran, R. : The mismatch repair system is required for S-phase checkpoint activation. Nature Genet. 33: 80-84, 2003. PubMed ID : 12447371 5. Chan, T. L.; Chan, Y. W.; Ho, J. W. C.; Chan, C.; Chan, A. S. Y.; Chan, E.; Lam, P. W. Y.; Tse, C. W.; Lee, K. C.; Lau, C. W.; Gwi, E.; Leung, S. Y.; Yuen, S. T. : MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population. Am. J. Hum. Genet. 74: 1035-1042, 2004. PubMed ID : 15042510 6. Desai, D. C.; Lockman, J. C.; Chadwick, R. B.; Gao, X.; Percesepe, A.; Evans, D. G. R.; Miyaki, M.; Yuen, S. T.; Radice, P.; Maher, E. R.; Wright, F. A.; de la Chapelle, A. : Recurrent germline mutation in MSH2 arises frequently de novo. J. Med. Genet. 37: 646-652, 2000. PubMed ID : 10978353 7. DeWeese, T. L.; Shipman, J. M.; Larrier, N. A.; Buckley, N. M.; Kidd, L. R.; Groopman, J. D.; Cutler, R. G.; te Riele, H.; Nelson, W. G. : Mouse embryonic stem cells carrying one or two defective Msh2 alleles respond abnormally to oxidative stress inflicted by low-level radiation. Proc. Nat. Acad. Sci. 95: 11915-11920, 1998. PubMed ID : 9751765 8. de Wind, N.; Dekker, M.; Berns, A.; Radman, M.; te Riele, H. : Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82: 321-330, 1995. PubMed ID : 7628020 9. Duval, A.; Raphael, M.; Brennetot, C.; Poirel, H.; Buhard, O.; Aubry, A.; Martin, A.; Krimi, A.; Leblond, V.; Gabarre, J.; Davi, F.; Charlotte, F.; and 15 others : The mutator pathway is a feature of immunodeficiency-related lymphomas. Proc. Nat. Acad. Sci. 101: 5002-5007, 2004. PubMed ID : 15047891 10. Ellison, A. R.; Lofing, J.; Bitter, G. A. : Functional analysis of human MLH1 and MSH2 missense variants and hybrid human-yeast MLH1 proteins in Saccharomyces cerevisiae. Hum. Molec. Genet. 10: 1889-1900, 2001. PubMed ID : 11555625 11. Esche, C.; Kruse, R.; Lamberti, C.; Friedl, W.; Propping, P.; Lehmann, P.; Ruzicka, T. : Muir-Torre syndrome: clinical features and molecular genetic analysis. Brit. J. Derm. 136: 913-917, 1997. PubMed ID : 9217825 12. Fishel, R.; Ewel, A.; Lee, S.; Lescoe, M. K.; Griffith, J. : Binding of mismatched microsatellite DNA sequences by the human MSH2 protein. Science 266: 1403-1405, 1994. PubMed ID : 7973733 13. Fishel, R.; Lescoe, M. K.; Rao, M. R. S.; Copeland, N. G.; Jenkins, N. A.; Garber, J.; Kane, M.; Kolodner, R. : The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027-1038, 1993. PubMed ID : 8252616 14. Foulkes, W. D.; Thiffault, I.; Gruber, S. B.; Horwitz, M.; Hamel, N.; Lee, C.; Shia, J.; Markowitz, A.; Figer, A.; Friedman, E.; Farber, D.; Greenwood, C. M. T.; and 21 others : The founder mutation MSH2*1906G-C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am. J. Hum. Genet. 71: 1395-1412, 2002. PubMed ID : 12454801 15. Froggatt, N. J.; Green, J.; Brassett, C.; Evans, D. G. R.; Bishop, D. T.; Kolodner, R.; Maher, E. R. : A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. J. Med. Genet. 36: 97-102, 1999. PubMed ID : 10051005 16. Genuardi, M.; Viel, A.; Bonora, D.; Capozzi, E.; Bellacosa, A.; Leonardi, F.; Valle, R.; Ventura, A.; Pedroni, M.; Boiocchi, M.; Neri, G. : Characterization of MLH1 and MSH2 alternative splicing and its relevance to molecular testing of colorectal cancer susceptibility. Hum. Genet. 102: 15-20, 1998. PubMed ID : 9490293 17. Gradia, S.; Acharya, S.; Fishel, R. : The human mismatch recognition complex hMSH2-hMSH6 functions as a novel molecular switch. Cell 91: 995-1005, 1997. PubMed ID : 9428522 18. Gradia, S.; Subramanian, D.; Wilson, T.; Acharya, S.; Makhov, A.; Griffith, J.; Fishel, R. : hMSH2-hMSH6 forms a hydrolysis-independent sliding clamp on mismatched DNA. Molec. Cell 3: 255-261, 1999. PubMed ID : 10078208 19. Hall, N. R.; Murday, V. A.; Chapman, P.; Williams, M. A.; Burn, J.; Finan, P. J.; Bishop, D. T. : Genetic linkage in Muir-Torre syndrome to the same chromosomal site as cancer family syndrome. Europ. J. Cancer 30A: 180-182, 1994. 20. Jeon, H. M.; Lynch, P. M.; Howard, L.; Ajani, J.; Levin, B.; Frazier, M. L. : Mutation of the hMSH2 gene in two families with hereditary nonpolyposis colorectal cancer. Hum. Mutat. 7: 327-333, 1996. PubMed ID : 8723682 21. Jin, Y. H.; Clark, A. B.; Slebos, R. J. C.; Al-Refai, H.; Taylor, J. A.; Kunkel, T. A.; Resnick, M. A.; Gordenin, D. A. : Cadmium is a mutagen that acts by inhibiting mismatch repair. Nature Genet. 34: 326-329, 2003. PubMed ID : 12796780 22. Kolodner, R. D.; Hall, N. R.; Lipford, J.; Kane, M. F.; Rao, M. R. S.; Morrison, P.; Wirth, L.; Finan, P. J.; Burn, J.; Chapman, P.; Earabino, C.; Merchant, E.; Bishops, D. T. : Structure of the human MSH2 locus and analysis of two Muir-Torre kindreds for msh2 mutations. Genomics 24: 516-526, 1994. PubMed ID : 7713503 23. Lamers, M. H.; Perrakis, A.; Enzlin, J. H.; Winterwerp, H. H. K.; de Wind, N.; Sixma, T. K. : The crystal structure of DNA mismatch repair protein MutS binding to a G/T mismatch. Nature 407: 711-717, 2000. PubMed ID : 11048711 24. Leach, F. S.; Nicolaides, N. C.; Papadopoulos, N.; Liu, B.; Jen, J.; Parsons, R.; Peltomaki, P.; Sistonen, P.; Aaltonen, L. A.; Nystrom-Lahti, M.; Guan, X.-Y.; Zhang, J.; and 23 others : Mutations of a MutS homolog in hereditary non-polyposis colorectal cancer. Cell 75: 1215-1225, 1993. PubMed ID : 8261515 25. Lishanski, A.; Ostrander, E. A.; Rine, J. : Mutation detection by mismatch binding protein, MutS, in amplified DNA: application to the cystic fibrosis gene. Proc. Nat. Acad. Sci. 91: 2674-2678, 1994. PubMed ID : 7511817 26. Liu, B.; Parsons, R. E.; Hamilton, S. R.; Petersen, G. M.; Lynch, H. T.; Watson, P.; Markowitz, S.; Willson, J. K. V.; Green, J.; de la Chapelle, A.; Kinzler, K. W.; Vogelstein, B. : hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 54: 4590-4594, 1994. PubMed ID : 8062247 27. Liu, T.; Stathopoulos, P.; Lindblom, P.; Rubio, C.; Wasteson Arver, B.; Iselius, L.; Holmberg, E.; Gronberg, H.; Lindblom, A. : MSH2 codon 322 gly to asp seems not to confer an increased risk for colorectal cancer susceptibility. (Letter) Europ. J. Cancer 34: 1981 only, 1998. 28. Lowsky, R.; DeCoteau, J. F.; Reitmair, A. H.; Ichinohasama, R.; Dong, W.-F.; Xu, Y.; Mak, T. W.; Kadin, M. E.; Minden, M. D. : Defects of the mismatch repair gene MSH2 are implicated in the development of murine and human lymphoblastic lymphomas and are associated with the aberrant expression of rhombotin-2 (Lmo-2) and Tal-1 (SCL). Blood 89: 2276-2282, 1997. PubMed ID : 9116269 29. Maliaka, Y. K.; Chudina, A. P.; Belev, N. F.; Alday, P.; Bochkov, N. P.; Buerstedde, J.-M. : CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations. Hum. Genet. 97: 251-255, 1996. PubMed ID : 8566964 30. Mangold, E.; Pagenstecher, C.; Leister, M.; Mathiak, M.; Rutten, A.; Friedl, W.; Propping, P.; Ruzicka, T.; Kruse, R. : A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. (Letter) J. Med. Genet. 41: 567-572, 2004. PubMed ID : 15235030 31. Mary, J.-L.; Bishop, T.; Kolodner, R.; Lipford, J. R.; Kane, M.; Weber, W.; Torhorst, J.; Muller, H.; Spycher, M.; Scott, R. J. : Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development. Hum. Molec. Genet. 3: 2067-2069, 1994. PubMed ID : 7874129 32. McMurray, C. T.; Tainer, J. A. : Cancer, cadmium and genome integrity. Natu re Genet. 34: 239-241, 2003. 33. Ni, T. T.; Marsischky, G. T.; Kolodner, R. D. : MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae. Molec. Cell 4: 439-444, 1999. PubMed ID : 10518225 34. Obmolova, G.; Ban, C.; Hsieh, P.; Yang, W. : Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA. Nature 4 07: 703-710, 2000. 35. Orth, K.; Hung, J.; Gazdar, A.; Bowcock, A.; Mathis, J. M.; Sambrook, J. : Genetic instability in human ovarian cancer cell lines. Proc. Nat. Acad. Sci. 91: 9495-9499, 1994. PubMed ID : 7937795 36. Pearson, C. E.; Ewel, A.; Acharya, S.; Fishel, R. A.; Sinden, R. R. : Human MSH2 binds to trinucleotide repeat DNA structures associated with neurodegenerative diseases. Hum. Molec. Genet. 6: 1117-1123, 1997. PubMed ID : 9215683 37. Peltomaki, P.; Aaltonen, L. A.; Sistonen, P.; Pylkkanen, L.; Mecklin, J.-P.; Jarvinen, H.; Green, J. S.; Jass, J. R.; Weber, J. L.; Leach, F. S.; Petersen, G. M.; Hamilton, S. R.; de la Chapelle, A.; Vogelstein, B. : Genetic mapping of a locus predisposing to human colorectal cancer. Scienc e 260: 810-812, 1993. 38. Pyatt, R. E.; Nakagawa, H.; Hampel, H.; Sedra, M.; Fuchik, M. B.; Comeras, I.; de la Chapelle, A.; Prior, T. W. : Identification of a deletion in the mismatch repair gene, MSH2, using mouse-human cell hybrids monosomal for chromosome 2. Clin. Genet. 63: 215-218, 2003. PubMed ID : 12694232 39. Reitmair, A. H.; Schmits, R.; Ewel, A.; Bapat, B.; Redston, M.; Mitri, A.; Waterhouse, P.; Mittrucker, H.-W.; Wakeham, A.; Liu, B.; Thomason, A.; Griesser, H.; Gallinger, S.; Ballhausen, W. G.; Fishel, R.; Mak, T. W. : MSH2 deficient mice are viable and susceptible to lymphoid tumours. Nature Genet. 11: 64-70, 1995. PubMed ID : 7550317 40. Ricciardone, M. D.; Ozcelik, T.; Cevher, B.; Ozdag, H.; Tuncer, M.; Gurgey, A.; Uzunalimoglu, O.; Cetinkaya, H.; Tanyeli, A.; Erken, E.; Ozturk, M. : Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1. Cancer Res. 59: 290-293, 1999. PubMed ID : 9927033 41. Umar, A.; Boyer, J. C.; Thomas, D. C.; Nguyen, D. C.; Risinger, J. I.; Boyd, J.; Ionov, Y.; Perucho, M.; Kunkel, T. A. : Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J. Biol. Chem. 269: 14367-14370, 1994. PubMed ID : 8182040 42. Vilkki, S.; Tsao, J.-L.; Loukola, A.; Poyhonen, M.; Vierimaa, O.; Herva, R.; Aaltonen, L. A.; Shibata, D. : Extensive somatic microsatellite mutations in normal human tissue. Cancer Res. 61: 4541-4544, 2001. PubMed ID : 11389087 43. Wagner, A.; Barrows, A.; Wijnen, J.; van der Klift, H.; Franken, P. F.; Verkuijlen, P.; Nakagawa, H.; Geugien, M.; Jaghmohan-Changur, S.; Breukel, C.; Meijers-Heijboer, H.; Morreau, H.; and 10 others : Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am. J. Hum. Genet. 72: 1088-1100, 2003. PubMed ID : 12658575 44. Wagner, A.; van der Klift, H.; Franken, P.; Wijnen, J.; Breukel, C.; Bezrookove, V.; Smits, R.; Kinarsky, Y.; Barrows, A.; Franklin, B.; Lynch, J.; Lynch, H.; Fodde, R. : A 10-Mb paracentric inversion of chromosome arm 2p inactivates MSH2 and is responsible for hereditary nonpolyposis colorectal cancer in a North-American kindred. Genes Chromosomes Cancer 35: 49-57, 2002. PubMed ID : 12203789 45. Wang, Q.; Lasset, C.; Desseigne, F.; Frappaz, D.; Bergeron, C.; Navarro, C.; Ruano, E.; Puisieux, A. : Neurofibromatosis and early onset of cancers in hMLH1-deficient children. Cancer Res. 59: 294-297, 1999. PubMed ID : 9927034 46. Wang, Y.; Cortez, D.; Yazdi, P.; Neff, N.; Elledge, S. J.; Qin, J. : BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14: 927-939, 2000. PubMed ID : 10783165 47. Wang, Y.; Friedl, W.; Sengteller, M.; Jungck, M.; Filges, I.; Propping, P.; Mangold, E. : A modified multiplex PCR assay for detection of large deletions in MSH2 or MLH1. Hum. Mutat. 19: 279-286, 2002. PubMed ID : 11857745 48. Warthin, A. S. : Heredity with reference to carcinoma. Arch. Intern. Med. 12: 546-555, 1913. 49. Wheeler, V. C.; Lebel, L.-A.; Vrbanac, V.; Teed, A.; te Riele, H.; MacDonald, M. E. : Mismatch repair gene Msh2 modifies the timing of early disease in Hdh(Q111) striatum. Hum. Molec. Genet. 12: 273-281, 2003. PubMed ID : 12554681 50. Whiteside, D.; McLeod, R.; Graham, G.; Steckley, J. L.; Booth, K.; Somerville, M. J.; Andrew, S. E. : A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple cafe-au-lait spots. Cancer Res. 62: 359-362, 2002. PubMed ID : 11809679 51. Wijnen, J.; Vasen, H.; Khan, P. M.; Menko, F. H.; van der Klift, H.; van Leeuwen, C.; van den Broek, M.; van Leeuwen-Cornelisse, I.; Nagengast, F.; Meijers-Heijboer, A.; Lindhout, D.; Griffioen, G.; Cats, A.; Kleibeuker, J.; Varesco, L.; Bertario, L.; Bisgaard, M. L.; Mohr, J.; Fodde, R. : Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. Am. J. Hum. Genet. 56: 1060-1066, 1995. PubMed ID : 7726159 52. Yan, H.; Papadopoulos, N.; Marra, G.; Perrera, C.; Jiricny, J.; Boland, C. R.; Lynch, H. T.; Chadwick, R. B.; de la Chapelle, A.; Berg, K.; Eshleman, J. R.; Yuan, W.; Markowitz, S.; Laken, S. J.; Lengauer, C.; Kinzler, K. W.; Vogelstein, B. : Conversion of diploidy to haploidy. Nature 403: 723-724, 2000. PubMed ID : 10693791 53. Yuan, Z. Q.; Wong, N.; Foulkes, W. D.; Alpert, L.; Manganaro, F.; Andreutti-Zaugg, C.; Iggo, R.; Anthony, K.; Hsieh, E.; Redston, M.; Pinsky, L.; Trifiro, M.; Gordon, P. H.; Lasko, D. : A missense mutation in both hMSH2 and APC in an Ashkenazi Jewish HNPCC kindred: implications for clinical screening. J. Med. Genet. 36: 790-793, 1999. PubMed ID : 10528862 ### CREATION DATE Victor A. McKusick : 4/14/2005 ### EDIT HISTORY mgross : 4/15/2005 mgross : 4/14/2005 mgross : 4/14/2005 Copyright © 1966-2005 Johns Hopkins University
6: | *609206 | Links
| EUKARYOTIC TRANSLATION ELONGATION FACTOR 1, EPSILON-1; EEF1E1
#### Alternative titles; symbols ELONGATION FACTOR p18 ### TABLE OF CONTENTS #### CLONING GENE FUNCTION MAPPING ANIMAL MODEL REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY ### TEXT #### CLONING By sequencing cDNAs randomly selected from a cDNA library derived from human umbilical cord CD34 (142230)-positive cells, Mao et al. (1998) obtained a full-length cDNA encoding EEF1E1. The deduced 174-amino acid protein is a homolog of the rodent elongation factor p18. #### GENE FUNCTION Park et al. (2005) found that human p18 was induced and translocated to the nucleus in response to DNA damage. Expression of p18 resulted in elevated p53 (191170) levels, while p18 depletion blocked p53 induction. p18 interacted directly with ATM (607585) and ATR (601215) in response to DNA damage. ATM activity was dependent on the level of p18, suggesting that p18 is required for activation of ATM. RT-PCR showed that p18 expression was low in several different human cancer cell lines and tissues. These results, as well as findings in p18 mutant mice, suggested that p18 is a haploinsufficient tumor suppressor and a key factor for ATM/ATR-mediated p53 activation. #### MAPPING By radiation hybrid analysis, Mao et al. (1998) mapped the EEF1E1 gene to chromosome 6p25.1-p23. #### ANIMAL MODEL Park et al. (2005) found that inactivation of both p18 alleles in mice caused embryonic lethality, whereas heterozygous mice showed high susceptibility to spontaneous tumors. ### REFERENCES 1. Mao, M.; Fu, G.; Wu, J.-S.; Zhang, Q.-H.; Zhou, J.; Kan, L.-X.; Huang, Q.-H.; He, K.-L.; Gu, B.-W.; Han, Z.-G.; Shen, Y.; Gu, J.; Yu, Y.-P.; Xu, S.-H.; Wang, Y.-X.; Chen, S.-J.; Chen, Z. : Identification of genes expressed in human CD34+ hematopoietic stem/progenitor cells by expressed sequence tags and efficient full-length cDNA cloning. Proc. Nat. Acad. Sci. 95: 8175-8180, 1998. PubMed ID : 9653160 2. Park, B.-J.; Kang, J. W.; Lee, S. W.; Choi, S.-J.; Shin, Y. K.; Ahn, Y. H.; Choi, Y. H.; Choi, D.; Lee, K. S.; Kim, S. : The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Cell 120: 209-221, 2005. PubMed ID : 15680327 ### CONTRIBUTORS Matthew B. Gross - updated : 2/16/2005 ### CREATION DATE Stylianos E. Antonarakis : 2/16/2005 ### EDIT HISTORY mgross : 2/16/2005 mgross : 2/16/2005 Copyright © 1966-2005 Johns Hopkins University
7: | *608952 | Links
| RAP1-INTERACTING FACTOR 1, YEAST, HOMOLOG OF
#### Alternative titles; symbols RIF1, YEAST, HOMOLOG OF; RIF1 ### TABLE OF CONTENTS #### CLONING GENE FUNCTION MAPPING REFERENCES CREATION DATE EDIT HISTORY ### TEXT #### CLONING By searching a database for sequences similar to S. pombe and S. cerevisiae Rif1, Silverman et al. (2004) identified human RIF1. The deduced protein contains 2,472 amino acids. Alignment of the human, mouse, and fugu proteins revealed 2 conserved N-terminal regions and a conserved C-terminal region. The first 340 amino acids contain 8 armadillo-type repeats, which are helical folds that typically occur in long arrays, creating an extended curved protein or RNA interaction surface. RIF1 also contains a central serine-rich region and a bipartite nuclear localization signal within the C-terminal conserved region. #### GENE FUNCTION Yeast Rif1 associates with telomeres and regulates their length. In contrast, Silverman et al. (2004) found that human RIF1 did not accumulate at functional telomeres, but localized to dysfunctional telomeres and to telomeric DNA clusters in human ALT (alternative lengthening of telomeres) cell lines, which maintain telomeric DNA in the absence of telomerase. They noted that this pattern of telomere association is typical of DNA damage response factors. After induction of double-strand breaks in ALT cells, RIF1 formed foci that colocalized with other DNA damage response factors. This response was strictly dependent on ATM (607585) and 53BP1 (605230), but was not affected by diminished function of ATR (601215), BRCA1 (113705), CHK2 (604373), NBS1 (602667), or MRE11 (600814). RIF1 inhibition resulted in radiosensitivity and a defect in the intra-S-phase checkpoint. Silverman et al. (2004) concluded that RIF1 contributes to ATM-mediated protection against DNA damage. #### MAPPING The International Radiation Hybrid Mapping Consortium mapped the RIF1 gene to chromosome 2 (SHGC-56421). ### REFERENCES 1. Silverman, J.; Takai, H.; Buonomo, S. B. C.; Eisenhaber, F.; de Lange, T. : Human Rif1, ortholog of a yeast telomeric protein, is regulated by ATM and 53BP1 and functions in the S-phase checkpoint. Genes Dev. 18: 2108-2119, 2004. PubMed ID : 15342490 ### CREATION DATE Patricia A. Hartz : 9/28/2004 ### EDIT HISTORY mgross : 9/28/2004 Copyright © 1966-2005 Johns Hopkins University
8: | *608438 | Links
| TOUSLED-LIKE KINASE 1; TLK1
#### Alternative titles; symbols KIAA0137 PROTEIN KINASE, UBIQUITOUS-BETA; PKU-BETA ### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE FUNCTION MAPPING REFERENCES CREATION DATE EDIT HISTORY ### TEXT #### DESCRIPTION The Tousled-like kinases, first described in Arabadopsis, are nuclear serine/threonine kinases that are potentially involved in the regulation of chromatin assembly. #### CLONING By sequencing size-fractionated clones obtained from a myeloid leukemia cell line cDNA library, Nagase et al. (1995) cloned TLK1, which they designated KIAA0137. The deduced protein contains a protein kinase ATP-binding motif. Northern blot analysis detected expression of TLK1 in all tissues and cell lines examined except lung. Highest expression was detected in testis. Using a TLK2 (608349) clone as probe, Yamakawa et al. (1997) cloned TLK1, which they called PKU-beta, by screening a placenta cDNA library. The deduced 787-amino acid protein has a 5-domain structure, with N-terminal nuclear localization signals followed by a nucleotide binding motif, and a single catalytic domain near the C terminus. TLK1 shares 86% sequence identity with TLK2 overall, and 94% identity in the catalytic region. Northern blot analysis detected a 4.2-kb transcript expressed primarily in fetal kidney and liver, and in placenta. Immunofluorescence analysis of transfected COS-1 cells localized TLK1 to the nucleus. By PCR amplification of sequences similar to Arabidopsis TSL, followed by screening several cDNA libraries, Sillje et al. (1999) cloned TLK1. The deduced 718-amino acid protein has a calculated molecular mass of 81.9 kD. By RNAse protection analysis of RNA isolated from various adult mouse organs, they found that Tlk1 is ubiquitously expressed. Western blot analysis detected endogenous HeLa cell TLK1 and TLK2 that migrated together at an apparent molecular mass of about 85 kD. Both proteins were also localized to the nucleus and were excluded from nucleoli. #### GENE FUNCTION Using myelin basic protein (MBP; 159430), casein (see 115450), and histone H1 (see 142709) as model substrates, Sillje et al. (1999) confirmed kinase activity in TLK1. MBP was readily phosphorylated, and histone was poorly phosphorylated. TLK1 was also capable of autophosphorylation, and only the phosphorylated form was catalytically active. Activity was also dependent upon asp-559 within the catalytic domain. The authors further found that both TLK1 and TLK2 displayed maximal activity during S phase of the cell cycle. Whereas protein levels were virtually constant throughout the cell cycle, both TLKs appeared to be regulated by cell-cycle-dependent phosphorylation. Inhibition of DNA replication caused a rapid loss of TLK activity, indicating that TLK function is tightly linked to ongoing DNA replication. With use of several human cell lines, Groth et al. (2003) determined that both TLK1 and TLK2 were novel targets of the DNA damage checkpoint. Both TLKs were rapidly inactivated upon exposure to ionizing radiation (IR), and the inactivation was directly mediated by the S-phase DNA damage checkpoint. IR-induced TLK1 inactivation required ATM (607585) and CHK1 (603078) function, and CHK1 phosphorylated TLK1 in vitro and in vivo at a site required for the inhibition of TLK1 in response to DNA damage. Groth et al. (2003) concluded that TLK1 is a target of CHK1 in the intra-S-phase DNA damage checkpoint. Krause et al. (2003) found that NBS1 (602667) was also part of the signaling pathway leading to transient suppression of TLK activity after double-strand breaks in the DNA, replication blockade, or low doses of ultraviolet irradiation. #### MAPPING By PCR analysis of a human-rodent cell hybrid panel, Nagase et al. (1995) mapped the TLK1 gene to chromosome 2. By FISH, Yamakawa et al. (1997) mapped the TLK1 gene to chromosome 8p22-p12. Hartz (2004) mapped the TLK1 gene to chromosome 2q31.1 based on an alignment of TLK1 sequences (GenBank AB004885 and GenBank D50927) with the genomic sequence. ### REFERENCES 1. Groth, A.; Lukas, J.; Nigg, E. A.; Sillje, H. H. W.; Wernstedt, C.; Bartek, J.; Hansen, K. : Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. EMBO J. 22: 1676-1687, 2003. PubMed ID : 12660173 2. Hartz, P. : Personal Communication. Baltimore, MD., 2/2/2004. 3. Krause, D. R.; Jonnalagadda, J. C.; Gatei, M. H.; Sillje, H. H. W.; Zhou, B.-B.; Nigg, E. A.; Khanna, K. : Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS and Chk1. Oncogene 22: 5927-5937, 2003. PubMed ID : 12955071 4. Nagase, T.; Seki, N.; Tanaka, A.; Ishikawa, K.; Nomura, N. : Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 2: 167-174, 1995. PubMed ID : 8590280 5. Sillje, H. H. W.; Takahashi, K.; Tanaka, K.; Van Houwe, G.; Nigg, E. A. : Mammalian homologues of the plant Tousled gene code for cell-cycle-regulated kinases with maximal activities linked to ongoing DNA replication. EMBO J. 18: 5691-5702, 1999. PubMed ID : 10523312 6. Yamakawa, A.; Kameoka, Y.; Hashimoto, K.; Yoshitake, Y.; Nishikawa, K.; Tanihara, K.; Date, T. : cDNA cloning and chromosomal mapping of genes encoding novel protein kinases termed PKU-alpha and PKU-beta, which have nuclear localization signal. Gene 202: 193-201, 1997. PubMed ID : 9427565 ### CREATION DATE Patricia A. Hartz : 2/2/2004 ### EDIT HISTORY cwells : 2/2/2004 Copyright © 1966-2005 Johns Hopkins University
9: | *608254 | Links
| PAX TRANSCRIPTION ACTIVATION DOMAIN-INTERACTING PROTEIN 1-LIKE; PAXIP1L
#### Alternative titles; symbols PAX TRANSACTIVATION DOMAIN-INTERACTING PROTEIN; PTIP ### TABLE OF CONTENTS #### CLONING GENE FUNCTION MAPPING ANIMAL MODEL REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 7q36 ### TEXT #### CLONING Using mouse Pax2 (167409) as bait in a yeast 2-hybrid screen of an embryonic mouse cDNA library, Lechner et al. (2000) cloned Paxip1l, which they called Ptip. The deduced 1,056-amino acid protein has a calculated molecular mass of 119.3 kD. Ptip contains 2 N-terminal and 3 C-terminal BRCA1 (113705) C-terminal (BRCT) domains separated by a glutamine-rich region. Northern blot analysis of mouse tissues detected ubiquitous expression of a 4.0-kb transcript, with highest expression in embryonic kidney and brain. PTIP was also expressed in all human and mouse cell lines examined. In mouse fibroblasts, Ptip localized to the nucleus. Differential solubilization revealed that Ptip fractionated with soluble chromatin and copurified with nuclear matrix proteins under high salt conditions. Western blot analysis detected endogenous mouse Ptip at an apparent molecular mass of 130 kD. #### GENE FUNCTION By yeast 2-hybrid analysis and in vitro binding assays, Lechner et al. (2000) found that mouse Ptip bound to the C-terminal transactivation domain of Pax2. Deletions in the C-terminal region of Pax2 containing the partial homeodomain and PSTY-rich domain diminished the interaction in a yeast 2-hybrid assay. The Pax2 octapeptide motif also affected the interaction. Manke et al. (2003) used a proteomic approach to identify phosphopeptide-binding modules mediating signal transduction events in the DNA damage response pathway. They identified a tandem BRCT domain in PTIP and in BRCA1 as phosphoserine- or phosphothreonine-specific binding modules that recognize substrates phosphorylated by the kinases ATM (607585) and ATR (601215) in response to gamma irradiation. PTIP tandem BRCT domains are responsible for phosphorylation-dependent protein localization into 53BP1 (605230)- and phospho-H2AX (601772)-containing nuclear foci, a marker of DNA damage. Manke et al. (2003) concluded that their findings provided a molecular basis for BRCT domain function in the DNA damage response and may help to explain why the BRCA1 BRCT domain mutation met1775 to arg (M1775R; 113705.0035), which fails to bind phosphopeptides, predisposes women to breast and ovarian cancer. #### MAPPING By radiation hybrid analysis and FISH, Lechner et al. (2000) mapped the PAXIP1L gene to chromosome 7q36. #### ANIMAL MODEL Cho et al. (2003) developed mice with a constitutive null Ptip allele. Homozygous mutants were developmentally retarded and disorganized, and they died by embryonic day 9.5 (E9.5). Ptip mutant cells appeared to replicate DNA, but they showed DNA damage preceding nuclear condensation at E7.5 and reduced levels of mitosis and widespread cell death by E8.5. Embryonic fibroblasts and stem cells from Ptip mutants failed to proliferate in culture, suggesting a fundamental defect in cell proliferation. Trophoblast cells from Ptip mutants were more sensitive to DNA-damaging agents. Condensation of chromatin and expression of phosphohistone H3 (see 601128) were also affected in Ptip mutants, and the authors suggested that these effects may underlie the inability of mutants to progress through mitosis. ### REFERENCES 1. Cho, E. A.; Prindle, M. J.; Dressler, G. R. : BRCT domain-containing protein PTIP is essential for progression through mitosis. Molec. Cell. Biol. 23: 1666-1673, 2003. PubMed ID : 12588986 2. Lechner, M. S.; Levitan, I.; Dressler, G. R. : PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. Nucleic Acids Res. 28: 2741-2751, 2000. PubMed ID : 10908331 3. Manke, I. A.; Lowery, D. M.; Nguyen, A.; Yaffe, M. B. : BRCT repeats as phosphopeptide-binding modules involved in protein targeting. Science 302: 636-639, 2003. PubMed ID : 14576432 ### CONTRIBUTORS Patricia A. Hartz - updated : 11/25/2003 ### CREATION DATE Ada Hamosh : 11/13/2003 ### EDIT HISTORY mgross : 11/25/2003 tkritzer : 11/17/2003 Copyright © 1966-2005 Johns Hopkins University
10: | *608130 | Links
| AMPK-RELATED PROTEIN KINASE 5
#### Alternative titles; symbols ARK5 KIAA0537 ### TABLE OF CONTENTS #### CLONING GENE FUNCTION MAPPING REFERENCES CREATION DATE EDIT HISTORY ### TEXT #### CLONING By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1998) cloned KIAA0537. The deduced 661-amino acid protein shares about 52% identity over 252 amino acids with plant SNF1-related protein kinase (605705). The KIAA0537 protein had an apparent molecular mass of about 75 kD by SDS-PAGE. RT-PCR detected highest expression in heart and brain, followed by skeletal muscle, kidney, ovary, placenta, lung, and liver. Little to no expression was detected in other tissues examined. Suzuki et al. (2003) found that an antibody directed against SNARK (608131) cross-reacted with a 74-kD protein that they called ARK5. By screening databases, they determined that KIAA0537 and ARK5 are identical. Overall, SNARK and ARK5 share 55% amino acid homology, including 84% similarity within the N-terminal catalytic domains. ARK5 also shares significant homology with several other AMP-activated protein kinases, including AMPK-alpha-1 (PRKAA1; 602739), AMPK-alpha-2 (PRKAA2; 600497), and MELK (607025). #### GENE FUNCTION By in vitro assay of ARK5 expressed by transfected HepG2 colon cancer cells, Suzuki et al. (2003) demonstrated phosphorylation of a synthetic test peptide. The phosphorylation was stimulated by AMP and did not require accessory binding proteins. Transfection of ARK5 also increased the survival of HepG2 cells exposed to glucose starvation and reduced oxygen tension. Increased cell survival was accompanied by phosphorylation of ARK5 on ser600 by AKT (see 164730), which activated ARK5 kinase activity. Activated ARK5 phosphorylated ATM (607585), which led to phosphorylation of p53 (191170). The authors proposed that ARK5 is a tumor cell survival factor that is activated by AKT and acts as an ATM kinase under conditions of nutrient starvation. #### MAPPING By radiation hybrid analysis, Nagase et al. (1998) mapped the ARK5 gene to chromosome 12. ### REFERENCES 1. Nagase, T.; Ishikawa, K.; Miyajima, N.; Tanaka, A.; Kotani, H.; Nomura, N.; Ohara, O. : Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. PubMed ID : 9628581 2. Suzuki, A.; Kusakai, G.; Kishimoto, A.; Lu, J.; Ogura, T.; Lavin, M. F.; Esumi, H. : Identification of a novel protein kinase mediating Akt survival signaling to the ATM protein. J. Biol. Chem. 278: 48-53, 2003. PubMed ID : 12409306 ### CREATION DATE Patricia A. Hartz : 9/29/2003 ### EDIT HISTORY mgross : 9/29/2003 Copyright © 1966-2005 Johns Hopkins University
11: | *607809 | GeneTests, Links
| ACETYL-CoA ACETYLTRANSFERASE 1; ACAT1
#### Alternative titles; symbols ACAT ACETOACETYL-CoA THIOLASE, MITOCHONDRIAL T2 MITOCHONDRIAL ACETOACETYL-CoA THIOLASE; MAT ### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE STRUCTURE MAPPING MOLECULAR GENETICS ALLELIC VARIANTS View List SEE ALSO REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 11q22.3-q23.1 ### TEXT #### DESCRIPTION The ACAT1 gene encodes mitochondrial acetyl-CoA acetyltransferase, a short-chain-length-specific thiolase (EC 2.3.1.9). Cytosolic acetoacetyl-CoA thiolase is encoded by the ACAT2 gene (100678). #### CLONING Fukao et al. (1990) cloned and sequenced cDNA encoding the precursor of hepatic mitochondrial acetoacetyl-CoA thiolase. The 427-amino acid precursor had a molecular mass of 45.2 kD. The sequence included a 33-residue leader peptide and a 394-amino acid subunit of the mature enzyme, which had a molecular mass of 41.4 kD. By Northern blotting, they analyzed the T2 gene expression in fibroblasts from 4 patients with 3-ketothiolase deficiency. In all 4 cell lines, the T2 mRNA had the same 1.7-kb transcript as that of the control; however, content was reduced in 2 cell lines and normal in the other 2. Human T2 is a homotetramer of 41-kD subunits. #### GENE STRUCTURE Kano et al. (1991) determined that the ACAT gene spans approximately 27 kb and contains 12 exons. #### MAPPING Using a plasmid clone of an EcoRI genomic fragment of the ACAT1 gene, containing exons 9 to 12, Masuno et al. (1992) assigned the ACAT1 locus to 11q22.3-q23.1 by in situ hybridization. Matsuda et al. (1996) determined the chromosomal locations of the Atm (607585) and Acat1 genes in mouse, rat, and Syrian hamster by direct R-banding fluorescence in situ hybridization. The 2 genes colocalized to mouse 9C-D, the proximal end of rat 8q24.1, and 12qa4-qa5 of Syrian hamster. The regions in the mouse and rat are homologous to human chromosome 11q. In the study of interspecific backcross mice, no recombinants were found among Atm, Npat (601448), and Acat1. #### MOLECULAR GENETICS In a German boy with 3-ketothiolase deficiency (203750) born of nonconsanguineous parents, Fukao et al. (1991) found compound heterozygosity for 2 mutations in the ACAT1 gene: an A347T mutation (607809.0001) inherited from the mother, and a mutation inherited from the father that abolished expression of the gene. This was apparently the first definition of a mutant ACAT allele. In a pregnant woman with alpha-methylacetoaceticaciduria (203750), Sewell et al. (1998) identified 2 mutations in exon 11 of the ACAT1 gene: a 3-bp deletion 1033delGAA (607908.0010), which caused deletion of glu345, and a 1-bp (A) insertion (1083insA) (607809.0011), which caused a frameshift and premature termination. Her child inherited only the trinucleotide deletion. Both of her husband's alleles were normal. In a Japanese patient with T2 deficiency, Fukao et al. (1998) found compound heterozygosity for mutations in the ACAT1 gene (607809.0012 and 607809.0013). In a Japanese patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency, Fukao et al. (2003) identified a novel initiator codon mutation (2T-C) in heterozygous state, with 149delC on the other allele. Fukao et al. (1993) had previously identified a 2T-A mutation in a T2-deficient patient. Fukao et al. (2003) performed in vivo transient expression analysis on 9 mutant T2 cDNAs harboring 1-base substitutions at the initiator methionine codon. They found that all the mutants produced wildtype T2 polypeptide to varying degrees, from 7.4% to 66% as compared with wildtype. They proposed that all 1-base substitutions at the initiator methionine codon in the T2 gene retain some residual T2 activity. ### ALLELIC VARIANTS (selected examples) #### .0001 3-@KETOTHIOLASE DEFICIENCY [ACAT1, ALA347THR] In a German boy with 3-ketothiolase deficiency (203750) born of nonconsanguineous parents, Fukao et al. (1991) found compound heterozygosity for 2 mutations in the ACAT1 gene: a G-to-A substitution, resulting in an ala347-to-thr substitution (A347T), inherited from the mother, and a mutation inherited from the father that abolished expression of the gene. Transfection analysis showed that the A347T substitution resulted in instability of the protein. The patient showed normal development until his first ketoacidotic attack at the age of 6 months, following which severe retardation developed. The diagnosis of 3-ketothiolase deficiency was made by urinary organic acid analysis during the attack. #### .0002 3-@KETOTHIOLASE DEFICIENCY [ACAT1, GLY150ARG] Fukao et al. (1992) studied a Caucasian family reported by Schutgens et al. (1982). The family was unusual in that the father and a son had 3-ketothiolase deficiency (203750). Three mutant alleles of the ACAT1 gene were found. The father was a compound heterozygote: one allele had a 547G-A mutation, resulting in a gly150-to-arg (G150R) substitution, and the other allele had a GT-to-TT transition at the 5-prime splice site of intron 8, causing skipping of exon 8 in the cDNA (607809.0003). The son was also a compound heterozygote: one allele, inherited from his mother, had an AG-to-CG transition at the 3-prime splice site of intron 10, causing skipping of exon 11 of the cDNA (607809.0004), and the other allele derived from the father had the G150R substitution. Another son was an obligatory carrier of the mutant allele causing exon 8 skipping. #### .0003 3-@KETOTHIOLASE DEFICIENCY [ACAT1, IVS8, G-T, +1] See 607809.0002 and Fukao et al. (1992). #### .0004 3-@KETOTHIOLASE DEFICIENCY [ACAT1, IVS10, A-C, -2] See 607809.0002 and Fukao et al. (1992). #### .0005 3-@KETOTHIOLASE DEFICIENCY [ACAT1, IVS10, G-C, -1] In a patient with 3-ketothiolase deficiency (203750) born in Canada of nonconsanguineous Vietnamese parents, Fukao et al. (1992) found by cDNA analysis with polymerase chain reaction (PCR) that the normal exon 11 sequence was missing and that the parents were carriers of this defect. When PCR-amplified genomic fragments around exon 11 were sequenced, an AG-to-AC mutation was found at the last nucleotide of intron 10, i.e., in the 3-prime splice site. The mutation was presumed to be responsible for exon 11 skipping. #### .0006 3-@KETOTHIOLASE DEFICIENCY [ACAT1, IVS11, T-C, +2] In a patient from the Dutch family in which 3-ketothiolase deficiency (203750) was first described by Daum et al. (1973), Fukao et al. (1993) demonstrated homozygosity for a 4-bp insertion (GCAG), a derived mutation. The primary mutation was an AG/gt to AG/gc transition at the 5-prime splice-junction site in intron 11. An alternative splice site 4 bp downstream was used, which caused a frameshift and replaced 39 C-terminal residues by 70 nonfunctional residues. Fukao et al. (1993) provided a 20-year follow-up on the proband in this family and on the 2 affected sibs in the Chilean family (see 607809.0007) reported by Daum et al. (1973). All had developed normally, had had no recurrence of acute metabolic decompensation since 1973 despite persistent abnormal organic aciduria (2-methyl-3-hydroxybutyrate, 2-methylacetoacetate), and were gainfully employed adults. They completed high school and 1 had attended university. #### .0007 3-@KETOTHIOLASE DEFICIENCY [ACAT1, MET1LYS] In the Chilean family in which Daum et al. (1973) first described 3-ketothiolase deficiency (203750), Fukao et al. (1993) demonstrated homozygosity for a mutation in the translation initiation codon of the ACAT1 gene, an ATG-to-AAG transversion. By expression analysis, they showed that the mutation severely impaired T2 mRNA translation. #### .0008 3-@KETOTHIOLASE DEFICIENCY [ACAT1, GLY379VAL] Fukao et al. (1994) reported a Caucasian girl, born to nonconsanguineous parents, in whom the diagnosis of 3-ketothiolase deficiency (203750) was made when she was 3 years old and after multiple ketoacidotic attacks. Her growth and development were normal, and there was no mental retardation. She was found to be a compound heterozygote; the maternal allele had a 1136G-to-T transversion, resulting in a gly379-to-val substitution (G379V) in the thiolase precursor. Cells transfected with cDNA carrying the G379V mutation showed no evidence of restored T2 activity. The paternal allele was associated with exon 8 skipping at the cDNA level. In the paternal allele at the gene level, a C-to-T transition causing a gln272-to-ter (Q272X) change was identified within exon 8, 13 bp from the 5-prime splice site of intron 8. Splicing experiments showed that the exonic mutation caused partial skipping of exon 8. This substitution was thought to alter the secondary structure of T2 pre-mRNA around exon 8 and thus impede normal splicing. They cited a similar situation reported by Steingrimsdottir et al. (1992), who detected aberrant splicing in the HGPRT (308000) gene resulting from a mutation located 13 nucleotides from the 5-prime splice site of intron 8 and causing exon 8 skipping in 90% of HGPRT transcripts. #### .0009 3-@KETOTHIOLASE DEFICIENCY [ACAT1, GLN272TER] See 607809.0008 and Fukao et al. (1994). #### .0010 3-@KETOTHIOLASE DEFICIENCY [ACAT1, GLU345DEL ] Sewell et al. (1998) described a compound heterozygous woman with 3-ketothiolase deficiency (203750) in whom 1 mutation was a deletion of nucleotides 1033 to 1035 (GAA), resulting in the deletion of glutamic acid at codon 345. The other mutation was an insertion of 1 adenine between nucleotides 1083 and 1084, causing premature termination. #### .0011 3-@KETOTHIOLASE DEFICIENCY [ACAT1, 1-BP INS, 1083A ] See 607809.0010 and Sewell et al. (1998). #### .0012 3-@KETOTHIOLASE DEFICIENCY [ACAT1, ASN93SER] See Fukao et al. (1998). #### .0013 3-@KETOTHIOLASE DEFICIENCY [ACAT1, ILE312THR] See Fukao et al. (1998). #### .0014 3-@KETOTHIOLASE DEFICIENCY [ACAT1, ALA333PRO] See Fukao et al. (1998). ### SEE ALSO Fukao et al. (1992) ### REFERENCES 1. Daum, R. S.; Scriver, C. R.; Mamer, O. A.; Delvin, E.; Lamm, P. H.; Goldman, H. : An inherited disorder of isoleucine catabolism causing accumulation of alpha-methylacetoacetate and alpha-methyl-beta-hydroxybutyrate and intermittent metabolic acidosis. Pediat. Res. 7: 149-160, 1973. PubMed ID : 4690360 2. Fukao, T.; Matsuo, N.; Zhang, G. X.; Urasawa, R.; Kubo, T.; Kohno, Y.; Kondo, N. : Single base substitutions at the initiator codon in the mitochondrial acetoacetyl-CoA thiolase (ACAT1/T2) gene result in production of varying amounts of wild-type T2 polypeptide. Hum. Mutat. 21: 587-592, 2003. PubMed ID : 12754704 3. Fukao, T.; Nakamura, H.; Song, X.-Q.; Nakamura, K.; Orii, K. E.; Kohno, Y.; Kano, M.; Yamaguchi, S.; Hashimoto, T.; Orii, T.; Kondo, N. : Characterization of N93S, I312T, and A333P missense mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency. Hum. Mutat. 12: 245-254, 1998. PubMed ID : 9744475 4. Fukao, T.; Yamaguchi, S.; Kano, M.; Orii, T.; Fujiki, Y.; Osumi, T.; Hashimoto, T. : Molecular cloning and sequence of the complementary DNA encoding human mitochondrial acetoacetyl-coenzyme A thiolase and study of the variant enzymes in cultured fibroblasts from patients with 3-ketothiolase deficiency. J. Clin. Invest. 86: 2086-2092, 1990. PubMed ID : 1979337 5. Fukao, T.; Yamaguchi, S.; Orii, T.; Osumi, T.; Hashimoto, T. : Molecular basis of 3-ketothiolase deficiency: identification of an AG to AC substitution at the splice acceptor site of intron 10 causing exon 11 skipping. Biochim. Biophys. Acta 1139: 184-188, 1992. PubMed ID : 1627655 6. Fukao, T.; Yamaguchi, S.; Orii, T.; Schutgens, R. B. H.; Osumi, T.; Hashimoto, T. : Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase: a complete analysis of two generations of a family with 3-ketothiolase deficiency. J. Clin. Invest. 89: 474-479, 1992. PubMed ID : 1346617 7. Fukao, T.; Yamaguchi, S.; Scriver, C. R.; Dunbar, G.; Wakazono, A.; Kano, M.; Orii, T.; Hashimoto, T. : Molecular studies of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in the two original families. Hum. Mutat. 2: 214-220, 1993. PubMed ID : 8103405 8. Fukao, T.; Yamaguchi, S.; Tomatsu, S.; Orii, T.; Frauendienst-Egger, G.; Schrod, L.; Osumi, T.; Hashimoto, T. : Evidence for a structural mutation (ala347-to-thr) in a German family with 3-ketothiolase deficiency. Biochem. Biophys. Res. Commun. 179: 124-129, 1991. PubMed ID : 1715688 9. Fukao, T.; Yamaguchi, S.; Wakazono, A.; Orii, T.; Hoganson, G.; Hashimoto, T. : Identification of a novel exonic mutation at -13 from 5-prime splice site causing exon skipping in a girl with mitochondrial acetoacetyl-coenzyme A thiolase deficiency. J. Clin. Invest. 93: 1035-1041, 1994. PubMed ID : 7907600 10. Kano, M.; Fukao, T.; Yamaguchi, S.; Orii, T.; Osumi, T.; Hashimoto, T. : Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene. Gene 109: 285-290, 1991. PubMed ID : 1684944 11. Masuno, M.; Kano, M.; Fukao, T.; Yamaguchi, S.; Osumi, T.; Hashimoto, T.; Takahashi, E.; Hori, T.; Orii, T. : Chromosome mapping of the human mitochondrial acetoacetyl-coenzyme A thiolase gene to 11q22.3-q23.1 by fluorescence in situ hybridization. Cytogenet. Cell Genet. 60: 121-122, 1992. PubMed ID : 1351831 12. Matsuda, Y.; Imai, T.; Shiomi, T.; Saito, T.; Yamauchi, M.; Fukao, T.; Akao, Y.; Seki, N.; Ito, H.; Hori, T. : Comparative genome mapping of the ataxia-telangiectasia region in mouse, rat, and Syrian hamster. Genomics 34: 347-352, 1996. PubMed ID : 8786135 13. Schutgens, R. B. H.; Middleton, B.; van der Blij, J. F.; Oorthuys, J. W. E.; Veder, H. A.; Vulsma, T.; Tegelaers, W. H. H. : Beta-ketothiolase deficiency in a family confirmed by in vitro enzymatic assays in fibroblasts. Europ. J. Pediat. 139: 39-42, 1982. PubMed ID : 7173255 14. Sewell, A. C.; Herwig, J.; Wiegratz, I.; Lehnert, W.; Niederhoff, H.; Song, X.-Q.; Kondo, N.; Fukao, T. : Mitochondrial acetoacetyl-CoA thiolase (beta-ketothiolase) deficiency and pregnancy. J. Inherit. Metab. Dis. 21: 441-442, 1998. PubMed ID : 9700610 15. Steingrimsdottir, H.; Rowley, G.; Dorado, G.; Cole, J.; Lehmann, A. R. : Mutations which alter splicing in the human hypoxanthine-guanine phosphoribosyltransferase gene. Nucleic Acids Res. 20: 1201-1208, 1992. PubMed ID : 1373235 ### CONTRIBUTORS Victor A. McKusick - updated : 7/11/2003 ### CREATION DATE Cassandra L. Kniffin : 5/21/2003 ### EDIT HISTORY carol : 11/30/2004 cwells : 7/15/2003 terry : 7/11/2003 carol : 5/23/2003 ckniffin : 5/22/2003 Copyright © 1966-2005 Johns Hopkins University
12: | *607705 | Links
| PROTEASOME ACTIVATOR SUBUNIT 4; PSME4
#### Alternative titles; symbols PROTEASOME ACTIVATOR, 200-KD; PA200 KIAA0077 ### TABLE OF CONTENTS #### CLONING GENE FUNCTION MAPPING REFERENCES CREATION DATE EDIT HISTORY Gene map locus Chr.2 ### TEXT #### CLONING By sequencing clones obtained from a size-fractionated myeloid cell line cDNA library, Nomura et al. (1994) cloned a partial PSME4 cDNA, which they designated KIAA0077. Northern blot analysis detected ubiquitous expression, with highest expression in skeletal muscle and testis, and lowest expression in colon and peripheral blood leukocytes. Ustrell et al. (2002) cloned full-length mouse and human PSME4, which they designated PA200. The deduced 1,843-amino acid proteins share over 90% sequence identity. PA200 contains a bipartite nuclear targeting sequence and several potential phosphorylation sites, many of which are sites for the DNA repair kinases ATM (607585) and PRKDC (600899). Two-dimensional gel electrophoresis of bovine testis PA200 resolved the 200-kD band into several isoelectric variants that were unaffected by phosphatase treatment. Western blot analysis of mouse tissues detected 3 species: a 200-kD species that was most abundant in testis; a 60-kD species that was most prominent in brain but also abundant in liver and lung; and a 160-kD species that was abundant in other organs. #### GENE FUNCTION Ustrell et al. (2002) found that PA200 purified from bovine testis activated proteasomal hydrolysis of peptides, but not proteins. It particularly activated the peptidylglutamyl peptidase activity, and activation was ATP-independent. Proteasome activation was also accompanied by the formation of a PA200-proteasome complex in HeLa cells. Following gamma irradiation, but not UV irradiation or peroxide treatment, the uniform nuclear distribution of endogenous PA200 in HeLa cells reorganized into punctate nuclear foci. Ustrell et al. (2002) hypothesized that PA200 is involved in DNA repair by recruiting proteasomes to double-strand breaks. #### MAPPING By analysis of a panel of human/rodent hybrid cell lines, Nomura et al. (1994) mapped the PSME4 gene to chromosome 2. ### REFERENCES 1. Nomura, N.; Nagase, T.; Miyajima, N.; Sazuka, T.; Tanaka, A.; Sato, S.; Seki, N.; Kawarabayasi, Y.; Ishikawa, K.; Tabata, S. : Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994. PubMed ID : 7584044 2. Ustrell, V.; Hoffman, L.; Pratt, G.; Rechsteiner, M. : PA200, a nuclear proteasome activator involved in DNA repair. EMBO J. 21: 3516-3525, 2002. PubMed ID : 12093752 ### CREATION DATE Patricia A. Hartz : 4/22/2003 ### EDIT HISTORY carol : 4/23/2003 carol : 4/23/2003 Copyright © 1966-2005 Johns Hopkins University
13: | *607593 | Links
| MEDIATOR OF DNA DAMAGE CHECKPOINT PROTEIN 1; MDC1
#### Alternative titles; symbols NUCLEAR FACTOR WITH BRCT DOMAINS PROTEIN 1; NFBD1 KIAA0170 ### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE FUNCTION MAPPING REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 6pter-p21.3 ### TEXT #### DESCRIPTION The MDC1 protein contains a forkhead homology-associated (FHA) domain and 2 BRCA1 (113705) C-terminal motifs (BRCTs) and is required for the intra-S-phase DNA damage checkpoint. #### CLONING Shang et al. (2003) identified nuclear factor with BRCT domains protein-1 (NFBD1) as a mammalian homolog of S. cerevisiae Rad9. By randomly sequencing cDNAs obtained from the human myeloid cell line KG-1, Nagase et al. (1996) cloned MDC1, which they called KIAA0170. The deduced MDC1 protein contains 2,089 amino acids. Northern blot analysis showed that MDC1 is ubiquitously expressed. Goldberg et al. (2003) identified MDC1 as a binding partner for the MRE11 complex (see MRE11; 600814). They determined that the MDC1 protein has a predicted molecular mass of 226.5 kD. It contains an FHA domain at its N terminus and 2 BRCTs at its C terminus. The central region of MDC1 has 19 consecutive repeats of an approximately 40-amino acid motif. Stewart et al. (2003) reported that MDC1 contains a large S/TQ cluster domain encompassing its N-terminal half. The central region of MDC1 has a large proline/serine/threonine-rich repeat domain. #### GENE FUNCTION Goldberg et al. (2003) showed that, in response to ionizing radiation, MDC1 was hyperphosphorylated in an ATM (607585)-dependent manner and rapidly relocalized to nuclei foci containing the MRE11 complex, phosphorylated histone H2AX (601772), and TP53BP1 (605230). Downregulation of MDC1 expression by small interfering RNA yielded a radioresistant DNA synthesis phenotype and prevented ionizing radiation-induced focus formation by the MRE11 complex. However, downregulation of MDC1 did not abolish the ionizing radiation-induced phosphorylation of NBS1 (602667), CHK2 (604373), and SMC1 (300040), or the degradation of CDC25A (116947). Furthermore, overexpression of the MDC1 FHA domain interfered with focus formation by MDC1 itself and by the MRE11 complex, and it induced a radioresistant DNA synthesis phenotype. Goldberg et al. (2003) concluded that MDC1-mediated focus formation by the MRE11 complex at sites of DNA damage is crucial for the efficient activation of the intra-S-phase checkpoint. Stewart et al. (2003) showed that MDC1 works with H2AX to promote recruitment of repair proteins to the site of DNA breaks and controls damage-induced cell-cycle arrest checkpoints. MDC1 formed foci that colocalized extensively with gamma-H2AX foci within minutes after exposure to ionizing radiation. H2AX was required for MDC1 foci formation, and MDC1 formed complexes with phosphorylated H2AX. Peptides containing the phosphorylated site on H2AX bound MDC1 in a phosphorylation-dependent manner. Stewart et al. (2003) used small interfering RNA to show that cells lacking MDC1 were sensitive to ionizing radiation and that MDC1 controlled the formation of damaged-induced TP53BP1, BRCA1, and MRN (MRE11, RAD50 (604040), NBS1, i.e., the MRE11 complex) foci, in part by promoting efficient H2AX phosphorylation. In addition, cells lacking MDC1 failed to activate the intra-S phase and G2/M phase cell cycle checkpoints properly after exposure to ionizing radiation, and this failure was associated with the inability to regulate CHK1 (603078) properly. Lou et al. (2003) found that MDC1 localized to sites of DNA breaks and associated with CHK2 after DNA damage. This association was mediated by the MDC1 FHA domain and the phosphorylated thr68 of CHK2. MDC1 was phosphorylated in an ATM/CHK2-dependent manner after DNA damage, suggesting that MDC1 may function in the ATM/CHK2 pathway. Consistent with this hypothesis, suppression of MDC1 expression resulted in defective S-phase checkpoint and reduced apoptosis in response to DNA damage, which could be restored by expression of wildtype MDC1, but not by MDC1 with a deleted FHA domain. Suppression of MDC1 expression resulted in decreased p53 (191170) stabilization in response to DNA damage. Lou et al. (2003) concluded that MDC1 is recruited through its FHA domain to the activated CHK2 and has a critical role in CHK2-mediated DNA damage responses. Shang et al. (2003) showed that NFBD1 is a 250-kD nuclear protein containing a forkhead-associated motif at its N terminus, 2 BRCT motifs at its C terminus, and 13 internal repetitions of a 41-amino acid sequence. Five minutes after gamma-irradiation, NFBD1 formed nuclear foci that colocalized with the phosphorylated form of H2AX and CHK2, 2 phosphorylation events involved in early DNA damage response. NFBD1 foci were also detected in response to camptothecin, etoposide, and methylmethanesulfonate treatments. Deletion of the forkhead-associated motif or the internal repeats of NFBD1 had no effect on DNA damage-induced NFBD1 foci formation. Conversely, deletion of the BRCT motifs abrogated damage-induced NFBD1 foci. Ectopic expression of the BRCT motifs reduced damage-induced NFBD1 foci and compromised phosphorylated CHK2- and phosphorylated H2AX-containing foci. Shang et al. (2003) concluded that NFBD1, like BRCA1 and TP53BP1, participates in the early response to DNA damage. #### MAPPING By analysis of human/rodent hybrid cell lines, Nagase et al. (1996) mapped the MDC1 gene to chromosome 6. ### REFERENCES 1. Goldberg, M.; Stucki, M.; Falck, J.; D'Amours, D.; Rahman, D.; Pappin, D.; Bartek, J.; Jackson, S. P. : MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 421: 952-956, 2003. PubMed ID : 12607003 2. Lou, Z.; Minter-Dykhouse, K.; Wu, X.; Chen, J. : MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways. Nature 421: 957-961, 2003. PubMed ID : 12607004 3. Nagase, T.; Seki, N.; Ishikawa, K.; Tanaka, A.; Nomura, N. : Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 3: 17-24, 1996. PubMed ID : 8724849 4. Shang, Y. L.; Bodero, A. J.; Chen, P.-L. : NFBD1, a novel nuclear protein with signature motifs of FHA and BRCT, and an internal 41-amino acid repeat sequence, is an early participant in DNA damage response. J. Biol. Chem. 278: 6323-6329, 2003. PubMed ID : 12475977 5. Stewart, G. S.; Wang, B.; Bignell, C. R.; Taylor, A. M. R.; Elledge, S. J. : MDC1 is a mediator of the mammalian DNA damage checkpoint. Nature 421: 961-966, 2003. PubMed ID : 12607005 ### CONTRIBUTORS Ada Hamosh - updated : 4/1/2003 ### CREATION DATE Ada Hamosh : 2/28/2003 ### EDIT HISTORY alopez : 5/22/2003 alopez : 4/2/2003 terry : 4/1/2003 ckniffin : 3/11/2003 mgross : 2/28/2003 Copyright © 1966-2005 Johns Hopkins University
14: | *606829 | GeneTests, Links
| FRDA GENE; FRDA
#### Alternative titles; symbols FRATAXIN X25 ### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE STRUCTURE GENE FUNCTION MOLECULAR GENETICS GENOTYPE/PHENOTYPE CORRELATIONS HISTORY ALLELIC VARIANTS View List SEE ALSO REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 9q13 ### TEXT #### DESCRIPTION The FRDA gene encodes the protein frataxin, which is involved in mitochondrial iron metabolism. #### CLONING By searching the candidate region defined by analysis of recombination events in families with Friedreich ataxia (229300), Montermini et al. (1995) reported that they had located a 150-kb region in chromosome 9q13 that represented the FRDA locus. Campuzano et al. (1996) identified potential exons in the region in chromosome 9q13 using cDNA selection and sequence analysis. One gene, isolated by this method and called X25 by the authors, encodes a 210-amino acid protein, termed frataxin. It was shown to be expressed in a range of tissues, most abundantly in heart. High levels of expression were also found in the spinal cord; lower levels were detected in the cerebellum, and no expression was demonstrated in the cerebral cortex. Koutnikova et al. (1997) cloned the complete coding region of mouse frataxin and studied its pattern of expression in developing and adult tissues. Frataxin mRNA was predominantly expressed in tissues with a high metabolic rate, including liver, kidney, brown fat, and heart. They showed that mouse and yeast frataxin homologs contain a potential mitochondrial targeting sequence in their N-terminal domains and that disruption of the yeast gene results in mitochondrial dysfunction. #### GENE STRUCTURE Campuzano et al. (1996) found that the FRDA gene contains 6 exons. #### GENE FUNCTION To study frataxin function, Campuzano et al. (1997) developed monoclonal antibodies raised against different regions of the frataxin protein. These antibodies detected a processed 18-kD protein in various human and mouse tissues and cell lines that is severely reduced in Friedreich ataxia patients. By immunocytofluorescence and immunocytoelectron microscopy, Campuzano et al. (1997) demonstrated that frataxin is located in mitochondria, associated with the mitochondrial membranes and crests. Analysis of cellular localization of various truncated forms of frataxin expressed in cultured cells and evidence of removal of an N-terminal epitope during protein maturation demonstrated that the mitochondrial targeting sequence is encoded by the first 20 amino acids. Given the shared clinical features between Friedreich ataxia, vitamin E deficiency, and some mitochondriopathies, Campuzano et al. (1997) suggested that their data indicate that a reduction in frataxin results in oxidative damage. Ristow et al. (2000) demonstrated that overexpression of frataxin in mammalian cells causes a Ca(2+)-induced upregulation of tricarboxylic acid cycle flux and respiration, which, in turn, leads to an increased mitochondrial membrane potential and results in an elevated cellular ATP content. Thus, frataxin appears to be a key activator of mitochondrial energy conversion and oxidative phosphorylation. Santos et al. (2001) examined the role of frataxin in neuronal differentiation by transfecting the P19 embryonic carcinoma cell line with antisense or sense frataxin constructs. During retinoic acid-induced neurogenesis of frataxin-deficient cells there was a striking rise in cell death, while cell division remained unaffected. However, frataxin deficiency did not affect cell survival in cells induced to differentiate into cardiomyocytes. Frataxin deficiency enhanced apoptosis of retinoic acid-stimulated cells, and the number of neuronal-like cells expressing MAP2 (157130) was dramatically reduced in these clones. In addition, antisense clones induced to differentiate into neuroectoderm with retinoic acid had increased production of reactive oxygen species, and only cells noncommitted to the neuronal lineages could be rescued by the addition of the antioxidant N-acetylcysteine (NAC). However, NAC treatment had no effect in increasing the number of terminally differentiated neuronal-like cells in frataxin-deficient clones. The authors suggested that frataxin deficiency may render cells susceptible to apoptosis after exposure to appropriate stimuli. Cavadini et al. (2002) showed that the mature form of human frataxin, when expressed in E. coli, assembles into a stable homopolymer that can bind approximately 10 atoms of iron per molecule of frataxin. As analyzed by gel filtration and electron microscopy, the homopolymer consists of globular particles of approximately 1 megadalton and orders rod-shaped polymers of these particles that accumulate small electron-dense cores. When the human frataxin precursor was expressed in S. cerevisiae, the mitochondrially-generated mature form was separated by gel filtration into monomer and a high molecular weight pool of approximately 600 kD, which was also present in mouse heart. In radiolabeled yeast cells, human frataxin was recovered by immunoprecipitation with approximately 5 atoms of iron bound per molecule. The authors suggested that FRDA may result from decreased mitochondrial iron storage due to frataxin deficiency, which may impair iron metabolism, promote oxidative damage, and lead to progressive iron accumulation. Shoichet et al. (2002) demonstrated that transgenic overexpression of human frataxin in murine 3T3-L1 cells increased cellular antioxidant defense. Subsequent activation of glutathione peroxidase and elevation of reduced thiols reduced the incidence of malignant transformation induced by reactive oxygen species, as observed by tumor formation in nude mice. The authors tentatively suggested a role for frataxin mutations in the early induction of cancer. #### Studies in the Yeast Homolog Babcock et al. (1997) characterized a gene in Saccharomyces cerevisiae whose predicted gene product had high sequence similarity to the human frataxin protein. The yeast gene (yeast frataxin homolog, YFH1) encodes a mitochondrial protein involved in iron homeostasis and respiratory function. Human frataxin also was shown to be a mitochondrial protein. Wilson and Roof (1997) showed that YFH1 localizes to mitochondria and is required to maintain mitochondrial DNA. They showed that the YFH1-homologous domain of frataxin functions in yeast and that a disease-associated missense mutation of this domain, or the corresponding domain in YFH1, reduces function. Using the yeast 2-hybrid assay (Fields and Song, 1989), Koutnikova et al. (1998) identified mitochondrial processing peptidase-beta (MPPB; 603131) as a frataxin protein partner. In in vitro assays, MPPB bound frataxin which is cleaved by the reconstituted MPP heterodimer. MPP cleavage of frataxin results in an intermediate form (amino acids 41 to 210) that is processed further to the mature form. In vitro and in vivo experiments suggested that 2 C-terminal missense mutations found in FRDA patients, I151F (606829.0004) and G127V (606829.0005), modulate interaction with MPP-beta, resulting in a slower maturation process at the normal cleavage site. The slower processing rate of frataxin carrying such missense mutations may therefore contribute to frataxin deficiency, in addition to an impairment of its function. Similar studies were reported by Gordon et al. (1999), with conflicting results. They performed in vitro experiments with MPP, wildtype and I154F human frataxin or its mutant yeast homolog, and purified mammalian or yeast mitochondria. These authors concluded that MPP was capable of 1-step processing of frataxin to the mature form, and that the I154F mutation had no effect on mitochondrial import and/or maturation of frataxin. Adamec et al. (2000) expressed a mature form of the YFH1 protein in E. coli and analyzed its function in vitro. The isolated protein is a soluble monomer that contains no iron and shows no significant tendency to self-associate. Aerobic addition of ferrous iron to the protein resulted in assembly of regular spherical multimers. Each multimer consists of approximately 60 subunits and can sequester more than 3,000 atoms of iron. Titration of the yeast protein with increasing iron concentrations supported a stepwise mechanism of multimer assembly. Sequential addition of an iron chelator and a reducing agent resulted in quantitative iron release with concomitant disassembly of the multimer, indicating that the yeast frataxin protein sequesters iron in an available form. Adamec et al. (2000) proposed that iron-dependent self-assembly of recombinant yeast frataxin protein reflects a physiologic role for frataxin in mitochondrial iron sequestration and bioavailability. Cavadini et al. (2000) showed that wildtype FRDA cDNA can complement the YFH1 protein-deficient yeast (YFH1-delta) by preventing the mitochondrial iron accumulation and oxidative damage associated with loss of YFH1. The G130V mutation (606829.0005) affected protein stability and resulted in low levels of mature frataxin, which were nevertheless sufficient to rescue YFH1-delta yeast. The W173G (606829.0007) mutation affected protein processing and stability and resulted in severe mature frataxin deficiency. Expression of the FRDA W173G cDNA in YFH1-delta yeast led to increased levels of mitochondrial iron which were not as elevated as in YFH1-deficient cells but were above the threshold for oxidative damage of mitochondrial DNA and iron-sulfur centers, causing a typical YFH1-delta phenotype. The authors concluded that frataxin functions like YFH1 protein, providing additional experimental support for the hypothesis that FRDA is a disorder of mitochondrial iron homeostasis. Gordon et al. (2001) mapped the 2 cleavage sites of the YFH1 protein precursor. Mutations blocking the first or the second cleavage of YFH1 protein did not interfere with its import from the cytoplasm or with its ability to complement phenotypes of the YFH1-delta mutant yeast strain. The first cleaved domain (domain I), consisting of 20 N-terminal amino acids, was able to import a nonmitochondrial passenger fusion protein. However, neither domain I nor other matrix-targeting signals alone could support efficient import of mature YFH1 protein. The second cleaved domain (domain II), consisting of an additional 31 N-terminal amino acids, was required as a spacer between a targeting signal and mature YFH1 protein. Likewise, when YFH1 protein constructs lacking domain I or II were expressed in vivo, they failed to attain appreciable steady-state amounts in mitochondria and could not complement phenotypes of the YFH1-delta mutant. Karthikeyan et al. (2002) found that the absence of frataxin in yeast leads to nuclear damage, as evidenced by inducibility of a nuclear DNA damage reporter, increased chromosomal instability including recombination and mutation, and greater sensitivity to DNA-damaging agents, as well as slow growth. Addition of a human frataxin mutant did not prevent nuclear damage, although it partially complemented the YFH1 mutant in preventing mitochondrial DNA loss. The effects in YFH1 mutants appeared to result from reactive oxygen species, since (1) YFH1 cells produce more hydrogen peroxide, (2) the effects are alleviated by the radical scavenger N-acetylcysteine, and (3) the glutathione peroxidase gene (GPX1; 138320) prevents an increase in mutation rates. The authors concluded that the frataxin protein has a protective role for the nucleus as well as the mitochondria. Adinolfi et al. (2002) compared the properties of 3 proteins from the frataxin family (bacterial CyaY from Escherichia coli, yeast Yfh1, and human frataxin) as representative of organisms of increasing complexity. The 3 proteins have the same fold but different thermal stabilities and iron-binding properties. While human frataxin has no tendency to bind iron, CyaY forms iron-promoted aggregates with a behavior similar to that of yeast frataxin. Mutants produced to identify the protein surface involved in iron-promoted aggregation demonstrated that the process is mediated by a negatively charged surface ridge. Mutation of 3 of these residues was sufficient to convert CyaY into a protein with properties similar to those of human frataxin. On the other hand, mutation of the exposed surface of the beta sheet, which contains most of the conserved residues, did not affect aggregation, suggesting to the authors that iron binding is a nonconserved part of a more complex cellular function of frataxins. Muhlenhoff et al. (2002) constructed a yeast strain (Gal-YFH1) that carried the YFH1 gene under the control of a galactose-regulated promoter. Yfh1p-deficient Gal-YFH1 cells were far less sensitive to oxidative stress than delta-yfh1 mutants, maintained mitochondrial DNA, and synthesized heme at wildtype rates. Yfh1p depletion caused a strong reduction in the assembly of mitochondrial Fe/S proteins, which may explain the respiratory deficiency of Gal-YFH1 cells. Yfh1p-depleted Gal-YFH1 cells show decreased maturation of cytosolic Fe/S proteins and accumulation of mitochondrial iron, which may be seen secondary to defects in cytosolic Fe/S protein assembly. The authors proposed a specific role of frataxin in the biosynthesis of cellular Fe/S proteins which excluded most of the previously suggested functions. Saccharomyces cerevisiae cells lacking the Yfh1 gene showed very low cytochrome content. Lesuisse et al. (2003) showed that in delta-yfh1 strains, the level of ferrochelatase (see 177000) was very low as a result of transcriptional repression of HEM15. However, the low amount of ferrochelatase was not the cause of heme deficiency in delta-yfh1 cells. Ferrochelatase, a mitochondrial protein able to mediate insertion of iron or zinc into the porphyrin precursor, made primarily the zinc protoporphyrin product. Yfh1p and ferrochelatase were shown to interact in vitro by BIAcore studies. Lesuisse et al. (2003) concluded that Yfh1 mediates iron use by ferrochelatase. Bulteau et al. (2004) found that aconitase (100850) activity can undergo reversible citrate-dependent modulation in response to prooxidants. Frataxin interacted with aconitase in a citrate-dependent fashion, reduced the level of oxidant-induced inactivation, and converted the inactive [3Fe-4S]1+ enzyme to the active [4Fe-4S]2+ form of the protein. Bulteau et al. (2004) concluded that frataxin is an iron chaperone protein that protects the aconitase [4Fe-4S]2+ cluster from disassembly and promotes enzyme reactivation. #### MOLECULAR GENETICS Mutation in the FRDA gene has been shown to cause one form of Friedreich ataxia (229300). Most patients with Friedreich ataxia have a GAA-repeat expansion in the FRDA gene. Delatycki et al. (1999) stated that 2% of cases of Friedreich ataxia are due to point mutations, the other 98% being due to expansion of a GAA trinucleotide repeat in intron 1. They indicated that 17 mutations had been described. Campuzano et al. (1996) screened 184 patients with Friedreich ataxia for point mutations by PCR amplification of exons. Three different point mutations were found (606829.0002- 606829.0004). Seventy-nine unrelated FRDA patients, including 5 with point mutations, were screened for the GAA repeat expansion in the first intron (606829.0001). In the group of 74 patients without a point mutation, 71 were found to be homozygous for expanded alleles, and 3 were heterozygous for the expanded repeat. The 5 patients shown to carry point mutations were all found to be heterozygous for the repeat, and the repeat and the polymorphism had different parental origin. Repeat expansions in the patients were typically between 200 and 900 copies. In controls, the repeat expansion varied from 7 to 22 copies. Delatycki et al. (1998) studied FRDA mutations in 66 Australian patients. One of 56 parents had a premutation with 1 normal allele and 1 allele of approximately 100 repeats in leukocyte DNA. His sperm showed an expanded allele in a tight range centering on a size of approximately 320 repeats. His affected son had repeat sizes of 1,040 and 540. Of 33 other father-to-offspring transmissions, 17 showed a definite decrease in allele size and 4 showed a decrease or no change; in 12 cases it was not possible to say if the allele had expanded or contracted in size. The authors stated that in all informative carrier father-to-affected child transmissions, other than in the premutation carrier, the expansion size decreased. Delatycki et al. (1998) concluded that expansion of the FRDA gene occurs in 2 stages, the first during meiosis followed by a second mitotic expansion. Gacy et al. (1998) showed that the GAA instability in Friedreich ataxia is a DNA-directed mutation caused by improper DNA structure at the repeat region. Unlike CAG or CGG repeats, which form hairpins, GAA repeats form a YRY triple helix containing non-Watson-Crick pairs. As with hairpins, triplex mediates intergenerational instability in 96% of transmissions. In families with Friedreich ataxia, GAA instability is not a function of the number of long alleles, ruling out homologous recombination or gene conversion as a major mechanism. The similarity of mutation pattern among triple repeat-related diseases indicates that all trinucleotide instability occurs by a common, intraallelic mechanism that depends on DNA structure. Secondary structure mediates instability by creating strong polymerase pause sites at or within the repeats, facilitating slippage or sister chromatid exchange. De Castro et al. (2000) analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. They found 7 compound heterozygous patients. In 4 patients, a point mutation that predicted a truncated frataxin was detected. Three of them were associated with classic early-onset Friedreich ataxia with an expanded GAA allele greater than 800 repeats. The fourth patient had disease onset at the late age of 29 years with a 350-GAA repeat expansion. In 2 patients manifesting the classic phenotype, no changes were observed by SSCP analysis. Linkage analysis in a family with 2 affected children with an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich patients are null mutations. In their collection of compound heterozygotes, clinical phenotypes seemed to be related to the GAA repeat number in the expanded allele. To investigate the genetic background of apparently idiopathic sporadic cerebellar ataxia, Schols et al. (2000) tested for CAG/CTG trinucleotide repeats causing spinocerebellar ataxia types 1, 2 (SCA2; 183090), 3 (SCA3; 109150), 6 (SCA6; 183086), 7 (SCA7; 164500), 8 (SCA8; 608768), and 12 (SCA12; 604326), and the GAA repeat of the frataxin gene in 124 patients, including 20 patients with the clinical diagnosis of multiple system atrophy. Patients with a positive family history, atypical Friedreich phenotype, or symptomatic (secondary) ataxia were excluded. Genetic analyses uncovered the most common Friedreich mutation in 10 patients with an age of onset between 13 and 36 years. The SCA6 mutation was present in 9 patients with disease onset between 47 and 68 years of age. The CTG repeat associated with SCA8 was expanded in 3 patients. One patient had SCA2 attributable to a de novo mutation from a paternally transmitted, intermediate allele. Schols et al. (2000) did not identify the SCA1, SCA3, SCA7, or SCA12 mutations in this group of idiopathic sporadic ataxia patients. No trinucleotide repeat expansion was detected in the multiple system atrophy subgroup. This study revealed the genetic basis in 19% of apparently idiopathic ataxia patients. SCA6 was the most frequent mutation in late-onset cerebellar ataxia. The authors concluded that the frataxin trinucleotide expansion should be investigated in all sporadic ataxia patients with onset before age 40, even when the phenotype is atypical for Friedreich ataxia. Sharma et al. (2002) used small-pool PCR to analyze somatic variability among 7,190 individual FRDA molecules from peripheral blood DNA of subjects carrying 12 different expanded alleles. Expanded alleles showed a length-dependent increase in somatic variability, with mutation loads ranging from 47 to 78%. There was a strong contraction bias among long alleles (more than 500 triplets), which showed a 4-fold higher frequency of large contractions versus expansions. Of all somatic mutations scored, 5% involved contractions of more than 50% of the original allele length, and 0.29% involved complete reversion to the normal/premutation length (60 triplets or fewer). These observations contrasted sharply with the strong expansion bias seen in CTG triplet repeats in myotonic dystrophy (DM1; 160900). No somatic variability was detected in more than 6000 individual FRDA molecules analyzed from 15 normal alleles (8 to 25 triplets). A premutation allele with 44 uninterrupted GAA repeats was found to be unstable, ranging in size from 6 to 113 triplets, thus establishing the threshold for somatic instability between 26 and 44 GAA triplets. The authors concluded that expanded GAA alleles in Friedreich ataxia are highly mutable and have a natural tendency to contract in vivo, and that these properties may depend on multiple factors, including DNA sequence, triplet-repeat length, and unknown cell type-specific factors. Sharma et al. (2004) reported 2 unrelated patients with late-onset Friedreich ataxia who were compound heterozygous for a large clearly pathogenic GAA expansion and a smaller 'borderline' GAA expansion in the FRDA gene. The first patient, who had expansions of 700 and 44 GAA repeats, developed ataxia symptoms in her early forties. The second patient, who had expansions of 915 and 66 GAA repeats, developed symptoms in his late twenties. Genomic analysis of several different tissues, including hair, skin, buccal cells, peripheral leukocytes, and fibroblasts, showed somatic instability of both the 44 and 66 repeat alleles. Cells from both patients showed an increase in mutation load, the proportion of individual FRDA molecules that differed in length from the constitutional allele by greater than 5%. Fifteen percent of the GAA-44 and 75% of the GAA-66 cells contained alleles with greater than 66 repeats. The 53-year-old asymptomatic brother of the first patient had alleles of 730 and 37 GAA repeats; the GAA-37 allele was somatically stable. Sharma et al. (2004) concluded that borderline expanded FRDA alleles ranging from 44 to 65 uninterrupted triplet repeats show somatic variability and may result in a disease phenotype if a large enough proportion of cells bear disease-causing expansions in pathologically affected tissues. Thus, persons who are compound heterozygous for a large repeat expansion and a borderline expansion have an increased risk of disease development. In order to gain insight into GAA triplet repeat instability, Clark et al. (2004) analyzed all triplet repeats in the human genome. They determined that the GAA triplet repeat has a significant tendency to expand compared with all other triplet repeats. Eighty-nine percent of GAA repeats of 8 or more map to the G/A islands of Alu elements, and 58% map to Alu element poly(A) tails. Clark et al. (2004) found that only 2 other GAA repeats of 8 or more share the central Alu location seen at the FRDA locus. Clark et al. (2004) theorized that the GAA repeat coevolved with Alu elements during primate genomic evolution. #### GENOTYPE/PHENOTYPE CORRELATIONS Filla et al. (1996) studied the relationship between the trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. The length of the FA alleles ranged from 201 to 1,186 repeat units. There was no overlap between the size of normal alleles and the size of alleles found in FA. The lengths of both the larger and the smaller alleles varied inversely with the age of onset of the disorder. Filla et al. (1996) reported that the mean allele length was significantly higher in FA patients with diabetes and in those with cardiomyopathy. They noted that there was meiotic instability with a median variation of 150 repeats. Isnard et al. (1997) examined the correlation between the severity of left ventricular hypertrophy in Friedreich ataxia and the number of GAA repeats. Left ventricular wall thickness was measured in 44 patients using M-mode echocardiography and correlated with GAA expansion size on the smaller allele (267 to 1200 repeats). A significant correlation was found (r = 0.51, p less than 0.001), highlighting an important role for frataxin in the regulation of cardiac hypertrophy. In a study of 187 patients with autosomal recessive ataxia, Durr et al. (1996) found that 140, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1,700 repeats of the trinucleotides. About one-quarter of the patients, despite being homozygous, had atypical Friedreich ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair of alleles) was associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs. The GAA repeats were unstable during transmission. Thus, the clinical spectrum of Friedreich ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion is useful for the diagnosis, prognosis, and genetic counseling. Pianese et al. (1997) presented data suggesting that (1) the FRDA GAA repeat is highly unstable during meiosis, (2) contractions outnumber expansions, (3) both parental source and sequence length are important factors in variability of FRDA expanded alleles, and (4) the tendency to contract or expand does not seem to be associated with particular haplotypes. Thus, they concluded that FRDA gene variability appears to be different from that found with other triplet diseases. Bidichandani et al. (1997) found an atypical FRDA phenotype associated with a remarkably slow rate of disease progression in a Caucasian family. It was caused by compound heterozygosity for a G130V missense mutation (606829.0005) and the GAA expansion of the X25 gene. The missense mutation G130V was the second mutation to be identified in the X25 gene and the first to be associated with a variant FRDA phenotype. This and the other reported missense mutation (I154F; 229300.0004) mapped within the highly conserved sequence domain in the C terminus of the frataxin gene. Since the G130V mutation was unlikely to affect the ability of the first 16 exons of the neighboring STM7 gene to encode a functional phosphatidylinositol phosphate kinase, Bidichandani et al. (1997) questioned the role of STM7 in Friedreich ataxia. Since Friedreich ataxia is an autosomal recessive disease, it does not show typical features observed in other dynamic mutation disorders, such as anticipation. Monros et al. (1997) analyzed the GAA repeat in 104 FA patients and 163 carrier relatives previously defined by linkage analysis. The GAA expansion was detected in all patients, most (94%) of them being homozygous for the mutation. They demonstrated that clinical variability in FA is related to the size of the expanded repeat: milder forms of the disease (late-onset FA and FA with retained reflexes) were associated with shorter expansions, especially with the smaller of the 2 expanded alleles. Absence of cardiomyopathy was also associated with shorter alleles. Dynamics of the GAA repeat were investigated in 212 parent-offspring pairs. Meiotic instability showed a sex bias: paternally transmitted alleles tended to decrease in a linear way that depended on the paternal expansion size, whereas maternal alleles either increased or decreased in size. All but 1 of the patients with late-onset FA were homozygous for the GAA expansion; the exceptional individual was heterozygous for the expansion and for another unknown mutation. All but 1 of the FA patients with retained reflexes exhibited an axonal sensory neuropathy. However, preservation of their tendon reflexes suggested that the physiologic pathways of the reflex arch remained functional. A close relationship was found between late-onset disease and absence of heart muscle disease. Delatycki et al. (1999) studied FRDA1 mutations in FA patients from Eastern Australia. Of the 83 people studied, 78 were homozygous for an expanded GAA repeat, while the other 5 had an expansion in one allele and a point mutation in the other. The authors presented a detailed study of 51 patients homozygous for an expanded GAA repeat. They identified an association between the size of the smaller of the 2 expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. However, no significant association was identified between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size was associated with bladder symptoms and the presence of foot deformity. #### HISTORY Duclos et al. (1993) identified a transcript containing the conserved sequences around the D9S5 locus. The 7-kb transcript corresponded to a gene designated X11 (APBA1; 602414) which extended at least 80 kb in a direction opposite D9S15. The gene was expressed in the brain, including the cerebellum, but was not detectable in several nonneuronal tissues and cell lines. In situ hybridization of adult mouse brain sections showed prominent expression in the granular layer of the cerebellum. Expression was also found in the spinal cord. The cDNA contained an open reading frame encoding a 708-amino acid sequence that showed no significant similarity to other known proteins but contained a unique, 24-residue, putative transmembrane segment. On the basis of these findings, Duclos et al. (1993) suggested that this 'pioneer' gene represents the FRDA gene. Further studies by Rodius et al. (1994) excluded X11 as a candidate for the Friedreich ataxia gene. Carvajal et al. (1995) reported the isolation of a gene from the FRDA critical region. Although no evidence of mutation was detected in the transcript, the sequence, which they designated STM7 (602745), represented only one of the shorter alternatively spliced species identified by Northern analysis and direct sequencing. Carvajal et al. (1995) still considered the gene a strong candidate for FRDA. Carvajal et al. (1996) reported that the X25 gene (frataxin-encoding gene) described by Campuzano et al. (1996) comprises part of STM7. They reported that the transcription of both STM7 and X25 occurs from the centromere toward the telomere, that the reported sequences of STM7 and X25 did not represent a full-length transcript, that multiple transcripts for each of these genes are present in Northern blots, and that several of these transcripts are of similar size. Carvajal et al. (1996) also reported that less than 10 kb separates the CpG island identified in the X25/exon 1 from the 3-prime end of STM7/exon 16. They further demonstrated that the recombinant protein corresponding to the STM7.1 transcript has phosphatidylinositol-4-phosphate 5-kinase activity. They noted that the ataxia-telangiectasia gene (607585) has C-terminal similarity to the catalytic domains of phosphatidylinositol phosphate 3-kinases. This homology, and the observation by Matsumoto et al. (1996) of an ataxia phenotype in mice lacking the type 1 inositol-1,4,5-triphosphate receptor (147265), provided support for a defect in the phosphoinositide pathway constituting the pathogenetic basis of Friedreich ataxia. Cossee et al. (1997) concluded that there was no strong argument for a role of STM7 in Friedreich ataxia, while the presence of mutations in the frataxin gene fulfilled all criteria required of the FRDA gene. In reply, Chamberlain et al. (1997) presented additional data and stated the opinion that 'Cossee et al. have failed to present either a plausible explanation for our original observations or a definitive argument to contradict our interpretation of the data.' In rebuttal, Pandolfo (1997) pointed out that no data have been presented showing the existence of STM7/frataxin transcripts with methods other than RT-PCR, the existence of a defect in PIP kinase activity in Friedreich patients, or the existence of disease-causing mutations in STM7. In a review article, Koenig and Mandel (1997) stated that there was strong evidence negating the claim that the frataxin exons are alternative 3-prime STM7 exons, namely, the structure of frataxin cDNAs and mouse intronless pseudogenes, the nature of point mutations found in some patients, and the size of the endogenous frataxin protein. ### ALLELIC VARIANTS (selected examples) #### .0001 FRIEDREICH ATAXIA [FRDA, (GAA)n EXPANSION ] FRIEDREICH ATAXIA WITH RETAINED REFLEXES, INCLUDED GAA triplet repeat expansions between 200 and 900 copies in the first intron of the frataxin gene occurred in 71 of 74 FRDA (229300) patients studied by Campuzano et al. (1996). In unaffected individuals, the triplet repeat expansion numbered between 7 and 20 units. Among 101 FRDA patients homozygous for GAA expansion within the X25 gene, Coppola et al. (1999) found that 11 patients from 8 families had FRDA with retained reflexes in the lower limbs (FARR; see 229300). The mean size of the smaller allele was significantly less (408 +/- 252 vs 719 +/- 184 GAA triplets) in FARR patients. #### .0002 FRIEDREICH ATAXIA [FRDA, LEU106TER ] In 2 affected members of a French family, Campuzano et al. (1996) identified compound heterozygosity for the FRDA expansion repeat (606829.0001) and a T-to-G transversion in exon 3 that changed a leucine (TTA) to a stop (TGA). The L106X mutation came from the father; the other allele carrying the expansion was from the mother. #### .0003 FRIEDREICH ATAXIA [FRDA, IVS3, A-G, -2 ] Campuzano et al. (1996) found compound heterozygosity in a member of a Spanish family for the FRDA expansion repeat (606829.0001) and an A-to-G transition which disrupted the acceptor splice site at the end of the third intron. #### .0004 FRIEDREICH ATAXIA [FRDA, ILE154PHE ] Campuzano et al. (1996) studied 5 patients from 3 different Italian families and identified a change from isoleucine-154 to phenylalanine in exon 4. These patients were heterozygous for the FRDA expansion repeat (606829.0001). This I154F mutation was found to occur in 1 out of 417 chromosomes examined from the same Southern Italian population. Isoleucine at this position was highly conserved across species. (Koutnikova et al. (1998) referred to this mutation as ILE151PHE.) #### .0005 FRIEDREICH ATAXIA [FRDA, GLY130VAL ] Bidichandani et al. (1997) found compound heterozygosity for the GAA triplet-repeat expansion (606829.0001) and a novel missense mutation, G130V, in 3 sibs with variant Friedreich ataxia (229300). Three of 6 sibs were affected: a male age 42, a male age 39, and a female age 35. Onset of disease was in the early teens, starting with weakness in the lower limbs and followed by gradual progression over the ensuing 20 years. Two brothers were still ambulatory, using either a walking stick or walker, and led fully productive working lives. Their upper limbs were affected to a lesser extent than their legs and lacked several key signs. They had sensory loss over the distal limbs, mild to moderate motor weakness, impaired position and vibratory sense, and hypo- or areflexia. Bilateral Babinski sign was also present in 1 brother. There was no atrophy, and muscle tone was normal. Notably, there was no dysarthria, and coordination was either very mildly affected or normal. Nerve conduction studies revealed slowing of motor-conduction velocities and absent sensory-evoked responses. Magnetic resonance imaging (MRI) revealed cervical spinal cord atrophy. No cardiac abnormalities were detected. Blood glucose levels were borderline elevated, and mild glucose intolerance was revealed in a 5-hour glucose-tolerance test. The sister was somewhat more physically incapacitated than her older 2 brothers. (Koutnikova et al. (1998) referred to this mutation as GLY127VAL.) By haplotype analysis in the 4 families that had been described with the G130V mutation, Delatycki et al. (1999) found results suggesting a common founder. #### .0006 FRIEDREICH ATAXIA [FRDA, MET1ILE ] In 3 independent families, Zuhlke et al. (1998) found that affected individuals were compound heterozygotes for the repeat expansion (606829.0001) and an ATG-to-ATT (met1-to-ile; M1I) mutation of the start codon of the FRDA gene. Haplotype analysis using 6 polymorphic chromosome 9 markers showed complete identity of haplotype in 2 of the 3 chromosomes with the point mutation; the third case showed partial conformity and may represent a single recombination event. A common ancestor was suspected. An M1I start codon mutation has been described in the HBB gene (141900.0430) as the cause of beta-0-thalassemia, in the OAT gene (258870.0001) as the cause of gyrate atrophy, in the PAH gene (261600.0048) as the cause of phenylketonuria, and in the PLP gene (312080.0015) as the cause of Pelizaeus-Merzbacher disease, but in all of these instances the nucleotide change represented an ATG-to-ATA transition. #### .0007 FRIEDREICH ATAXIA [FRDA, TRP173GLY] In 2 unrelated patients with Friedreich ataxia (229300), Cossee et al. (1999) identified a TGG-to-GGG change in exon 5a of the FRDA gene, resulting in a trp173-to-gly (W173G) substitution. ### SEE ALSO Bidichandani et al. (1998); Gray and Johnson (1997); Montermini et al. (1997); Ohshima et al. (1998); Puccio and Koenig (2000); Sakamoto et al. (1999) ### REFERENCES 1. Adamec, J.; Rusnak, F.; Owen, W. G.; Naylor, S.; Benson, L. M.; Gacy, A. M.; Isaya, G. : Iron-dependent self-assembly of recombinant yeast frataxin: implications for Friedreich ataxia. Am. J. Hum. Genet. 67: 549-562, 2000. PubMed ID : 10930361 2. Adinolfi, S.; Trifuoggi, M.; Politou, A. S.; Martin, S.; Pastore, A. : A structural approach to understanding the iron-binding properties of phylogenetically different frataxins. Hum. Molec. Genet. 11: 1865-1877, 2002. PubMed ID : 12140189 3. Babcock, M.; de Silva, D.; Oaks, R.; Davis-Kaplan, S.; Jiralerspong, S.; Montermini, L.; Pandolfo, M.; Kaplan, J. : Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276: 1709-1712, 1997. PubMed ID : 9180083 4. Bidichandani, S. I.; Ashizawa, T.; Patel, P. I. : Atypical Friedreich ataxia caused by compound heterozygosity for a novel missense mutation and the GAA triplet-repeat expansion. (Letter) Am. J. Hum. Genet. 60: 1251-1256, 1997. PubMed ID : 9150176 5. Bidichandani, S. I.; Ashizawa, T.; Patel, P. I. : The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. Am. J. Hum. Genet. 62: 111-121, 1998. PubMed ID : 9443873 6. Bulteau, A.-L.; O'Neill, H. A.; Kennedy, M. C.; Ikeda-Saito, M.; Isaya, G.; Szweda, L. I. : Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science 305: 242-245, 2004. PubMed ID : 15247478 7. Campuzano, V.; Montermini, L.; Lutz, Y.; Cova, L.; Hindelang, C.; Jiralerspong, S.; Trottier, Y.; Kish, S. J.; Faucheux, B.; Trouillas, P.; Authier, F. J.; Durr, A.; Mandel, J.-L.; Vescovi, A.; Pandolfo, M.; Koenig, M. : Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum. Molec. Genet. 6: 1771-1780, 1997. PubMed ID : 9302253 8. Campuzano, V.; Montermini, L.; Molto, M. D.; Pianese, L.; Cossee, M.; Cavalcanti, F.; Monros, E.; Rodius, F.; Duclos, F.; Monticelli, A.; Zara, F.; Canizares, J.; Koutnikova, H.; Bidichandani, S. I.; Gellera, C.; Brice, A.; Trouillas, P.; De Michele, G.; Filla, A.; De Frutos, R.; Palau, F.; Patel, P. I.; Di Donato, S.; Mandel, J. -L.; Cocozza, S.; Koenig, M.; Pandolfo, M. : Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271: 1423-1427, 1996. PubMed ID : 8596916 9. Carvajal, J. J.; Pook, M. A.; dos Santos, M.; Doudney, K.; Hillermann, R.; Minogue, S.; Williamson, R.; Hsuan, J. J.; Chamberlain, S. : The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4-phosphate 5-kinase. Nature Genet. 14: 157-162, 1996. PubMed ID : 8841185 10. Carvajal, J. J.; Pook, M. A.; Doudney, K.; Hillermann, R.; Wilkes, D.; Al-Mahdawi, S.; Williamson, R.; Chamberlain, S. : Friedreich's ataxia: a defect in signal transduction? Hum. Molec. Genet. 4: 1411-1419, 1995. PubMed ID : 7581382 11. Cavadini, P.; Gellera, C.; Patel, P. I.; Isaya, G. : Human frataxin maintains mitochondrial iron homeostasis in Saccharomyces cerevisiae. Hum. Molec. Genet. 9: 2523-2530, 2000. PubMed ID : 11030757 12. Cavadini, P.; O'Neill, H. A.; Benada, O.; Isaya, G. : Assembly and iron-binding properties of human frataxin, the protein deficient in Friedrich ataxia. Hum. Molec. Genet. 11: 217-227, 2002. PubMed ID : 11823441 13. Chamberlain, S.; Pook, M.; Carvajal, J.; Doudney, K.; Hillermann, R. : Frataxin fracas. (Letter) Nature Genet. 15: 337-338, 1997. PubMed ID : 9090376 14. Clark, R. M.; Dalgliesh, G. L.; Endres, D.; Gomez, M.; Taylor, J.; Bidichandani, S. I. : Expansion of GAA triplet repeats in the human genome: unique origin of the FRDA mutation at the center of an Alu. Genomics 83: 373-383, 2004. PubMed ID : 14962663 15. Coppola, G.; De Michele, G.; Cavalcanti, F.; Pianese, L.; Perretti, A.; Santoro, L.; Vita, G.; Toscano, A.; Amboni, M.; Grimaldi, G.; Salvatore, E.; Caruso, G.; Filla, A. : Why do some Friedreich's ataxia patients retain tendon reflexes? A clinical, neurophysiological and molecular study. J. Neurol. 246: 353-357, 1999. PubMed ID : 10399865 16. Cossee, M.; Campuzano, V.; Koutnikova, H.; Fischbeck, K.; Mandel, J.-L.; Koenig, M.; Bidichandani, S. I.; Patel, P. I.; Molte, M. D.; Canizares, J.; De Frutos, R.; Pianese, L.; Cavalcanti, F.; Monticelli, A.; Cocozza, S.; Montermini, L.; Pandolfo, M. : Frataxin fracas. (Letter) Nature Genet. 15: 337-338, 1997. PubMed ID : 9090376 17. Cossee, M.; Durr, A.; Schmitt, M.; Dahl, N.; Trouillas, P.; Allinson, P.; Kostrzewa, M.; Nivelon-Chevallier, A.; Gustavson, K.-H.; Kohlschutter, A.; Muller, U.; Mandel, J.-L.; and 11 others : Friedreich's ataxia: point mutations and clinical presentation of compound heterozygotes. Ann. Neurol. 45: 200-206, 1999. PubMed ID : 9989622 18. De Castro, M.; Garcia-Planells, J.; Monros, E.; Canizares, J.; Vazquez-Manrique, R.; Vilchez, J. J.; Urtasun, M.; Lucus, M.; Navarro, G.; Izquierdo, G.; Molto, M. D.; Palau, F. : Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients. Hum. Genet. 106: 86-92, 2000. PubMed ID : 10982187 19. Delatycki, M. B.; Knight, M.; Koenig, M.; Cossee, M.; Williamson, R.; Forrest, S. M. : G130V, a common FRDA point mutation, appears to have arisen from a common founder. Hum. Genet. 105: 343-346, 1999. PubMed ID : 10543403 20. Delatycki, M. B.; Paris, D.; Gardner, R. J. M.; Forshaw, K.; Nicholson, G. A.; Nassif, N.; Williamson, R.; Forrest, S. M. : Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene. J. Med. Genet. 35: 713-716, 1998. PubMed ID : 9733027 21. Delatycki, M. B.; Paris, D. B. B. P.; Gardner, R. J. M.; Nicholson, G. A.; Nassif, N.; Storey, E.; MacMillan, J. C.; Collins, V.; Williamson, R.; Forrest, S. M. : Clinical and genetic study of Friedreich ataxia in an Australian population. Am. J. Med. Genet. 87: 168-174, 1999. PubMed ID : 10533031 22. Duclos, F.; Boschert, U.; Sirugo, G.; Mandel, J.-L.; Hen, R.; Koenig, M. : Gene in the region of the Friedreich ataxia locus encodes a putative transmembrane protein expressed in the nervous system. Proc. Nat. Acad. Sci. 90: 109-113, 1993. PubMed ID : 7678331 23. Durr, A.; Cossee, M.; Agid, Y.; Campuzano, V.; Mignard, C.; Penet, C.; Mandel, J.-L.; Brice, A.; Koenig, M. : Clinical and genetic abnormalities in patients with Friedreich's ataxia. New Eng. J. Med. 335: 1169-1175, 1996. PubMed ID : 8815938 24. Fields, S.; Song, O. : A novel genetic system to detect protein-protein interactions. (Letter) Nature 340: 245-246, 1989. PubMed ID : 2547163 25. Filla, A.; De Michele, G.; Cavalcanti, F.; Pianese, L.; Monticelli, A.; Campanella, G.; Cocozza, S. : The relationship between trinucleotide (GAA) repeat length and clinical features in Friedreich ataxia. Am. J. Hum. Genet. 59: 554-560, 1996. PubMed ID : 8751856 26. Gacy, A. M.; Goellner, G. M.; Spiro, C.; Chen, X.; Gupta, G.; Bradbury, E. M.; Dyer, R. B.; Mikesell, M. J.; Yao, J. Z.; Johnson, A. J.; Richter, A.; Melancon, S. B.; McMurray, C. T. : GAA instability in Friedreich's ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases. Molec. Cell 1: 583-593, 1998. PubMed ID : 9660942 27. Gordon, D. M.; Kogan, M.; Knight, S. A. B.; Dancis, A.; Pain, D. : Distinct roles for two N-terminal cleaved domains in mitochondrial import of the yeast frataxin homolog, Yfh1p. Hum. Molec. Genet. 10: 259-269, 2001. PubMed ID : 11159945 28. Gordon, D. M.; Shi, Q.; Dancis, A.; Pain, D. : Maturation of frataxin within mammalian and yeast mitochondria: one-step processing by matrix processing peptidase. Hum. Molec. Genet. 8: 2255-2262, 1999. PubMed ID : 10545606 29. Gray, J. V.; Johnson, K. J. : Waiting for frataxin. Nature Genet. 16: 323-325, 1997. PubMed ID : 9241261 30. Isnard, R.; Kalotka, H.; Durr, A.; Cossee, M.; Schmitt, M.; Pousset, F.; Thomas, D.; Brice, A.; Koenig, M.; Komajda, M. : Correlation between left ventricular hypertrophy and GAA trinucleotide repeat length in Friedreich's ataxia. Circulation 95: 2247-2249, 1997. PubMed ID : 9142000 31. Karthikeyan, G.; Lewis, L. K.; Resnick, M. A. : The mitochondrial protein frataxin prevents nuclear damage. Hum. Molec. Genet. 11: 1351-1362, 2002. PubMed ID : 12019217 32. Koenig, M.; Mandel, J.-L. : Deciphering the cause of Friedreich ataxia. Curr. Opin. Neurobiol. 7: 689-694, 1997. PubMed ID : 9384553 33. Koutnikova, H.; Campuzano, V.; Foury, F.; Dolle, P.; Cazzalini, O.; Koenig, M. : Studies of human, mouse and yeast homologues indicate a mitochondrial function for frataxin. Nature Genet. 16: 345-351, 1997. PubMed ID : 9241270 34. Koutnikova, H.; Campuzano, V.; Koenig, M. : Maturation of wild-type and mutated frataxin by the mitochondrial processing peptidase. Hum. Molec. Genet. 7: 1485-1489, 1998. PubMed ID : 9700204 35. Lesuisse, E.; Santos, R.; Matzanke, B. F.; Knight, S. A. B.; Camadro, J.-M.; Dancis, A. : Iron use for haeme synthesis is under control of the yeast frataxin homologue (Yfh1). Hum. Molec. Genet. 12: 879-889, 2003. PubMed ID : 12668611 36. Matsumoto, M.; Nakagawa, T.; Inoue, T.; Nagata, E.; Tanaka, K.; Takano, H.; Minowa, O.; Kuno, J.; Sakakibara, S.; Yamada, M.; Yoneshima, H.; Miyawaki, A; Fukuichi, T.; Furuichi, T.; Okano, H.; Mikoshiba, K.; Noda, T. : Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-triphosphate receptor. Nature 379: 168-171, 1996. PubMed ID : 8538767 37. Monros, E.; Molto, M. D.; Martinez, F.; Canizares, J.; Blanca, J.; Vilchez, J. J.; Prieto, F.; de Frutos, R.; Palau, F. : Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. Am. J. Hum. Genet. 61: 101-110, 1997. PubMed ID : 9245990 38. Montermini, L.; Andermann, E.; Labuda, M.; Richter, A.; Pandolfo, M.; Cavalcanti, F.; Pianese, L.; Iodice, L.; Farina, G.; Monticelli, A.; Turano, M.; Filla, A.; De Michele, G.; Cocozza, S. : The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. Hum. Molec. Genet. 6: 1261-1266, 1997. PubMed ID : 9259271 39. Montermini, L.; Rodius, F.; Pianese, L.; Molto, M. D.; Cossee, M.; Campuzano, V.; Cavalcanti, F.; Monticelli, A.; Palau, F.; Gyapay, G.; Wenhert, M.; Zara, F.; Patel, P. I.; Cocozza, S.; Koenig, M.; Pandolfo, M. : The Friedreich ataxia critical region spans a 150-kb interval on chromosome 9q13. Am. J. Hum. Genet. 57: 1061-1067, 1995. PubMed ID : 7485155 40. Muhlenhoff, U.; Richhardt, N.; Ristow, M.; Kispal, G.; Lill, R. : The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins. Hum. Molec. Genet. 11: 2025-2036, 2002. PubMed ID : 12165564 41. Ohshima, K.; Montermini, L.; Wells, R. D.; Pandolfo, M. : Inhibitory effects of expanded GAA-TTC triplet repeats from intron I of the Friedreich ataxia gene on transcription and replication in vivo. J. Biol. Chem. 273: 14588-14595, 1998. PubMed ID : 9603975 42. Pandolfo, M. : Personal Communication. Montreal, Canada, 4/28/1997. 43. Pianese, L.; Cavalcanti, F.; De Michele, G.; Filla, A.; Campanella, G.; Calabrese, O.; Castaldo, I.; Monticelli, A.; Cocozza, S. : The effect of parental gender on the GAA dynamic mutation in the FRDA gene. (Letter) Am. J. Hum. Genet. 60: 460-463, 1997. PubMed ID : 9012421 44. Puccio, H.; Koenig, M. : Recent advances in the molecular pathogenesis of Friedreich ataxia. Hum. Molec. Genet. 9: 887-892, 2000. PubMed ID : 10767311 45. Ristow, M.; Pfister, M. F.; Yee, A. J.; Schubert, M.; Michael, L.; Zhang, C.-Y.; Ueki, K.; Michael, M. D., II; Lowell, B. B.; Kahn, C. R. : Frataxin activates mitochondrial energy conversion and oxidative phosphorylation. Proc. Nat. Acad. Sci. 97: 12239-12243, 2000. PubMed ID : 11035806 46. Rodius, F.; Duclos, F.; Wrogemann, K.; Le Paslier, D.; Ougen, P.; Billault, A.; Belal, S.; Musenger, C.; Brice, A.; Durr, A.; Mignard, C.; Sirugo, G.; Weissenbach, J.; Cohen, D.; Hentati, F.; Ben Hamida, M.; Mandel, J.-L.; Koenig, M. : Recombinations in individuals homozygous by descent localize the Friedreich ataxia locus in a cloned 450-kb interval. Am. J. Hum. Genet. 54: 1050-1059, 1994. PubMed ID : 8198128 47. Sakamoto, N.; Chastain, P. D.; Parniewski, P.; Ohshima, K.; Pandolfo, M.; Griffith, J. D.; Wells, R. D. : Sticky DNA: self-association properties of long GAA-TTC repeats in R-R-Y triplex structures from Friedrich's ataxia. Molec. Cell 3: 465-475, 1999. PubMed ID : 10230399 48. Santos, M. M.; Ohshima, K.; Pandolfo, M. : Frataxin deficiency enhances apoptosis in cells differentiating into neuroectoderm. Hum. Molec. Genet. 10: 1935-1944, 2001. PubMed ID : 11555630 49. Schols, L.; Szymanski, S.; Peters, S.; Przuntek, H.; Epplen, J. T.; Hardt, C.; Riess, O. : Genetic background of apparently idiopathic sporadic cerebellar ataxia. Hum. Genet. 107: 132-137, 2000. PubMed ID : 11030410 50. Sharma, R.; Bhatti, S.; Gomez, M.; Clark, R. M.; Murray, C.; Ashizawa, T.; Bidichandani, S. I. : The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions. Hum. Molec. Genet. 11: 2175-2187, 2002. PubMed ID : 12189170 51. Sharma, R.; De Biase, I.; Gomez, M.; Delatycki, M. B.; Ashizawa, T.; Bidichandani, S. I. : Friedreich ataxia in carriers of unstable borderline GAA triple-repeat alleles. Ann. Neurol. 56: 898-901, 2004. PubMed ID : 15562408 52. Shoichet, S. A.; Baumer, A. T.; Stamenkovic, D.; Sauer, H.; Pfeiffer, A. F. H.; Kahn, C. R.; Muller-Wieland, D.; Richter, C.; Ristow, M. : Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro. Hum. Molec. Genet. 11: 815-821, 2002. PubMed ID : 11929854 53. Wilson, R. B.; Roof, D. M. : Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nature Genet. 16: 352-357, 1997. PubMed ID : 9241271 54. Zuhlke, C.; Laccone, F.; Cossee, M.; Kohlschutter, A.; Koenig, M.; Schwinger, E. : Mutation of the start codon in the FRDA1 gene: linkage analysis of three pedigrees with the ATG to ATT transversion points to a unique common ancestor. Hum. Genet. 103: 102-105, 1998. PubMed ID : 9737785 ### CONTRIBUTORS Cassandra L. Kniffin - updated : 4/29/2005 George E. Tiller - updated : 2/21/2005 Ada Hamosh - updated : 8/25/2004 Patricia A. Hartz - updated : 3/11/2004 George E. Tiller - updated : 9/23/2003 George E. Tiller - updated : 7/10/2003 George E. Tiller - updated : 7/8/2003 George E. Tiller - updated : 2/24/2003 George E. Tiller - updated : 10/29/2002 George E. Tiller - updated : 9/18/2002 ### CREATION DATE Cassandra L. Kniffin : 4/4/2002 ### EDIT HISTORY wwang : 5/18/2005 wwang : 5/13/2005 ckniffin : 4/29/2005 wwang : 3/9/2005 terry : 2/21/2005 tkritzer : 8/25/2004 terry : 8/25/2004 carol : 7/2/2004 mgross : 3/11/2004 mgross : 3/11/2004 terry : 3/11/2004 cwells : 9/23/2003 cwells : 7/10/2003 cwells : 7/8/2003 ckniffin : 3/11/2003 cwells : 2/24/2003 cwells : 10/29/2002 cwells : 9/18/2002 carol : 4/26/2002 ckniffin : 4/24/2002 ckniffin : 4/24/2002 Copyright © 1966-2005 Johns Hopkins University
15: | *606605 | Links
| 3-PRIME @REPAIR EXONUCLEASE 1; TREX1
#### Alternative titles; symbols ATR-INTERACTING PROTEIN; ATRIP DNase III ### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE FUNCTION MAPPING REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 3p21.3-p21.2 ### TEXT #### DESCRIPTION The multistep processes of DNA replication, repair, and recombination require the excision of nucleotides from DNA 3-prime termini. Enzymes containing 3-prime-to-5-prime exonuclease activity, such as TREX1, remove mismatched, modified, fragmented, and normal nucleotides to generate the appropriate 3-prime termini for subsequent steps in the DNA metabolic pathways. TREX1 was identified as ATRIP, the human homolog of the Schizosaccharomyces pombe Rad26 protein and Drosophila melanogaster Mus304 protein. It has 2 coiled-coil domains and multiple sites for potential phosphorylation by ATR (601215) or ATM (see 607585). ATRIP and ATR are mutually dependent partners in cell cycle signaling pathways. #### CLONING By micropeptide sequence analysis of the 30-kD bovine Trex1 protein, PCR with degenerate primers, and EST database searching, Mazur and Perrino (1999) obtained cDNAs encoding mouse and human TREX1 and TREX2 (300370). Sequence analysis predicted that the 304-amino acid TREX1 protein is 44% identical to TREX2. (Mazur and Perrino (2001) corrected the TREX1 sequence to 314 amino acids). TREX1 contains 3 conserved exonuclease motifs, with an HxAxxD sequence in the third motif. Functional analysis confirmed that the 3-prime-to-5-prime exonuclease activity of the recombinant protein is comparable to that of the native protein and prefers mismatched 3-prime termini. Mazur and Perrino (1999) concluded that the TREX proteins are small, independent 3-prime excision enzymes, whereas the multifunctional p53 (191170) and WRN (RECQL2; 604611) proteins, which also have 3-prime-to-5-prime exonuclease activity, are much larger. Using rabbit Trex1 to search an EST database, Hoss et al. (1999) also isolated human TREX1, which they termed DNase III. Northern blot analysis revealed expression of a 1.15-kb TREX1 transcript in all tissues tested. Mazur and Perrino (2001) used 5-prime RACE to identify the flanking region of TREX1. Genomic sequence analysis suggested that TREX1 open reading frames are produced by a variety of mechanisms, including alternate promoter usage, alternative splicing, and varied sites for 3-prime cleavage. RT-PCR analysis detected ubiquitous expression of TREX1. Cortez et al. (2001) searched for substrates of ATM and ATR and identified a protein of 86 kD, which they called ATRIP for 'ATR-interacting protein.' The full-length cDNA encodes a 791-amino acid protein with a coiled-coil domain near its N terminus. RNA blotting indicated that ATRIP is expressed in all tissues tested. Cortez et al. (2001) also identified an alternatively spliced exon encoding amino acids 658 to 684 near the C-terminus. RT-PCR from 2 cell lines indicated that both forms were expressed. #### GENE FUNCTION ATRIP is phosphorylated by ATR, regulates ATR expression, and is an essential component of the DNA damage checkpoint pathway. Cortez et al. (2001) demonstrated that ATR and ATRIP both localize to intranuclear foci after DNA damage or inhibition of replication. Deletion of ATR mediated by the Cre recombinase caused the loss of ATR and ATRIP expression, loss of DNA damage checkpoint responses, and cell death. Therefore, ATR is essential for the viability of human somatic cells. Small interfering RNA directed against ATRIP caused the loss of both ATRIP and ATR expression and the loss of checkpoint responses to DNA damage. Cortez et al. (2001) concluded that ATRIP and ATR are mutually dependent partners in cell cycle checkpoint signaling pathways. The function of the ATR-ATRIP protein kinase complex is crucial for the cellular response to replication stress and DNA damage. Zou and Elledge (2003) demonstrated that replication protein A (RPA) complex, which associates with single-stranded DNA, is required for recruitment of ATR to sites of DNA damage and for ATR-mediated CHK1 (603078) activation in human cells. In vitro, RPA stimulates the binding of ATRIP to single-stranded DNA. The binding of ATRIP to RPA-coated single-stranded DNA enables the ATR-ATRIP complex to associate with DNA and stimulates phosphorylation of the RAD17 (603139) protein that is bound to DNA. Furthermore, Ddc2, the budding yeast homolog of ATRIP, is specifically recruited to double-stranded DNA breaks in an RPA-dependent manner. A checkpoint-deficient mutant of RPA, rfa1-t11, is defective for recruiting Ddc2 to single-stranded DNA both in vivo and in vitro. Zou and Elledge (2003) concluded that RPA-coated single-stranded DNA is the critical structure at sites of DNA damage that recruits the ATR-ATRIP complex and facilitates its recognition of substrates for phosphorylation and the initiation of checkpoint signaling. #### MAPPING Hoss et al. (1999) and Mazur and Perrino (2001) identified clones containing the TREX1 gene that map to chromosome 3p21.3-p21.2. ### REFERENCES 1. Cortez, D.; Guntuku, S.; Qin, J.; Elledge, S. J. : ATR and ATRIP: partners in checkpoint signaling. Science 294: 1713-1716, 2001. PubMed ID : 11721054 2. Hoss, M.; Robins, P.; Naven, T. J. P.; Pappin, D. J. C.; Sgouros, J.; Lindahl, T. : A human DNA editing enzyme homologous to the Escherichia coli DnaQ/MutD protein. EMBO J. 18: 3868-3875, 1999. PubMed ID : 10393201 3. Mazur, D. J.; Perrino, F. W. : Structure and expression of the TREX1 and TREX2 3-prime-to-5-prime exonuclease genes. J. Biol. Chem. 276: 14718-14727, 2001. PubMed ID : 11278605 4. Mazur, D. J.; Perrino, F. W. : Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3-prime-to-5-prime exonucleases. J. Biol. Chem. 274: 19655-19660, 1999. PubMed ID : 10391904 5. Zou, L.; Elledge, S. J. : Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300: 1542-1548, 2003. PubMed ID : 12791985 ### CONTRIBUTORS Ada Hamosh - updated : 6/17/2003 Paul J. Converse - updated : 1/28/2002 ### CREATION DATE Ada Hamosh : 1/10/2002 ### EDIT HISTORY alopez : 6/19/2003 terry : 6/17/2003 ckniffin : 3/11/2003 alopez : 1/28/2002 alopez : 1/10/2002 Copyright © 1966-2005 Johns Hopkins University
16: | *605230 | Links
| TUMOR PROTEIN p53-BINDING PROTEIN 1; TP53BP1
#### Alternative titles; symbols 53BP1 ### TABLE OF CONTENTS #### CLONING GENE FUNCTION BIOCHEMICAL FEATURES MAPPING ANIMAL MODEL REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q15-q21 ### TEXT #### CLONING Using a yeast 2-hybrid system, Iwabuchi et al. (1994) isolated partial cDNAs encoding TP53BP1, which they called 53BP1. Northern blot analysis detected TP53BP1 transcripts of 11 and 6.8 kb in all tissues tested except lung and liver. By screening skeletal muscle and T-cell cDNA libraries, Iwabuchi et al. (1998) isolated a full-length cDNA encoding TP53BP1. The deduced 1,972-amino acid TP53BP1 protein has a predicted molecular mass of 217 kD and shows homology in its C-terminal 247 amino acids to the C terminus of the tumor suppressor protein BRCA1 (113705). Western blot analysis revealed that TP53BP1 is expressed as a greater than 220-kD protein. Immunofluorescence microscopy demonstrated a complex localization pattern for TP53BP1 with or without the presence of p53. TP53BP1 was present in both the cytoplasm and nucleus in some cells and only in the nucleus in others. Furthermore, there were 2 nuclear staining patterns, one homogeneous staining and the other dot staining. #### GENE FUNCTION Iwabuchi et al. (1994) showed that TP53BP1 binds to the conformationally sensitive central domain of wildtype p53 (191170) but not to mutant p53 in vitro. Iwabuchi et al. (1994) also demonstrated that TP53BP1 and TP53BP2 (602143) do not bind to the C-terminal oligomerization domain or the N-terminal transcriptional activation domain of p53. Immunoblot analysis by Iwabuchi et al. (1998) showed that expression of TP53BP1 or TP53BP2 enhances the transactivation function of p53 and induces the expression of p21 (CDKN1A; 116899). Wang et al. (2002) used small interfering RNA directed against TP53BP1 in mammalian cells to demonstrate that TP53BP1 is a key transducer of the DNA damage checkpoint signal. TP53BP1 was required for p53 accumulation, G2/M checkpoint arrest, and the intra-S-phase checkpoint in response to ionizing radiation. TP53BP1 played a partially redundant role in phosphorylation of the downstream checkpoint effector proteins BRCA1 and CHK2 (604373) but was required for the formation of BRCA1 foci in a hierarchical branched pathway for the recruitment of repair and signaling proteins to sites of DNA damage. DiTullio et al. (2002) demonstrated that 53BP1 also regulates ATM (607585)-dependent phosphorylation events in response to ionizing radiation. #### BIOCHEMICAL FEATURES 53BP1 is a conserved checkpoint protein with properties of a DNA double-strand break sensor. Huyen et al. (2004) solved the structure of the domain of 53BP1 that recruits it to sites of double-strand breaks. This domain consists of 2 tandem tudor folds with a deep pocket at their interface formed by residues conserved in the budding yeast Rad9 and fission yeast Rhp9/Crb2 orthologs. In vitro, the 53BP1 tandem tudor domain bound histone H3 (see 601128) methylated on lys79 using residues that form the walls of the pocket; these residues were also required for recruitment of 53BP1 to double-strand breaks. Suppression of DOT1L (607375), the enzyme that methylates lys79 of histone H3, also inhibited recruitment of 53BP1 to double-strand breaks. Because methylation of histone H3 lys79 was unaltered in response to DNA damage, Huyen et al. (2004) proposed that 53BP1 senses double-strand breaks indirectly through changes in higher-order chromatin structure that expose the 53BP1 binding site. #### MAPPING Iwabuchi et al. (1998) mapped the TP53BP1 gene to 15q15-q21 by FISH. #### ANIMAL MODEL Manis et al. (2004) generated mice deficient in 53bp1 and showed that the protein was dispensable for V(D)J recombination and somatic hypermutation in B lymphocytes, but it was critical for Igh class switch recombination of constant region genes. Manis et al. (2004) proposed that 53BP1 is involved in the DNA damage response to double-stranded breaks. ### REFERENCES 1. DiTullio, R. A., Jr.; Mochan, T. A.; Venere, M.; Bartkova, J.; Sehested, M.; Bartek, J.; Halazonetis, T. D. : 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer. Nature Cell Biol. 4: 998-1002, 2002. Note: Erratum: Nature Cell Biol. 5: 84 only, 2003. PubMed ID : 12447382 2. Huyen, Y.; Zgheib, O.; DiTullio, R. A., Jr.; Gorgoulis, V. G.; Zacharatos, P.; Petty, T. J.; Sheston, E. A.; Mellert, H. S.; Stavridi, E. S.; Halazonetis, T. D. : Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432: 406-411, 2004. PubMed ID : 15525939 3. Iwabuchi, K.; Bartel, P. L.; Li, B.; Marraccino, R.; Fields, S. : Two cellular proteins that bind to wild-type but not mutant p53. Proc. Nat. Acad. Sci. 91: 6098-6102, 1994. PubMed ID : 8016121 4. Iwabuchi, K.; Li, B.; Massa, H. F.; Trask, B. J.; Date, T.; Fields, S. : Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2. J. Biol. Chem. 273: 26061-26068, 1998. PubMed ID : 9748285 5. Manis, J. P.; Morales, J. C.; Xia, Z.; Kutok, J. L.; Alt, F. W.; Carpenter, P. B. : 53BP1 links DNA damage-response pathways to immunoglobulin heavy chain class-switch recombination. Nature Immun. 5: 481-487, 2004. PubMed ID : 15077110 6. Wang, B.; Matsuoka, S.; Carpenter, P. B.; Elledge, S. J. : 53BP1, a mediator of the DNA damage checkpoint. Science 298: 1435-1438, 2002. PubMed ID : 12364621 ### CONTRIBUTORS Ada Hamosh - updated : 12/10/2004 Paul J. Converse - updated : 5/5/2004 Patricia A. Hartz - updated : 2/26/2003 Ada Hamosh - updated : 11/22/2002 ### CREATION DATE Paul J. Converse : 8/28/2000 ### EDIT HISTORY alopez : 12/15/2004 terry : 12/10/2004 mgross : 5/5/2004 mgross : 5/5/2004 ckniffin : 3/11/2003 mgross : 3/4/2003 mgross : 2/26/2003 cwells : 11/25/2002 terry : 11/22/2002 mgross : 8/28/2000 Copyright © 1966-2005 Johns Hopkins University
17: | *605114 | Links
| SPO11, S. CEREVISIAE, HOMOLOG OF; SPO11
### TABLE OF CONTENTS #### TEXT REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 20q13.2-q13.3 ### TEXT Meiotic recombination and proper segregation of chromosomes are initiated by the formation of double-strand breaks (DSBs) in paired homologs. SPO11 in yeast is required for meiotic DSB formation and is covalently linked to the 5-prime end of DSBs during meiosis. Using oligonucleotides from an EST with similarity to the Drosophila Spo11 homolog, Romanienko and Camerini-Otero (1999) designed PCR primers to clone Spo11 from a mouse testis cDNA library. They used mouse Spo11 to clone the human homolog, which encodes a deduced 396-amino acid protein. In both the human and mouse proteins, region I contains the putative active site tyrosine, and regions II, III, and IV comprise a Toprim (topoisomerase and primase) domain including an invariant glutamate residue in region II and a DXD motif in region IV. Toprim domains are conserved in many proteins involved in DNA replication and repair. The human and the mouse SPO11 proteins share 82% amino acid identity, but only 20 to 30% with other eukaryotic homologs such as Drosophila and C. elegans. Both the mouse and human SPO11 exons 2 and 8 are subject to alternative splicing. Northern blot analysis showed that mouse Spo11 is expressed in testis and thymus as a 1.8-kb mRNA, whereas human SPO11 is expressed in testis as a 2.0-kb transcript. RT-PCR revealed that human SPO11 is also expressed in prostate, fetal testis, thymus, and some carcinoma cell lines. Shannon et al. (1999) independently cloned mouse and human SPO11 cDNAs and demonstrated that mouse Spo11 is expressed only in testicular germ cells, specifically in juvenile pachytene spermatocytes and mid-to-late pachytene spermatocytes. By FISH, Romanienko and Camerini-Otero (1999) mapped the mouse Spo11 gene near the telomere on chromosome 2H4 and the human SPO11 gene in a region of syntenic homology on 20q13.2-q13.3. This region of chromosome 20 is known to be amplified in breast and ovarian cancer and, when amplified, correlates with increased genomic instability in human papillomavirus-transformed cell lines. Romanienko and Camerini-Otero (2000) generated mice with targeted disruption of the Spo11 gene. Homozygosity for this disruption resulted in infertility. Spermatocytes arrested prior to pachytene with little or no synapsis and underwent apoptosis. Rad51 (179617) and Dmc1 (602721) foci in meiotic chromosome spreads were not detected, indicating that DSBs were not formed. Cisplatin-induced DSBs restored Rad51 and Dmc1 foci and promoted synapsis. Spo11 localized to discrete foci during leptotene and to homologously synapsed chromosomes. Other mouse mutants that arrest during meiotic prophase (Atm (607585) -/-, Dmc1 -/-, Mei1 (608797) -/-, and Morc (603205) -/-) showed altered Spo11 protein localization and expression. The authors speculated that there is an additional role for Spo11, after it generates DSBs, in synapsis. Baudat et al. (2000) reported that disruption of mouse Spo11 led to severe gonadal abnormalities from defective meiosis. Spermatocytes suffered apoptotic death during early prophase. Oocytes reached the diplotene/dictyate stage in nearly normal numbers, but most died soon after birth. Consistent with a conserved function in initiating meiotic recombination, Dmc1 and Rad51 foci formation was abolished. Spo11 -/- meiocytes also displayed homologous chromosome synapsis defects, similar to fungi but distinct from flies and nematodes. The authors proposed that recombination initiation precedes and is required for normal synapsis in mammals. Their results also supported the view that mammalian checkpoint responses to meiotic recombination and/or synapsis defects are sexually dimorphic. ### REFERENCES 1. Baudat, F.; Manova, K.; Yuen, J. P.; Jasin, M.; Keeney, S. : Chromosome synapsis defects and sexually dimorphic meiotic progression in mice lacking Spo11. Molec. Cell 6: 989-998, 2000. PubMed ID : 11106739 2. Romanienko, P. J.; Camerini-Otero, R. D. : The mouse Spo11 gene is required for meiotic chromosome synapsis. Molec. Cell 6: 975-987, 2000. PubMed ID : 11106738 3. Romanienko, P. J.; Camerini-Otero, R. D. : Cloning, characterization, and localization of mouse and human SPO11. Genomics 61: 156-169, 1999. PubMed ID : 10534401 4. Shannon, M.; Richardson, L.; Christian, A.; Handel, M. A.; Thelen, M. P. : Differential gene expression of mammalian SPO11/TOP6A homologs during meiosis. FEBS Lett. 462: 329-334, 1999. PubMed ID : 10622720 ### CONTRIBUTORS Stylianos E. Antonarakis - updated : 12/14/2000 ### CREATION DATE Yen-Pei C. Chang : 7/6/2000 ### EDIT HISTORY mgross : 7/13/2004 ckniffin : 3/11/2003 mgross : 12/14/2000 mgross : 12/14/2000 carol : 7/13/2000 carol : 7/6/2000 carol : 7/6/2000 Copyright © 1966-2005 Johns Hopkins University
18: | #605027 | Links
| LYMPHOMA, NON-HODGKIN, FAMILIAL
#### Alternative titles; symbols NON-HODGKIN LYMPHOMA; NHL LYMPHOMA, NON-HODGKIN, CAUSED BY SOMATIC MUTATION, INCLUDED ### TABLE OF CONTENTS #### TEXT REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 2q33-q34 ### TEXT A number sign (#) is used for this entry because non-Hodgkin lymphoma is associated with somatic mutations in a number of genes, including CASP10 (601762), ATM (607585), RAD54L (603615), and BRAF (164757). Wiernik et al. (2000) analyzed 11 published reports of multigenerational familial non-Hodgkin lymphoma (NHL) and 18 previously unreported families with familial NHL for evidence of anticipation. They determined the difference in disease-free survival between generations and the difference in the age of onset for each affected parent-child pair. To avoid ascertainment bias, the analyses were also performed separately using only parent-child pairs with age of onset greater than 25 years. In addition, the age-of-onset distribution of the studied cases was compared with that of the Surveillance Epidemiology and End Results (SEER) program using data for 1973 to 1998. The median age of onset in the child and parent generations of all families (48.5 and 78.3 years, respectively) and in the selected pairs (52.5 and 71.5 years, respectively) was significantly different. A significant difference was observed between the ages of onset between the child generation and that of the SEER population but not between the parent generation and the SEER population. Wiernik et al. (2000) concluded that anticipation in familial NHL is a genuine phenomenon and suggests a genetic role in the disorder. ### REFERENCES 1. Wiernik, P. H.; Wang, S. Q.; Hu, X.-P.; Marino, P.; Paietta, E. : Age of onset evidence for anticipation in familial non-Hodgkin's lymphoma. Brit. J. Haemat. 108: 72-79, 2000. PubMed ID : 10651726 ### CONTRIBUTORS Victor A. McKusick - updated : 1/20/2004 Victor A. McKusick - updated : 8/23/2002 ### CREATION DATE Victor A. McKusick : 6/1/2000 ### EDIT HISTORY cwells : 1/22/2004 terry : 1/20/2004 ckniffin : 3/11/2003 mgross : 9/10/2002 tkritzer : 9/10/2002 terry : 8/23/2002 mgross : 6/1/2000 Copyright © 1966-2005 Johns Hopkins University
19: | *604610 | Links
| RECQ PROTEIN-LIKE 3; RECQL3
#### Alternative titles; symbols DNA HELICASE, RECQ-LIKE, TYPE 2; RECQ2 BLM GENE; BLM ### TABLE OF CONTENTS #### TEXT CLONING GENE FUNCTION MOLECULAR GENETICS GENE FAMILY ANIMAL MODEL ALLELIC VARIANTS View List REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q26.1 ### TEXT The RecQ gene family is named after the E. coli gene. RecQ is an E. coli gene that is a member of the RecF recombination pathway, a pathway of genes in which mutations abolish the conjugational recombination proficiency and ultraviolet resistance of a mutant strain. RECQL (600537) is a human gene isolated from HeLa cells, the product of which possesses DNA-dependent ATPase, DNA helicase, and 3-prime-to-5-prime single-stranded DNA translocation activities. #### CLONING The hypermutability of Bloom syndrome (210900) cells includes hyperrecombinability. Ellis et al. (1995) noted that although cells from all persons with Bloom syndrome exhibit the diagnostic high sister chromatid exchange (SCE) rate, in some persons a minor population of low SCE lymphocytes exist in the blood. Lymphoblastoid cell lines (LCLs) with low SCE rates can be developed from these low SCE lymphocytes. In multiple low SCE LCLs examined from 11 patients with BS, polymorphic loci distal to BLM on 15q had become homozygous in LCLs from 5 persons, whereas polymorphic loci proximal to the BLM locus remained heterozygous in all low SCE LCLs. These observations supported the hypothesis that low SCE lymphocytes arose through recombination within the BLM locus in persons with BS who had inherited paternally and maternally derived BLM alleles mutated at different sites. Such a recombination event in a precursor stem cell in these compound heterozygotes thus gave rise to a cell whose progeny had a functionally wildtype gene and phenotypically a low SCE rate (Ellis et al., 1995). Ellis et al. (1995) used the low SCE LCLs in which reduction to homozygosity had occurred for localizing BLM by an approach referred to as somatic crossover point (SCP) mapping. The precise map position of BLM was determined by comparing the genotypes of the recombinant low SCE LCLs from the 5 persons mentioned above with their constitutional genotypes at loci in the region around BLM. The strategy was to identify the most proximal polymorphic locus possible that was constitutionally heterozygous and that had been reduced to homozygosity in the low SCE LCLs, and to identify the most distal polymorphic locus possible that had remained constitutionally heterozygous in them. The BLM gene would have to be in the short interval defined by the reduced (distal) and the unreduced (proximal) heterozygous markers. The power of this approach was limited only by the density of polymorphic loci available in the immediate vicinity of BLM. A candidate for BLM was identified by direct selection of a cDNA derived from a 250-kb segment of the genome in 15q26.1 to which BLM had been assigned by SCP mapping. cDNA analysis of the candidate gene identified a 4,437-bp cDNA that encoded a 1,417-amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. #### GENE FUNCTION Ellis and German (1996) reported that the BLM protein has similarity to 2 other proteins that are members of the RecQ family of helicases, namely the gene product encoded by RECQL2 (604611), also called WRN, and the product of the yeast gene SGS1. SGS1 was identified by a mutation that suppressed the slow-growth phenotype of mutations in the topoisomerase gene (see 126420). These proteins have 42 to 44% amino acid identity across the conserved helicase motifs. In addition, the proteins are of similar length and contain highly negatively charged N-terminal regions and highly positively charged C-terminal regions. Ellis and German (1996) noted that these similarities in overall structure have raised the possibility that the proteins play similar roles in metabolism. Since the SGS1 gene product is known to interact with the products of the yeast topoisomerase genes, they predicted that the BLM and WRN genes interact with human topoisomerases. Ellis et al. (1999) described the effects on the abnormal cellular phenotype of BS, namely an excessive rate of SCE, when normal BLM cDNA was stably transfected into 2 types of BS cells, SV40-transformed fibroblasts and Epstein-Barr virus-transformed lymphoblastoid cells. The experiments proved that BLM cDNA encodes a functional protein capable of restoring to or toward normal the uniquely characteristic high-SCE phenotype of BS cells. Yankiwski et al. (2000) found that the BLM protein is located in the nucleus of normal human cells in the nuclear domain 10 (ND10; see 604587) or promyelocytic leukemia nuclear bodies. These structures are punctate deposits of proteins disrupted upon viral infection and in certain human malignancies. BLM was found primarily in ND10 except during S phase, when it colocalized with the WRN gene product, in the nucleolus. BLM colocalized with a select subset of telomeres in normal cells and with large telomeric clusters seen in simian virus 40-transformed normal fibroblasts. During S phase, Bloom syndrome cells expel micronuclei containing sites of DNA synthesis. The BLM protein is likely to be part of a DNA surveillance mechanism operating during S phase. Von Kobbe et al. (2002) confirmed interaction between BLM and WRN in immunoprecipitates of soluble nuclear extracts of HeLa cells. Immunolocalization of endogenous BLM and exogenously expressed WRN in several human cell lines showed colocalization of the 2 helicases in some nuclear foci and not in others, suggesting that their interaction is dynamic. Using pull-down assays with several truncation mutants, von Kobbe et al. (2002) determined that the BLM-binding regions of WRN include the N-terminal exonuclease domain and the RQC-containing regions. They mapped the WRN-binding region of BLM to the middle of the molecule. Von Kobbe et al. (2002) showed that BLM, by binding the exonuclease domain of WRN, inhibited WRN exonuclease activity. BLM had no effect on WRN helicase activity. Bloom syndrome cells show marked genomic instability; in particular, hyperrecombination between sister chromatids and homologous chromosomes. Karow et al. (2000) investigated the mechanism by which the BLM protein normally suppresses hyperrecombination. They showed that in vitro BLM selectively binds Holliday junctions formed during genetic recombination and acts on recombination intermediates containing a Holliday junction to promote ATP-dependent branch migration. They presented a model in which BLM disrupts potentially recombinogenic molecules that arise at sites of stalled replication forks. They suggested that their results have implications for the role of BLM as an antirecombinase in the suppression of tumorigenesis. Using various truncations of the BLM protein attached to green fluorescent protein, Kaneko et al. (1997) found that only the BLM protein truncated at amino acid 1357, containing an intact helicase domain and 2 arms, was transported to the nucleus, indicating that BLM protein translocates into the nucleus and that the distal arm of the bipartite basic residues in the C terminus of the BLM protein is essential for targeting the nucleus. Wang et al. (2000) used immunoprecipitation and mass spectrometry analyses to identify BRCA1 (113705)-associated proteins. They found that BRCA1 is part of a large multisubunit protein complex of tumor suppressors, DNA damage sensors, and signal transducers. They named this complex BASC, for 'BRCA1-associated genome surveillance complex.' Among the DNA repair proteins identified in the complex were ATM (607585), BLM, MSH2 (609309), MSH6 (600678), MLH1 (120436), the RAD50 (604040)-MRE11 (600814)-NBS1 (602667) complex, and the RFC1 (102579)-RFC2 (600404)-RFC4 (102577) complex. Confocal microscopy demonstrated that BRCA1, BLM, and the RAD50-MRE11-NBS1 complex colocalize to large nuclear foci. Wang et al. (2000) suggested that BASC may serve as a sensor of abnormal DNA structures and/or as a regulator of the postreplication repair process. By coimmunoprecipitation and in vitro pull-down assays, Beamish et al. (2002) verified direct interaction between ATM and BLM. By mutation analysis, they mapped the BLM-binding domain of ATM to residues 82 through 89. The ATM-binding region of BLM mapped to residues 636 to 1,074. Beamish et al. (2002) determined that the mitosis-associated hyperphosphorylation of BLM was partially dependent upon ATM phosphorylating thr99 and thr122 in the N-terminal region of BLM. Radiation-induced phosphorylation of BLM at thr99 was dose-dependent in normal cells and was defective in AT cells. BS lymphoblasts showed radiosensitivity that could be corrected by transfection of wildtype BLM but not by transfection of a thr99 phosphorylation-minus mutant. This phosphorylation-minus mutant did not alter SCE frequency, indicating that radiosensitivity and increased SCE are mediated by separate BLM domains. Wu et al. (2000) determined that BLM and topoisomerase III-alpha (TOP3A; 601243) colocalized in the nucleus of human cells and coimmunoprecipitated from cell extracts. By in vitro binding assays with truncated BLM mutants, the authors identified 2 independent domains that mediate the interaction with TOP3A. One domain resides between residues 143 and 212 in the N-terminal domain of BLM, and the other resides between residues 1266 and 1417 in the C-terminal domain. Dutertre et al. (2002) noted that BLM is phosphorylated and is excluded from the nuclear matrix during mitosis. BLM immunopurified from mitosis-arrested HeLa cells was phosphorylated and showed 3-prime-to-5-prime DNA helicase activity. Coimmunoprecipitation experiments revealed that phosphorylated BLM interacted with TOP3A. BLM was dephosphorylated in response to ionizing radiation and by inhibition of CDC2 (116940)/cyclin B (123836). Upon dephosphorylation, BLM relocalized to an insoluble subcellular compartment. Mohaghegh and Hickson (2001) reviewed the DNA helicase deficiencies associated with cancer predisposition and premature aging disorders. Opresko et al. (2002) found that, in vitro, TRF2 (602027) showed high affinity for BLM and for WRN, and that TRF2 interaction with either helicase resulted in stimulation of its activity. WRN or BLM, partnered with replication protein A (RPA; see 179835), actively unwound long telomeric duplex regions that were pre-bound by TRF2. Telomerase-negative immortalized human cells maintain telomeres by alternative lengthening of telomeres (ALT) pathway(s), which may involve homologous recombination. Stavropoulos et al. (2002) found that endogenous BLM protein colocalized with telomeric foci in ALT human cells but not telomerase-positive immortal cell lines or primary cells. BLM interacted in vivo with the telomeric protein TRF2 in ALT cells, as detected by FRET and coimmunoprecipitation. Transient overexpression of GFP-BLM resulted in marked, ALT cell-specific increases in telomeric DNA. The association of BLM with telomeres and its effect on telomere DNA synthesis required a functional helicase domain. The authors suggested that BLM may facilitate recombination-driven amplification of telomeres in ALT cells. Franchitto and Pichierri (2002) reviewed the roles of RECQL2 and RECQL3 in resolution of a stall in DNA replication, as well as their possible interaction with the MRE11-RAD50-NBS1 complex. Components of this complex are mutated in 2 genetic instability syndromes, Nijmegen breakage syndrome (251260) and ataxia telangiectasia-like disorder (604391). Imamura and Campbell (2003) showed that the human BLM gene can suppress both the temperature-sensitive growth defect and the DNA damage sensitivity of the yeast DNA replication mutant Dna2-1. This yeast mutant is defective in a helicase/nuclease that is required either to coordinate with the crucial Fen1 nuclease of the yeast in Okazaki fragment maturation or to compensate for yeast Fen1 when its activity is impaired. Using coimmunoprecipitation from yeast extracts, Imamura and Campbell (2003) showed that human BLM interacts with both Dna2 and Fen1 of S. cerevisiae, suggesting that it participates in the same steps of DNA replication or repair as these 2 yeast proteins. Wu and Hickson (2003) demonstrated that BLM and TOP3A together effect the resolution of a recombination intermediate containing a double Holliday junction. The mechanism, which they termed double-junction dissolution, is distinct from classical Holliday junction resolution and prevents exchange of flanking sequences. Loss of such an activity explains many of the cellular phenotypes of Bloom syndrome. Wu and Hickson (2003) proposed that double Holliday junctions are formed during the homologous recombination-dependent repair of daughter strand gaps that arise during replication, and that the dissolution of these double Holliday junctions by BLM prevents the diagnostically high sister chromatid exchange frequency seen in Bloom syndrome cells. Furthermore, BLM-catalyzed double-junction dissolution may act to suppress tumorigenesis by preventing loss of heterozygosity, a feature associated with BLM deficiency in mice, through the suppression of ectopic recombination and crossing-over between homologous chromosomes. By coimmunoprecipitation of HeLa cell nuclear extracts, Meetei et al. (2003) identified 3 distinct multiprotein complexes associated with BLM, all of which were different from the BASC complex reported by Wang et al. (2000). One of the complexes, designated BRAFT, contained the Fanconi anemia core complementation group proteins FANCA (607139), FANCG (602956), FANCC (227645), FANCE (600901), and FANCF (603467), as well as Topo III-alpha and RPA. BLM complexes isolated from an FA cell line had a lower molecular mass, likely due to loss of FANCA and other FA components. BLM- and FANCA-associated complexes had DNA unwinding activity, and BLM was required for this activity. #### MOLECULAR GENETICS In patients with Bloom syndrome, (Ellis et al., 1995) identified chain-terminating mutations in the BLM gene. Mutation analysis in the first 13 unrelated persons with BS examined permitted the identification of 7 unique mutations in 10 of them. The fact that 4 of the 7 mutations resulted in premature termination of translation indicated that the cause of most Bloom syndrome is the loss of enzymatic activity of the BLM gene product. Identification of loss-of-function mutations in BLM is consistent with the autosomal recessive transmission, and the homology of BLM and RecQ suggested that BLM has enzymatic activity. Ellis et al. (1995) suggested that the absence of the BLM gene product probably destabilizes other enzymes that participate in DNA replication and repair, perhaps through direct interaction and through more general responses to DNA damage. In 4 persons of Jewish ancestry, a 6-bp deletion and a 7-bp insertion at nucleotide 2281 were identified, and each of the 4 persons were homozygous for the mutation. Homozygosity was predictable because linkage disequilibrium had been detected in Ashkenazi Jews with Bloom syndrome between BLM, D15S127, and FES (Ellis et al., 1994). Thus a person who carried this deletion/insertion mutation was a founder of Ashkenazi Jewish population and nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor. In a patient with Bloom syndrome and both high- and low-SCE cell lines, Foucault et al. (1997) identified compound heterozygosity for a cys1036-to-phe (C1036F; 604610.0004) substitution in the C-terminal region of the peptide and an unidentified mutation affecting expression of the RECQL3 gene. Foucault et al. (1997) concluded that somatic intragenic recombination resulted in cells that had an untranscribed allele carrying the 2 parental RECQL3 mutations and a wildtype allele which allowed reversion to the low SCE phenotype. Topoisomerase II-alpha (126430) mRNA and protein levels were decreased in the high SCE cells, whereas they were normal in the corresponding low SCE cells. Foucault et al. (1997) proposed that in addition to its putative helicase activity, RECQL3 might be involved in transcription regulation. #### GENE FAMILY In their Table I, Lindor et al (2000) provided a comparison of the 5 human RECQ helicases identified to that time. The RECQL3 gene is deficient in Bloom syndrome. The RECQL2 gene is deficient in Werner syndrome (277700), and the RECQL4 gene (603780) is deficient in Rothmund-Thomson syndrome (268400). No disorder had been related to RECQ1 (RECQL) or RECQL5 (603781). #### ANIMAL MODEL Chester et al. (1998) found that mouse embryos homozygous for a targeted mutation in the murine Bloom syndrome gene are developmentally delayed and die by embryonic day 13.5. They determined that the interrupted gene is the homolog of the human BLM gene by its homologous sequence, its chromosomal location, and the demonstration of high numbers of sister chromatid exchanges in cultured murine Blm -/- fibroblasts. The proportional dwarfism seen in the human is consistent with the small size and developmental delay (12 to 24 hours) seen during midgestation in murine Blm -/- embryos. The growth retardation in mutant embryos can be accounted for by a wave of increased apoptosis in the epiblast restricted to early postimplantation embryogenesis. Mutant embryos do not survive past day 13.5, and at this time exhibit severe anemia. Red blood cells and their precursors from Blm -/- embryos are heterogeneous in appearance and have increased numbers of macrocytes and micronuclei. Both the apoptotic wave and the appearance of micronuclei in red blood cells are likely cellular consequences of damaged DNA caused by effects on replicating or segregating chromosomes. Kusano et al. (2001) demonstrated that Drosophila Dmblm is identical to mus309, a locus originally identified in a mutagen-sensitivity screen. One mus309 allele, which carries a stop codon between 2 of the helicase motifs, causes partial male sterility and complete female sterility. Mutant males produce an excess of XY sperm and nullo sperm, consistent with a high frequency of nondisjunction and/or chromosome loss. These phenotypes of mus309 suggest that Dmblm functions in DNA double-strand break repair. The mutant Dmblm phenotypes were partially rescued by an extra copy of the DNA repair gene Ku70 (152690), indicating that the 2 genes functionally interact in vivo. Heppner Goss et al. (2002) used homologous recombination to disrupt the mouse Blm gene to simulate BLM(Ash), a frameshift mutation in the BLM gene present in 1% of Ashkenazi Jews. Mice heterozygous for this mutation developed lymphoma earlier than wildtype littermates in response to challenge with murine leukemia virus at birth and twice the number of intestinal tumors when crossed with mice carrying mutation in the APC gene (175100). Heppner Goss et al. (2002) concluded that Blm is a modifier of tumor formation in the mouse and that Blm haploinsufficiency is associated with tumor predisposition. Adams et al. (2003) studied the Drosophila BLM ortholog MUS309 and demonstrated that mutants are severely impaired in their ability to carry out repair DNA synthesis during synthesis-dependent strand annealing. Consequently, repair in the mutants is completed by error-prone pathways that create large deletions. Adams et al. (2003) concluded that their results suggested a model in which BLM maintains genomic stability by promoting efficient repair DNA synthesis and thereby prevents double-strand break repair by less precise pathways. Guo et al. (2004) exploited the high rate of mitotic recombination in Bloom syndrome protein (Blm)-deficient embryonic stem cells to generate a genomewide library of homozygous mutant cells from heterozygous mutations induced with a revertible gene trap retrovirus. Guo et al. (2004) screened this library for cells with defects in DNA mismatch repair (MMR), a system that detects and repairs base-base mismatches. They demonstrated the recovery of cells with homozygous mutations in known and novel mismatch repair genes. Guo et al. (2004) identified DNMT1 (126375) as a novel MMR gene and confirmed that Dnmt1-deficient embryonic stem cells exhibit microsatellite instability, providing a mechanistic explanation for the role of DNMT1 in cancer. Yusa et al. (2004) used a tetracycline-regulated Blm allele, Blm(tet), to introduce biallelic mutations across the genome in mouse embryonic stem cells. Transient loss of Blm expression induced homologous recombination not only between sister chromatids but also between homologous chromosomes. Yusa et al. (2004) considered that the phenotype of embryonic stem cells bearing biallelic mutations would be maintained after withdrawal of the tetracycline analog doxycycline. Indeed, a combination of N-ethyl-N-nitrosourea mutagenesis and transient loss of Blm expression enabled them to generate an embryonic stem cell library with genomewide biallelic mutations. The library was evaluated by screening for mutants of glycosylphosphatidylinositol-anchor biosynthesis, which involves at least 23 genes distributed throughout the genome. Mutants derived from 12 different genes were obtained and 2 unknown mutants were simultaneously isolated. Yusa et al. (2004) concluded that their results indicated that phenotype-based genetic screening with Blm(tet) is very efficient and raises possibilities for identifying gene functions in embryonic stem cells. ### ALLELIC VARIANTS (selected examples) #### .0001 BLOOM SYNDROME [RECQL3, 6-BP DEL/7-BP INS ] In 4 ostensibly unrelated persons of Jewish ancestry with Bloom syndrome (210900), Ellis et al. (1995) found homozygosity for a 6-bp deletion/7-bp insertion at nucleotide 2281 of the BLM cDNA. Deletion of ATCTGA and insertion of TAGATTC caused the insertion of the novel codons for LDSR after amino acid 736, and after these codons there was a stop codon. Ellis et al. (1995) concluded that a person carrying this deletion/insertion mutation was a founder of the Ashkenazi-Jewish population, and that nearly all Ashkenazi Jews with Bloom syndrome inherited the mutation identical by descent from this common ancestor. Identification of the mutation by a PCR test was now possible for screening for carriers among Ashkenazim. Straughen et al. (1998) described a rapid method for detecting the 6-bp deletion/7-bp insertion, a predominant Ashkenazi Jewish mutation in Bloom syndrome. They commented that in the Bloom syndrome registry, one or both parents of 52 of the 168 registered persons are Ashkenazi Jews. Using a convenient PCR assay, Ellis et al. (1998) found the 6-bp del/7-bp ins mutation, blm(Ash), on 58 of 60 chromosomes transmitted by Ashkenazi parents to persons with Bloom syndrome. In contrast, in 91 unrelated non-Ashkenazic persons with BS whom they examined, blm(Ash) was identified in only 5, these coming from Spanish-speaking Christian families from the southwestern United States, Mexico, or El Salvador. These data, along with haplotype analyses, showed that blm(Ash) was independently established through a founder effect in Ashkenazi Jews and in immigrants to formerly Spanish colonies. This striking observation underscored the complexity of Jewish history and demonstrated the importance of migration and genetic drift in the formation of human populations. In a study of the frequency of the BLM 6-bp del/7-bp ins mutation in a group of Ashkenazi Jews, unselected for personal or family history of Bloom syndrome, Oddoux et al. (1999) found the mutation in 5 of 1,155 individuals, yielding a frequency of 1/231 (95% CI, 1/123-1/1,848). The low frequency is consistent with an absence of heterozygote advantage for carriers of 1 copy of the mutant allele. The frequency of heterozygotes for other autosomal recessive conditions within their panel had been validated in other studies, suggesting that the test panel was representative of the Ashkenazi Jewish population. Those frequencies were Tay-Sachs disease, 1/28; cystic fibrosis, 1/25; Gaucher disease, 1/15; BRCA2, 6174delT, 1/106; Canavan disease, 1/41; and Fanconi anemia complementation group C, 1/116. To determine whether carriers of BLM mutations are at increased risk of colorectal cancer, Gruber et al. (2002) genotyped 1,244 cases of colorectal cancer and 1,839 controls, both of Ashkenazi Jewish ancestry, to estimate the relative risk of colorectal cancer among carriers of the BLM(Ash) founder mutation. Ashkenazi Jews with colorectal cancer were more than twice as likely to carry the BLM(Ash) mutation than Ashkenazi Jewish controls without colorectal cancer (odds ratio = 2.45, 95% CI 1.3 to 4.8; P = 0.0065). Gruber et al. (2002) verified that the APC I1307K mutation (175100.0029) did not confound their results. #### .0002 BLOOM SYNDROME [RECQL3, 3-BP DEL, 631CAA] In a Japanese patient with Bloom syndrome (210900), Ellis et al. (1995) found homozygosity for a deletion of CAA at nucleotide position 631-633, resulting in a stop codon at amino acid position 186. #### .0003 BLOOM SYNDROME [RECQL3, ILE843THR] In an Italian patient with Bloom syndrome (210900), Ellis et al. (1995) identified homozygosity for a T-to-C transition at nucleotide 2596 that resulted in an isoleucine to threonine amino acid substitution at position 843. #### .0004 BLOOM SYNDROME [RECQL3, CYS1036PHE] In a patient with Bloom syndrome (210900), Foucault et al. (1997) identified compound heterozygosity for a 3181G-T transversion in the RECQL3 gene resulting in a cys1036-to-phe (C1036F) substitution in the C-terminal region of the peptide and an unidentified mutation affecting expression of the RECQL3 gene. The patient was initially believed to be homozygous for the C1036F mutation, but SSCP analysis, direct sequencing of RT-PCR products, and EcoRI digestion using a restriction site created by the mutation showed that the mutation was not present in low SCE cells from the patient. No EcoRI digestion was observed on paternal PCR products. Partial EcoRI digestion was seen with PCR products from maternal and patient DNA and from high- and low-SCE cells from the patient, and direct sequencing confirmed the presence of both a wildtype and mutated sequence at nucleotide 3181 in the high- and low-SCE cell lines, indicating heterozygosity for the mutation. Foucault et al. (1997) concluded that somatic intragenic recombination resulted in cells that had an untranscribed allele carrying the 2 parental RECQL3 mutations and a wildtype allele which allowed reversion to the low-SCE phenotype. ### REFERENCES 1. Adams, M. D.; McVey, M.; Sekelsky, J. J. : Drosophila BLM in double-strand break repair by synthesis-dependent strand annealing. Science 299: 265-267, 2003. PubMed ID : 12522255 2. Beamish, H.; Kedar, P.; Kaneko, H.; Chen, P.; Fukao, T.; Peng, C.; Beresten, S.; Gueven, N.; Purdie, D.; Lees-Miller, S.; Ellis, N.; Kondo, N.; Lavin, M. F. : Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM. J. Biol. Chem. 277: 30515-30523, 2002. PubMed ID : 12034743 3. Chester, N.; Kuo, F.; Kozak, C.; O'Hara, C. D.; Leder, P. : Stage-specific apoptosis, developmental delay, and embryonic lethality in mice homozygous for a targeted disruption in the murine Bloom's syndrome gene. Genes Dev. 12: 3382-3393, 1998. PubMed ID : 9808625 4. Dutertre, S.; Sekhri, R.; Tintignac, L. A.; Onclercq-Delic, R.; Chatton, B.; Jaulin, C.; Amor-Gueret, M. : Dephosphorylation and subcellular compartment change of the mitotic Bloom's syndrome DNA helicase in response to ionizing radiation. J. Biol. Chem. 277: 6280-6286, 2002. PubMed ID : 11741924 5. Ellis, N. A.; Ciocci, S.; Proytcheva, M.; Lennon, D.; Groden, J.; German, J. : The Ashkenazic Jewish Bloom syndrome mutation blm(Ash) is present in non-Jewish Americans of Spanish ancestry. Am. J. Hum. Genet. 63: 1685-1693, 1998. PubMed ID : 9837821 6. Ellis, N. A.; German, J. : Molecular genetics of Bloom's syndrome. Hum. Molec. Genet. 5: 1457-1463, 1996. PubMed ID : 8875252 7. Ellis, N. A.; Groden, J.; Ye, T.-Z.; Straughen, J.; Lennon, D. J.; Ciocci, S.; Proytcheva, M.; German, J. : The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 83: 655-666, 1995. PubMed ID : 7585968 8. Ellis, N. A.; Lennon, D. J.; Proytcheva, M.; Alhadeff, B.; Henderson, E. E.; German, J. : Somatic intragenic recombination within the mutated locus BLM can correct the high SCE phenotype of Bloom syndrome cells. Am. J. Hum. Genet. 57: 1019-1027, 1995. PubMed ID : 7485150 9. Ellis, N. A.; Proytcheva, M.; Sanz, M. M.; Ye, T.-Z.; German, J. : Transfection of BLM into cultured Bloom syndrome cells reduces the sister-chromatid exchange rate toward normal. Am. J. Hum. Genet. 65: 1368-1374, 1999. PubMed ID : 10521302 10. Ellis, N. A.; Roe, A. M.; Kozloski, J.; Proytcheva, M.; Falk, C.; German, J. : Linkage disequilibrium between the FES, D15S127, and BLM loci in Ashkenazi Jews with Bloom syndrome. Am. J. Hum. Genet. 55: 453-460, 1994. PubMed ID : 8079989 11. Foucault, F.; Vaury, C.; Barakat, A.; Thibout, D.; Planchon, P.; Jaulin, C.; Praz, F.; Amor-Gueret, M. : Characterization of a new BLM mutation associated with a topoisomerase II-alpha defect in a patient with Bloom's syndrome. Hum. Molec. Genet. 6: 1427-1434, 1997. PubMed ID : 9285778 12. Franchitto, A.; Pichierri, P. : Protecting genomic integrity during DNA replication: correlation between Werner's and Bloom's syndrome gene products and the MRE11 complex. Hum. Molec. Genet. 11: 2447-2453, 2002. PubMed ID : 12351580 13. Gruber, S. B.; Ellis, N. A.; Scott, K. K.; Almog, R.; Kolachana, P.; Bonner, J. D.; Kirchhoff, T.; Tomsho, L. P.; Nafa, K.; Pierce, H.; Low, M.; Satagopan, J.; and 12 others : BLM heterozygosity and the risk of colorectal cancer. Science 297: 2013 only, 2002. Note: Erratum: Science 298: 751 only, 2002. PubMed ID : 12242432 14. Guo, G.; Wang, W.; Bradley, A. : Mismatch repair genes identified using genetic screens in Blm-deficient embryonic stem cells. Nature 429: 891-895, 2004. PubMed ID : 15215866 15. Heppner Goss, K.; Risinger, M. A.; Kordich, J. J.; Sanz, M. M.; Straughen, J. E.; Slovek, L. E.; Capobianco, A. J.; German, J.; Boivin, G. P.; Groden, J. : Enhanced tumor formation in mice heterozygous for Blm mutation. Science 297: 2051-2053, 2002. PubMed ID : 12242442 16. Imamura, O.; Campbell, J. L. : The human Bloom syndrome gene suppresses the DNA replication and repair defects of yeast dna2 mutants. Proc. Nat. Acad. Sci. 100: 8193-8198, 2003. PubMed ID : 12826610 17. Kaneko, H.; Orii, K. O.; Matsui, E.; Shimozawa, N.; Fukao, T.; Matsumoto, T.; Shimamoto, A.; Furuichi, Y.; Hayakawa, S.; Kasahara, K.; Kondo, N. : BLM (the causative gene of Bloom syndrome) protein translocation into the nucleus by a nuclear localization signal. Biochem. Biophys. Res. Commun. 240: 348-353, 1997. PubMed ID : 9388480 18. Karow, J. K.; Constantinou, A.; Li, J.-L.; West, S. C.; Hickson, I. D. : The Bloom's syndrome gene product promotes branch migration of Holliday junctions. Proc. Nat. Acad. Sci. 97: 6504-6508, 2000. PubMed ID : 10823897 19. Kusano, K.; Johnson-Schlitz, D. M.; Engels, W. R. : Sterility of Drosophila with mutations in the Bloom syndrome gene--complementation by Ku70. Science 291: 2600-2602, 2001. PubMed ID : 11283371 20. Lindor, N. M.; Furuichi, Y.; Kitao, S.; Shimamoto, A.; Arndt, C.; Jalal, S. : Rothmund-Thomson syndrome due to RECQ4 helicase mutations: report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome. Am. J. Med. Genet. 90: 223-228, 2000. PubMed ID : 10678659 21. Meetei, A. R.; Sechi, S.; Wallisch, M.; Yang, D.; Young, M. K.; Joenje, H.; Hoatlin, M. E.; Wang, W. : A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. Molec. Cell. Biol. 23: 3417-3426, 2003. PubMed ID : 12724401 22. Mohaghegh, P.; Hickson, I. D. : DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders. Hum. Molec. Genet. 10: 741-746, 2001. PubMed ID : 11257107 23. Oddoux, C.; Clayton, C. M.; Nelson, H. R.; Ostrer, H. : Prevalence of Bloom syndrome heterozygotes among Ashkenazi Jews. (Letter) Am. J. Hum. Genet. 64: 1241-1243, 1999. PubMed ID : 10090915 24. Opresko, P. L.; von Kobbe, C.; Laine, J.-P.; Harrigan, J.; Hickson, I. D.; Bohr, V. A. : Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J. Biol. Chem. 277: 41110-41119, 2002. PubMed ID : 12181313 25. Stavropoulos, D. J.; Bradshaw, P. S.; Li, X.; Pasic, I.; Truong, K.; Ikura, M.; Ungrin, M.; Meyn, M. S. : The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum. Molec. Genet. 11: 3135-3144, 2002. PubMed ID : 12444098 26. Straughen, J. E.; Johnson, J.; McLaren, D.; Proytcheva, M.; Ellis, N.; German, J.; Groden, J. : A rapid method for detecting the predominant Ashkenazi Jewish mutation in the Bloom's syndrome gene. Hum. Mutat. 11: 175-178, 1998. PubMed ID : 9482582 27. von Kobbe, C.; Karmakar, P.; Dawut, L.; Opresko, P.; Zeng, X.; Brosh, R. M., Jr.; Hickson, I. D.; Bohr, V. A. : Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins. J. Biol. Chem. 277: 22035-22044, 2002. PubMed ID : 11919194 28. Wang, Y.; Cortez, D.; Yazdi, P.; Neff, N.; Elledge, S. J.; Qin, J. : BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev. 14: 927-939, 2000. PubMed ID : 10783165 29. Wu, L.; Davies, S. L.; North, P. S.; Goulaouic, H.; Riou, J.-F.; Turley, H.; Gatter, K. C.; Hickson, I. D. : The Bloom's syndrome gene product interacts with topoisomerase III. J. Biol. Chem. 275: 9636-9644, 2000. PubMed ID : 10734115 30. Wu, L.; Hickson, I. D. : The Bloom's syndrome helicase suppresses crossing over during homologous recombination. Nature 426: 870-874, 2003. PubMed ID : 14685245 31. Yankiwski, V.; Marciniak, R. A.; Guarente, L.; Neff, N. F. : Nuclear structure in normal and Bloom syndrome cells. Proc. Nat. Acad. Sci. 97: 5214-5219, 2000. PubMed ID : 10779560 32. Yusa, K.; Horie, K.; Kondoh, G.; Kouno, M.; Maeda, Y.; Kinoshita, T.; Takeda, J. : Genome-wide phenotype analysis in ES cells by regulated disruption of Bloom's syndrome gene. Nature 429: 896-899, 2004. PubMed ID : 15215867 ### CONTRIBUTORS Patricia A. Hartz - updated : 1/18/2005 Marla J. F. O'Neill - updated : 12/22/2004 George E. Tiller - updated : 9/2/2004 Ada Hamosh - updated : 7/22/2004 Ada Hamosh - updated : 12/30/2003 George E. Tiller - updated : 12/3/2003 Victor A. McKusick - updated : 8/27/2003 Patricia A. Hartz - updated : 7/7/2003 Ada Hamosh - updated : 2/6/2003 Patricia A. Hartz - updated : 1/7/2003 Patricia A. Hartz - updated : 12/16/2002 Ada Hamosh - updated : 9/30/2002 George E. Tiller - updated : 6/19/2001 Ada Hamosh - updated : 4/4/2001 Victor A. McKusick - updated : 3/13/2001 Paul J. Converse - updated : 11/16/2000 Ada Hamosh - updated : 8/31/2000 Victor A. McKusick - updated : 8/7/2000 Victor A. McKusick - updated : 7/26/2000 Victor A. McKusick - updated : 2/25/2000 ### CREATION DATE Victor A. McKusick : 2/25/2000 ### EDIT HISTORY mgross : 4/14/2005 mgross : 1/18/2005 carol : 1/12/2005 carol : 1/12/2005 terry : 12/22/2004 carol : 9/3/2004 terry : 9/2/2004 alopez : 7/26/2004 terry : 7/22/2004 alopez : 7/6/2004 alopez : 12/31/2003 terry : 12/30/2003 mgross : 12/3/2003 tkritzer : 8/28/2003 tkritzer : 8/27/2003 carol : 8/8/2003 carol : 7/10/2003 mgross : 7/7/2003 alopez : 5/29/2003 alopez : 5/29/2003 terry : 5/29/2003 ckniffin : 3/11/2003 alopez : 2/10/2003 alopez : 2/10/2003 terry : 2/6/2003 mgross : 1/7/2003 mgross : 1/7/2003 mgross : 1/3/2003 terry : 12/16/2002 alopez : 9/30/2002 tkritzer : 9/30/2002 carol : 1/14/2002 cwells : 6/20/2001 cwells : 6/19/2001 alopez : 4/5/2001 terry : 4/4/2001 cwells : 3/27/2001 cwells : 3/26/2001 terry : 3/13/2001 joanna : 1/17/2001 joanna : 1/17/2001 joanna : 1/17/2001 joanna : 1/17/2001 mgross : 11/16/2000 alopez : 9/5/2000 terry : 8/31/2000 mcapotos : 8/28/2000 mcapotos : 8/10/2000 terry : 8/7/2000 mcapotos : 8/1/2000 mcapotos : 7/26/2000 mcapotos : 7/26/2000 alopez : 7/26/2000 terry : 7/20/2000 alopez : 2/25/2000 alopez : 2/25/2000 alopez : 2/25/2000 alopez : 2/25/2000 alopez : 2/25/2000 Copyright © 1966-2005 Johns Hopkins University
20: | +604373 | GeneTests, Links
| CHECKPOINT KINASE 2, S. POMBE, HOMOLOG OF; CHEK2
#### Alternative titles; symbols CHK2 RAD53, S. CEREVISIAE, HOMOLOG OF; RAD53 CDS1, S. POMBE, HOMOLOG OF BREAST AND COLORECTAL CANCER, SUSCEPTIBILITY TO, INCLUDED HBCC, SUSCEPTIBILITY TO, INCLUDED ### TABLE OF CONTENTS #### DESCRIPTION CLONING GENE FUNCTION MOLECULAR GENETICS ANIMAL MODEL ALLELIC VARIANTS View List REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 22q12.1 ### TEXT #### DESCRIPTION CHK2, a protein kinase that is activated in response to DNA damage, is involved in cell cycle arrest. #### CLONING In response to DNA damage and replication blocks, cells prevent cell cycle progression through the control of critical cell cycle regulators. To investigate checkpoint conservation, Matsuoka et al. (1998) used PCR and database analysis to identify CHK2, the mammalian homolog of Saccharomyces cerevisiae Rad53 and Schizosaccharomyces pombe cds1+, protein kinases required for DNA damage and replication checkpoints. The longest human cDNA encoded a 543-amino acid protein with 83% identity to mouse Chk2 and 34% identity to Drosophila Dmnk, a protein highly expressed in ovaries for which a function in meiosis had been suggested. Human CHK2 protein is 26% identical to Rad53 and 26% identical to cds1+. Sequence analysis revealed a single forkhead-associated (FHA) domain, a 60-amino acid protein interaction domain essential for activation in response to DNA damage that is conserved in the Rad53/cds1+ family of kinases. CHK2 has a potential regulatory region rich in SQ and TQ amino acid pairs. Northern blot analysis revealed wide expression of small amounts of CHK2 mRNA with larger amounts in human testis, spleen, colon, and peripheral blood leukocytes. CHK2 complemented the lethality of a Rad53 deletion. Blasina et al. (1999) and Chaturvedi et al. (1999) independently identified CHK2. #### GENE FUNCTION Matsuoka et al. (1998) demonstrated that CHK2 was rapidly phosphorylated and activated in response to replication blocks and DNA damage. The response to DNA damage occurred in an ATM (see 607585)-dependent manner. In vitro, CHK2 phosphorylated CDC25C (157680) on serine-216, a site known to be involved in negative regulation of CDC25C. This is the same site phosphorylated by the protein kinase CHK1 (603078), which suggests that, in response to DNA damage and DNA replicational stress, CHK1 and CHK2 may phosphorylate CDC25C to prevent entry into mitosis. Brown et al. (1999) referred to CHK2 as human CDS1. Affinity-purified antibodies to CHK2 recognized an endogenous 65-kD protein in 293 cells and 65-kD protein in cells transfected with a plasmid encoding untagged CHK2. When several human tissues were analyzed by immunoblotting, CHK2 protein was detected only in testis. Brown et al. (1999) found that CHK2 was modified by phosphorylation and activated in response to ionizing radiation, and was also modified in response to hydroxyurea treatment. Functional ATM protein was required for CHK2 modification after ionizing radiation but not after hydroxyurea treatment. Like its fission yeast counterpart, CHK2 phosphorylated CDC25C to promote the binding of 14-3-3 proteins (see 113508). These findings suggest that the checkpoint function of CHK2 is conserved in yeast and mammals. Chehab et al. (2000) expressed CHK2 in human cells and analyzed its cell cycle profile. Wildtype, but not catalytically inactive, CHK2 led to G1 arrest after DNA damage. The arrest was inhibited by cotransfection of a dominant-negative p53 (TP53; 191170) mutant, indicating that CHK2 acted upstream of p53. In vitro, CHK2 phosphorylated p53 on serine-20 and dissociated preformed complexes of p53 with MDM2 (164785), a protein that targets p53 for degradation. In vivo, ectopic expression of wildtype CHK2 led to increased p53 stabilization after DNA damage, whereas expression of a dominant-negative CHK2 mutant abrogated both phosphorylation of p53 on serine-20 and p53 stabilization. Thus, in response to DNA damage, CHK2 stabilizes the p53 tumor suppressor protein leading to cell cycle arrest in G1. Lee et al. (2000) reported that CHK2 regulates BRCA1 (113705) function after DNA damage by phosphorylating serine-988 of BRCA1. Lee et al. (2000) demonstrated that CHK2 and BRCA1 interact and colocalize within discrete nuclear foci but separate after gamma irradiation. Phosphorylation of BRCA1 at serine-988 is required for the release of BRCA1 from CHK2. This phosphorylation is also important for the ability of BRCA1 to restore survival after DNA damage in the BRCA1-mutated cell line HCC1937. When exposed to ionizing radiation, eukaryotic cells activate checkpoint pathways to delay the progression of the cell cycle. Defects in the ionizing radiation-induced S-phase checkpoint cause 'radioresistant DNA synthesis,' a phenomenon that has been identified in cancer-prone patients suffering from ataxia-telangiectasia. The CDC25A phosphatase (116947) activates the cyclin-dependent kinase 2 (CDK2; 116953) needed for DNA synthesis, but becomes degraded in response to DNA damage or stalled replication. Falck et al. (2001) reported a functional link between ATM, checkpoint signaling kinase CHK2, and CDC25A, and implicated this mechanism in controlling the S-phase checkpoint. Falck et al. (2001) showed that ionizing radiation-induced destruction of CDC25A requires both ATM and the CHK2-mediated phosphorylation of CDC25A on serine-123. An ionizing radiation-induced loss of CDC25A protein prevents dephosphorylation of CDK2 and leads to a transient blockade of DNA replication. Falck et al. (2001) also showed that tumor-associated CHK2 alleles cannot bind or phosphorylate CDC25A, and that cells expressing these CHK2 alleles, elevated CDC25A, or a CDK2 mutant unable to undergo inhibitory phosphorylation (CDK2AF) fail to inhibit DNA synthesis when irradiated. Falck et al. (2001) concluded that their results support CHK2 as a candidate tumor suppressor, and identify the ATM--CHK2--CDC25A--CDK2 pathway as a genomic integrity checkpoint that prevents radioresistant DNA synthesis. Falck et al. (2002) demonstrated that experimental blockade of either the NBS1 (602667)-MRE11 (600814) function or the CHK2-triggered events leads to a partial radioresistant DNA synthesis phenotype in human cells. In contrast, concomitant interference with NBS1-MRE11 and the CHK2-CDC25A-CDK2 pathways entirely abolishes inhibition of DNA synthesis induced by ionizing radiation, resulting in complete radioresistant DNA synthesis analogous to that caused by defective ATM. In addition, CDK2-dependent loading of CDC45 (603465) onto replication origins, a prerequisite for recruitment of DNA polymerase, was prevented upon irradiation of normal or NBS1/MRE11-defective cells but not cells with defective ATM. Falck et al. (2002) concluded that in response to ionizing radiation, phosphorylation of NBS1 and CHK2 by ATM triggers 2 parallel branches of the DNA damage-dependent S-phase checkpoint that cooperate by inhibiting distinct steps of DNA replication. By transfection of human embryonic kidney and adenocarcinoma cells with CHEK2 carrying various domain or point mutations, Ahn et al. (2002) demonstrated that the phosphorylation of thr68 by ATM promotes oligomerization of CHEK2 via binding of the thr68-phosphorylated region in 1 CHEK2 molecule to the unphosphorylated FHA domain of another. CHEK2 also phosphorylates its own FHA domain, and this modification reduces its affinity for thr68-phosphorylated CHEK2. Ahn et al. (2002) concluded that oligomerization of CHEK2 increases the efficiency of transautophosphorylation, resulting in the release of active CHEK2 monomers that proceed to enforce checkpoint control in irradiated cells. Lopes et al. (2001) used the 2-dimensional gel type technique to examine replication intermediates in response to hydroxyurea-induced replication blocks in S. cerevisiae. They showed that hydroxyurea-treated Rad53 mutants accumulate unusual DNA structures at replication forks. The persistence of these abnormal molecules during recovery from the hydroxyurea block correlates with the inability to dephosphorylate Rad53. Further, Rad53 is required to properly maintain stable replication forks during the block. Lopes et al. (2001) proposed that Rad53 prevents collapse of the fork when replication pauses. To characterize the mechanisms controlling replication fork integrity in S. cerevisiae, Sogo et al. (2002) analyzed replication intermediates formed in response to replication blocks using electron microscopy. At the forks, wildtype cells accumulated short single-stranded regions, which likely causes checkpoint activation, whereas Rad53 mutants exhibited extensive single-stranded gaps and hemi-replicated intermediates, consistent with a lagging-strand synthesis defect. Furthermore, Rad53 mutant cells accumulated Holliday junctions through fork reversal. Sogo et al. (2002) speculated that, in checkpoint mutants, abnormal replication intermediates begin to form because of uncoordinated replication and are further processed by unscheduled recombination pathways, causing genome instability. Yang et al. (2002) determined that PML (102578) and CHEK2 mediated p53-independent apoptosis following gamma irradiation of several human cell lines. Endogenous CHEK2 bound PML within PML nuclear bodies. Following gamma irradiation, CHEK2 phosphorylated PML on ser117, causing dissociation of the 2 proteins. Yang et al. (2002) concluded that this pathway to gamma irradiation-induced apoptosis utilizes ATM, CHEK2, and PML. #### MOLECULAR GENETICS Bell et al. (1999) identified heterozygous germline mutations in CHK2 in patients with Li-Fraumeni syndrome-2 (609265). Bell et al. (1999) suggested that CHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and that their observations provided a link between the central role of p53 (191170) inactivation in human cancer and the well-defined G2 checkpoint in yeast. Vahteristo et al. (2001) analyzed the CHK1 (603078), CHK2, and p53 genes for mutations in 44 Finnish families with Li-Fraumeni syndrome, Li-Fraumeni-like syndrome (see 151623), or a phenotype suggestive of Li-Fraumeni syndrome. Five different disease-causing mutations were observed in 7 families: 4 in the p53 gene and 1 in the CHK2 gene. The CHK2 mutation occurred in 2 families and was the same as that reported by Bell et al. (1999): 1100delC (604373.0001). The families originated from different parts of Finland, were not known to be related, and segregated different chromosome 22 haplotypes. Thus, 1100delC is clearly a disease-causing mutation and represents a mutation hotspot in the CHK2 gene. The phenotypes of the 2 families were considered atypical because of the lack of sarcomas or childhood cancers. In contrast, the family with this mutation reported by Bell et al. (1999) had classic LFS. Ino et al. (2000) concluded that the CHK2 gene is not the target of somatic inactivation in malignant gliomas. Bell et al. (1999) identified a C-to-T transition at nucleotide 433 of the CHK2 gene resulting in an arginine-to-tryptophan substitution at codon 145 (R145W) in a colon cancer (114500) cell line. Lee et al. (2001) demonstrated inactivating mutations of both alleles of CHEK2 in a sporadic colon carcinoma cell line; the 2 mutations were A247D and R145W (604373.0003). Because inherited CHK2 mutations are found in some Li-Fraumeni cancer syndrome families, Miller et al. (2002) examined the role of CHK2 mutations in sporadic cancer. They found missense mutations affecting the forkhead and kinase domains in 4 of 57 osteosarcomas (259500), 1 of 20 ovarian cancers, and 1 of 35 nonsmall cell lung cancers. The finding of CHK2 gene mutations were consistent with osteosarcoma being a defining tumor of Li-Fraumeni syndrome. The occurrence of CHK2 mutations in sporadic cancers emphasized the importance of the stress pathway, which includes TP53. Mutations in BRCA1 (113705) and BRCA2 (600185) confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, Meijers-Heijboer et al. (2002) analyzed the CHEK2 gene, which was considered a plausible candidate gene because it encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53. They found that CHEK2*1100delC (604373.0001), a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals and 5.1% in individuals with breast cancer derived from 718 families that did not carry mutations in BRCA1 or BRCA2, including 13.5% of individuals from families with male breast cancer. They estimated that the CHEK2*1100delC variant results in an approximately 2-fold increase of breast cancer risk in women and a 10-fold increase of risk in men. By contrast, the variant conferred no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggested that the biologic mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway. Among 578 men with prostate cancer (176807), Dong et al. (2003) found 28 (4.8%) germline CHEK2 mutations, 16 of which were unique. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in 9 families, including 2 frameshift and 3 missense mutations. Sixteen of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathologic effect of CHEK2 mutations in prostate cancer development. Analysis of 2 frameshift mutations revealed abnormal splicing in one and a dramatic reduction of CHEK2 protein levels in both. To investigate whether CHEK2 variants confer susceptibility to breast cancer, Schutte et al. (2003) screened the full CHEK2 coding sequence in BRCA1/BRCA2-negative breast cancer cases from 89 pedigrees with 3 or more cases of breast cancer. One novel germline variant and 2 other mutations were identified, but none occurred at significantly elevated frequency in familial breast cancer cases compared with controls. Schutte et al. (2003) concluded that the 1100delC may be the only CHEK2 allele that makes an appreciable contribution to breast cancer susceptibility. Meijers-Heijboer et al. (2003) identified the 1100delC variant in affected members of families segregating a breast and colorectal cancer phenotype. The 1100delC mutation was not, however, the major predisposing factor for the phenotype, but appeared to act in synergy with at least 1 unknown susceptibility gene. In Poland, there are 3 polymorphic variants of CHEK2, which, in aggregate, are present in 5.5% of the population. Two of these, 1100delC (604373.0001) and IVS2+1G-A, are rare and result in premature protein truncation; a third is a common missense variant, I157T (604373.0002). Cybulski et al. (2004) found that all 3 variants are associated with an increased risk of prostate cancer in Poland. Cybulski et al. (2004) ascertained the prevalence of each of these alleles in 4,008 cancer cases and 4,000 controls, all from Poland. The majority of the common cancer sites were represented. Positive associations with protein-truncating alleles were seen for cancer of the thyroid, breast, and prostate. The missense variant I157T was associated with an increased risk of breast cancer, colon cancer, kidney cancer, prostate cancer, and thyroid cancer. The range of cancers associated with mutations of the CHEK2 gene may be much greater than previously thought. #### ANIMAL MODEL Hirao et al. (2000) generated Chk2-deficient mouse embryonic cells by gene targeting. Chk2 -/- embryonic stem cells failed to maintain gamma-irradiation-induced arrest in the G2 phase of the cell cycle. Chk2 -/- thymocytes were resistant to DNA damage-induced apoptosis. Chk2 -/- cells were defective for p53 stabilization and for induction of p53-dependent transcripts such as p21 in response to gamma irradiation. Reintroduction of the Chk2 gene restored p53-dependent transcription in response to gamma irradiation. Chk2 directly phosphorylated p53 on serine 20, which is known to interfere with Mdm2 binding. Hirao et al. (2000) concluded that this provides a mechanism for increased stability of p53 by prevention of ubiquitination in response to DNA damage. They further concluded, in light of the finding of 2 mutations in CHK2 in patients with Li-Fraumeni syndrome (Bell et al., 1999), that the results provided a mechanistic link between Chk2 and p53 to explain the phenotypic similarity of these 2 genetically distinct Li-Fraumeni syndrome families. Thus, like p53, Chk2 may contribute to a wide range of human cancers. In an effort to clarify the roles of Chek2 and Atm in tumorigenesis, Hirao et al. (2002) compared the G1/S checkpoint, apoptosis, and expression of p53 proteins in thymocytes isolated from Chek2-null mice and Atm-null mice. They determined that Chek2 can regulate p53-dependent apoptosis in an Atm-independent manner. Radiation-induced apoptosis was restored in Chek2-null thymocytes by reintroduction of the wildtype Chek2 gene, but not by a Chek2 gene in which the sites phosphorylated by Atm or Atr (601215) were mutated to alanine. ### ALLELIC VARIANTS (selected examples) #### .0001 LI-FRAUMENI SYNDROME 2 [CHEK2, 1-BP DEL, 1100C] BREAST CANCER, SUSCEPTIBILITY TO, INCLUDED PROSTATE CANCER, SUSCEPTIBILITY TO, INCLUDED BREAST AND COLORECTAL CANCER, SUSCEPTIBILITY TO, INCLUDED In a family with Li-Fraumeni syndrome-2 (609265), Bell et al. (1999) identified deletion of a cytosine at nucleotide 1100 of the CHK2 gene, resulting in premature truncation in the kinase domain of the CHK2 protein. This heterozygous germline mutation was present in all 3 affected family members but was absent from unaffected family members and from 100 control alleles. Affected individuals had classic Li-Fraumeni syndrome with death from breast cancer, glioma, histiocytoma, and sarcoma. Family members had wildtype p53 (191170). Vahteristo et al. (2001) identified the 1100delC mutation in the CHK2 gene in 2 families considered to have an atypical form of Li-Fraumeni syndrome because of the lack of sarcomas and childhood cancers in affected individuals. Meijers-Heijboer et al. (2002) found that an 1100delC variant of CHEK2, which results in truncation of the kinase activity, results in an approximately 2-fold increase of breast cancer (114480) risk in women and a 10-fold increase of risk in men. In Finland, Vahteristo et al. (2002) found that the frequency of 1100delC was 2.0% among an unselected population-based cohort of 1,035 patients with breast cancer, as compared with the 1.4% frequency found among 1,885 population control subjects (P = 0.182). However, a 3.1% frequency was found among those 358 patients with a positive family history, giving P = 0.021 compared with population controls. Furthermore, patients with bilateral breast cancer were 6-fold more likely to be 1100delC carriers than were patients with unilateral cancer (P = 0.007). Analysis of the 1100delC variant in an independent set of 507 patients with familial breast cancer with no BRCA1 (113705) or BRCA2 (600185) mutations confirmed a significantly elevated frequency of the 1-bp deletion. Tissue microarray analysis indicated that breast tumors from patients with 1100delC mutations showed reduced CHEK2 immunostaining. The results indicated that CHEK2 acts as a low-penetrance tumor-suppressor gene in breast cancer and that it makes a significant contribution to familial clustering of breast cancer, including families with only 2 affected relatives, which are more common than families that include larger numbers of affected women. Dong et al. (2003) found this frameshift mutation in exon 10 in 1 of 298 men with familial prostate cancer (176807), 1 of 400 men with sporadic prostate cancer, and 4 of 178 prostate cancer tumor samples. The mutation was not found in 423 unaffected men. Meijers-Heijboer et al. (2003) defined a subset of families with hereditary breast cancer characterized by the presence of colorectal cancer cases (HBCC). The 1100delC variant was present in 18% of 55 families with HBCC, as compared with 4% of 380 families with breast cancer and without colorectal cancer. The 1100delC mutation was not, however, the major predisposing factor for the HBCC phenotype, but appeared to act in synergy with at least 1 unknown susceptibility gene. To evaluate the breast cancer risk associated with the 1100delC variant, the CHEK2 Breast Cancer Case-Control Consortium (2004) genotype 10,860 breast cancer cases and 9,065 controls from 10 case-control studies in 5 countries. The 1100delC variant was found in 201 cases (1.9%) and in 64 controls (0.7%), giving an estimated odds ratio of 2.34. There was some evidence of a higher prevalence of the 1100delC variant among cases with a first-degree relative affected with breast cancer (odds ratio 1.44) and of a trend for a higher breast cancer odds ratio at younger ages at diagnosis. These results confirmed that the 1100delC variant confers an increased risk of breast cancer and that this risk is apparent in women unselected for family history. The results were consistent with the hypothesis that the 1100delC variant multiples the risks associated with susceptibility alleles in other genes to increase the risk of breast cancer. Comparing data for 34 breast cancer patients with a germline 1100delC mutation with those for 102 breast cancer patients without this mutation, de Bock et al. (2004) concluded that carrying the 1100delC mutation is an adverse prognostic indicator. Mutation carriers more frequently had a female first- or second-degree relative with breast cancer and had a more unfavorable prognosis regarding the occurrence of contralateral breast cancer and distant metastasis-free survival. #### .0002 LI-FRAUMENI SYNDROME 2 [CHEK2, ILE157THR] In an individual with Li-Fraumeni syndrome-variant (see LFS2; 609265), Bell et al. (1999) identified a T-to-C transition at nucleotide 470 of the CHK2 gene resulting in an isoleucine-to-threonine substitution at codon 157 (I157T). This nonconservative substitution was within the forkhead homology-association domain of CHK2. The proband (who was a cigarette smoker) had developed 3 primary tumors: breast cancer, melanoma, and lung cancer. In a study of prostate cancer (176807), Dong et al. (2003) found that the most common mutation of CHK2 was I157T, which was present in 7 of 298 men with familial prostate cancer, 6 men with sporadic prostate cancer, and 5 of 423 unaffected men. Their study indicated that this mutation is relatively common in normal healthy control individuals. #### .0003 LI-FRAUMENI SYNDROME 2 [CHEK2, ARG145TRP ] In affected members of a family with Li-Fraumeni syndrome-2 (609265), Lee et al. (2001) found an arg145-to-trp (R145W) missense mutation of the CHEK2 gene, which destabilizes the encoded protein, reducing its half-life from more than 120 minutes to 30 minutes. This effect was abrogated by treatment of cells with a proteosome inhibitor, suggesting that the mutation is targeted through this degradation pathway. Both the 1100delC (604373.0001) and the R145W germline mutations in CHEK2 were associated with loss of the wildtype allele in the corresponding tumor specimens, and neither tumor harbored a somatic TP53 (191170) mutation. #### .0004 LI-FRAUMENI SYNDROME 2 [CHEK2, 1-BP DEL, 1422T ] In a patient with Li-Fraumeni syndrome-variant (see LFS2; 609265), Bell et al. (1999) detected deletion of a T at nucleotide 1422 of the CHK2 gene. The proband had multiple colonic polyps, colorectal cancer, bilateral ocular melanomas, and had a family history of sarcomas and breast, colorectal, gastric, and lung cancers. #### .0005 OSTEOSARCOMA, SOMATIC [CHEK2, PRO85LEU ] In a sporadic case of osteosarcoma (259500) and a case of nonsmall cell lung cancer, Miller et al. (2002) found a pro85-to-leu (P85L) missense mutation of the CHEK2 gene. #### .0006 OSTEOSARCOMA, SOMATIC [CHEK2, ALA17SER] Miller et al. (2002) found an ala17-to-ser (A17S) missense mutation in a case of osteosarcoma (259500). #### .0007 PROSTATE CANCER, SOMATIC [CHEK2, ARG180HIS ] In 1 of 400 men with sporadic prostate cancer (176807), none of 298 men with familial prostate cancer, and none of 423 unaffected men, Dong et al. (2003) found a 539G-A transition in exon 3 of the CHEK2 gene predicted to result in an arg180-to-his (R180H) mutation. #### .0008 PROSTATE CANCER, SOMATIC [CHEK2, ARG181CYS ] In 1 of 178 prostate cancer (176807) tumor samples, Dong et al. (2003) found a 541C-T transition in exon 3 of the CHEK2 gene predicted to result in an arg181-to-cys (R181C) mutation. The mutation was not found in any of 298 men with familial prostate cancer, 400 men with sporadic prostate cancer, or 423 unaffected men. #### .0009 PROSTATE CANCER, SOMATIC [CHEK2, ARG181HIS ] In 1 of 400 men with sporadic prostate cancer (176807), Dong et al. (2003) found a 542G-A transition in exon 3 of the CHEK2 gene predicted to result in an arg181-to-his (R181H) mutation. The mutation was not found in any of 298 men with familial prostate cancer, 178 prostate cancer tumor samples, or 423 unaffected men. #### .0010 PROSTATE CANCER, SOMATIC [CHEK2, GLU239TER] In 1 of 400 men with sporadic prostate cancer (176807), Dong et al. (2003) found a 715G-T germline mutation in exon 5 of the CHEK2 gene, predicted to result in a glu239-to-ter (E239X) truncating change in the protein. The mutation occurred in the kinase domain and was presumed to result in loss of kinase activity. #### .0011 PROSTATE CANCER, SOMATIC [CHEK2, GLU239LYS] In 1 of 298 men with familial prostate cancer (176807), Dong et al. (2003) found a germline 715G-A transition in exon 5 of the CHEK2 gene, predicted to result in a glu239-to-lys (E239K) mutation in the kinase domain. The same mutation was found in 1 of 178 prostate cancer tumor samples. ### REFERENCES 1. Ahn, J.-Y.; Li, X.; Davis, H. L.; Canman, C. E. : Phosphorylation of threonine 68 promotes oligomerization and autophosphorylation of the Chk2 protein kinase via the forkhead-associated domain. J. Biol. Chem. 277: 19389-19395, 2002. PubMed ID : 11901158 2. Bell, D. W.; Varley, J. M.; Szydlo, T. E.; Kang, D. H.; Wahrer, D. C. R.; Shannon, K. E.; Lubratovich, M.; Verselis, S. J.; Isselbacher, K. J.; Fraumeni, J. F.; Birch, J. M.; Li, F. P.; Garber, J. E.; Haber, D. A. : Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286: 2528-2531, 1999. PubMed ID : 10617473 3. Blasina, A.; de Weyer, I. V.; Laus, M. C.; Luyten, W. H.; Parker, A. E.; McGowan, C. H. : A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr. Biol. 14: 1-10, 1999. 4. Brown, A. L.; Lee, C.-H.; Schwarz, J. K.; Mitiku, N.; Piwnica-Worms, H.; Chung, J. H. : A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage. Proc. Nat. Acad. Sci. 96: 3745-3750, 1999. PubMed ID : 10097108 5. Chaturvedi, P.; Eng, W. K.; Zhu, Y.; Mattern, M. R.; Mishra, R.; Hurle, M. R.; Zhang, X.; Annan, R. S.; Lu, Q.; Faucette, L. F.; Scott, G. F.; Li, X.; Carr, S. A.; Johnson, R. K.; Winkler, J. D.; Zhou, B. B. : Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Oncogene 18: 4047-4054, 1999. PubMed ID : 10435585 6. Chehab, N. H.; Malikzay, A.; Appel, M.; Halazonetis, T. D. : Chk2/hCds1 functions as a DNA damage checkpoint in G-1 by stabilizing p53. Genes Dev. 14: 278-288, 2000. PubMed ID : 10673500 7. CHEK2 Breast Cancer Case-Control Consortium : CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am. J. Hum. Genet. 74: 1175-1182, 2004. Note: Erratum: Am. J. Hum. Genet. 76: 196 only, 2005. PubMed ID : 15122511 8. Cybulski, C.; Gorski, B.; Huzarski, T.; Masojc, B.; Mierzejewski, M.; Debniak, T.; Teodorczyk, U.; Byrski, T.; Gronwald, J.; Matyjasik, J.; Zlowocka, E.; Lenner, M.; and 12 others : CHEK2 is a multiorgan cancer susceptibility gene. Am. J. Hum. Genet. 75: 1131-1135, 2004. PubMed ID : 15492928 9. Cybulski, C.; Huzarski, T.; Gorski, B.; Masojc, B.; Mierzejewski, M.; Debniak, T.; Gliniewicz, B.; Matyjasik, J.; Zlowocka, E.; Kurzawski, G.; Sikorski, A.; Posmyk, M.; Szwiec, M.; Czajka, R.; Narod, S. A.; Lubinski, J. : A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res. 64: 2677-2679, 2004. PubMed ID : 15087378 10. de Bock, G. H.; Schutte, M.; Krol-Warmerdam, E. M. M.; Seynaeve, C.; Blom, J.; Brekelmans, C. T. M.; Meijers-Heijboer, H.; van Asperen, C. J.; Cornelisse, C. J.; Devilee, P.; Tollenaar, R. A. E. M.; Klijn, J. G. M. : Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J. Med. Genet. 41: 731-735, 2004. PubMed ID : 15466005 11. Dong, X.; Wang, L.; Taniguchi, K.; Wang, X.; Cunningham, J. M.; McDonnell, S. K.; Qian, C.; Marks, A. F.; Slager, S. L.; Peterson, B. J.; Smith, D. I.; Cheville, J. C.; Blute, M. L.; Jacobsen, S. J.; Schaid, D. J.; Tindall, D. J.; Thibodeau, S. N.; Liu, W. : Mutations in CHEK2 associated with prostate cancer risk. Am. J. Hum. Genet. 72: 270-280, 2003. PubMed ID : 12533788 12. Falck, J.; Mailand, N.; Syljuasen, R. G.; Bartek, J.; Lukas, J. : The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410: 842-847, 2001. PubMed ID : 11298456 13. Falck, J.; Petrini, J. H. J.; Williams, B. R.; Lukas, J.; Bartek, J. : The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nature Genet. 30: 290-294, 2002. PubMed ID : 11850621 14. Hirao, A.; Cheung, A.; Duncan, G.; Girard, P.-M.; Elia, A. J.; Wakeham, A.; Okada, H.; Sarkissian, T.; Wong, J. A.; Sakai, T.; de Stanchina, E.; Bristow, R. G.; Suda, T.; Lowe, S. W.; Jeggo, P. A.; Elledge, S. J.; Mak, T. W. : Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Molec. Cell. Biol. 22: 6521-6532, 2002. PubMed ID : 12192050 15. Hirao, A.; Kong, Y.-Y.; Matsuoka, S.; Wakeham, A.; Ruland, J.; Yoshida, H.; Liu, D.; Elledge, S. J.; Mak, T. W. : DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science 287: 1824-1827, 2000. PubMed ID : 10710310 16. Ino, Y.; Wahrer, D. C. R.; Bell, D. W.; Haber, D. A.; Louis, D. N. : Mutation analysis of the hCHK2 gene in primary human malignant gliomas. (Letter) Neurogenetics 3: 45-46, 2000. PubMed ID : 11085597 17. Lee, J.-S.; Collins, K. M.; Brown, A. L.; Lee, C.-H.; Chung, J. H. : hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature 404: 201-204, 2000. PubMed ID : 10724175 18. Lee, S. B.; Kim, S. H.; Bell, D. W.; Wahrer, D. C. R.; Schiripo, T. A.; Jorczak, M. M.; Sgroi, D. C.; Garber, J. E.; Li, F. P.; Nichols, K. E.; Varley, J. M.; Godwin, A. K.; Shannon, K. M.; Harlow, E.; Haber, D. A. : Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni syndrome. Cancer Res. 61: 8062-8067, 2001. PubMed ID : 11719428 19. Lopes, M.; Cotta-Ramusino, C.; Pellicioli, A.; Liberi, G.; Plevani, P.; Muzi-Falconi, M.; Newlon, C. S.; Foiani, M. : The DNA replication checkpoint response stabilizes stalled replication forks. Nature 412: 557-561, 2001. PubMed ID : 11484058 20. Matsuoka, S.; Huang, M.; Elledge, S. J. : Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science 282: 1893-1897, 1998. PubMed ID : 9836640 21. Meijers-Heijboer, H.; van den Ouweland, A.; Klijn, J.; Wasielewski, M.; de Snoo, A.; Oldenburg, R.; Hollestelle, A.; Houben, M.; Crepin, E.; van Veghel-Plandsoen, M.; Elstrodt, F.; van Duijn, C.; and 29 others : Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nature Genet. 31: 55-59, 2002. PubMed ID : 11967536 22. Meijers-Heijboer, H.; Wijnen, J.; Vasen, H.; Wasielewski, M.; Wagner, A.; Hollestelle, A.; Elstrodt, F.; van den Bos, R.; de Snoo, A.; Tjon A Fat, G.; Brekelmans, C.; Jagmohan, S.; and 11 others : The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am. J. Hum. Genet. 72: 1308-1314, 2003. PubMed ID : 12690581 23. Miller, C. W.; Ikezoe, T.; Krug, U.; Hofmann, W.-K.; Tavor, S.; Vegesna, V.; Tsukasaki, K.; Takeuchi, S.; Koeffler, H. P. : Mutations of the CHK2 gene are found in some osteosarcomas, but are rare in breast, lung, and ovarian tumors. Genes Chromosomes Cancer 33: 17-21, 2002. PubMed ID : 11746983 24. Schutte, M.; Seal, S.; Barfoot, R.; Meijers-Heijboer, H.; Wasielewski, M.; Evans, D. G.; Eccles, D.; Meijers, C.; Lohman, F.; Klijn, J.; van den Ouweland, A.; Breast Cancer Linkage Consortium; Futreal, P. A.; Nathanson, K. L.; Weber, B. L.; Easton, D. F.; Stratton, M. R.; Rahman, N. : Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am. J. Hum. Genet. 72: 1023-1028, 2003. PubMed ID : 12610780 25. Sogo, J. M.; Lopes, M.; Foiani, M. : Fork reversal and ssDNA accumulation at stalled replication forks owing to checkpoint defects. Science 297: 599-602, 2002. PubMed ID : 12142537 26. Vahteristo, P.; Bartkova, J.; Eerola, H.; Syrjakoski, K.; Ojala, S.; Kilpivaara, O.; Tamminen, A.; Kononen, J.; Aittomaki, K.; Heikkila, P.; Holli, K.; Blomqvist, C.; Bartek, J.; Kallioniemi, O.-P.; Nevanlinna, H. : A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am. J. Hum. Genet. 71: 432-438, 2002. PubMed ID : 12094328 27. Vahteristo, P.; Tamminen, A.; Karvinen, P.; Eerola, H.; Eklund, C.; Aaltonen, L. A.; Blomqvist, C.; Aittomaki, K.; Nevanlinna, H. : p53, CHK2, and CHK1 genes in Finnish families with Li-Fraumeni syndrome: further evidence of CHK2 in inherited cancer predisposition. Cancer Res. 61: 5718-5722, 2001. PubMed ID : 11479205 28. Yang, S.; Kuo, C.; Bisi, J. E.; Kim, M. K. : PML-dependent apoptosis after DNA damage is regulated by the checkpoint kinase hCds1/Chk2. Nature Cell Biol. 4: 865-870, 2002. PubMed ID : 12402044 ### CONTRIBUTORS Victor A. McKusick - updated : 2/17/2005 Victor A. McKusick - updated : 11/12/2004 Victor A. McKusick - updated : 5/21/2004 Victor A. McKusick - updated : 5/20/2003 Ada Hamosh - updated : 5/9/2003 Patricia A. Hartz - updated : 3/14/2003 Victor A. McKusick - updated : 1/29/2003 Patricia A. Hartz - updated : 11/8/2002 Victor A. McKusick - updated : 8/20/2002 Ada Hamosh - updated : 8/7/2002 Victor A. McKusick - updated : 5/6/2002 Ada Hamosh - updated : 3/28/2002 Victor A. McKusick - updated : 2/15/2002 Victor A. McKusick - updated : 1/30/2002 Victor A. McKusick - updated : 10/11/2001 Ada Hamosh - updated : 8/14/2001 Victor A. McKusick - updated : 5/11/2001 Ada Hamosh - updated : 4/10/2001 Patti M. Sherman - updated : 7/26/2000 Ada Hamosh - updated : 3/10/2000 Ada Hamosh - updated : 3/10/2000 ### CREATION DATE Ada Hamosh : 12/27/1999 ### EDIT HISTORY mgross : 3/17/2005 tkritzer : 2/23/2005 terry : 2/17/2005 carol : 12/10/2004 alopez : 11/18/2004 alopez : 11/18/2004 terry : 11/12/2004 alopez : 5/28/2004 terry : 5/21/2004 carol : 3/17/2004 cwells : 11/7/2003 carol : 6/4/2003 tkritzer : 6/3/2003 terry : 5/20/2003 cwells : 5/13/2003 terry : 5/9/2003 mgross : 3/18/2003 terry : 3/14/2003 terry : 3/12/2003 ckniffin : 3/11/2003 carol : 2/12/2003 carol : 2/12/2003 tkritzer : 1/29/2003 terry : 1/29/2003 tkritzer : 11/14/2002 tkritzer : 11/12/2002 tkritzer : 11/8/2002 tkritzer : 8/23/2002 tkritzer : 8/22/2002 terry : 8/20/2002 alopez : 8/8/2002 terry : 8/7/2002 alopez : 5/6/2002 alopez : 5/6/2002 alopez : 5/6/2002 carol : 3/29/2002 cwells : 3/29/2002 terry : 3/28/2002 cwells : 3/6/2002 cwells : 2/22/2002 terry : 2/15/2002 alopez : 2/6/2002 terry : 1/30/2002 carol : 12/5/2001 carol : 11/5/2001 mcapotos : 10/31/2001 terry : 10/11/2001 carol : 9/27/2001 carol : 9/20/2001 alopez : 8/17/2001 terry : 8/14/2001 mcapotos : 5/22/2001 mcapotos : 5/17/2001 terry : 5/11/2001 alopez : 4/11/2001 alopez : 4/11/2001 terry : 4/10/2001 mcapotos : 8/8/2000 mcapotos : 7/31/2000 psherman : 7/26/2000 alopez : 3/10/2000 alopez : 3/10/2000 alopez : 12/27/1999 Copyright © 1966-2005 Johns Hopkins University
Items 1 - 20 of 55 |
| of 3 |  | Next
Display Show
| Disclaimer | Write to the Help Desk | Privacy Policy NCBI | NLM | NIH

May 16 2005 17:16:29