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1: | *182279 | GeneTests, Links
| SMALL NUCLEAR RIBONUCLEOPROTEIN POLYPEPTIDE N; SNRPN
#### Alternative titles; symbols SMN ### TABLE OF CONTENTS #### TEXT REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q12 ### TEXT Small nuclear ribonucleoprotein particles (snRNP) found in spliceosomes contain small RNAs U1 (180680), U2 (180690), U4, U5 (180691), and U6 (180692), and associated polypeptides. Some of these polypeptides are present in all 5 of these snRNPs and others are unique to U1 or U2 snRNPs or have tissue-limited expression patterns. SnRNP associated proteins have epitopes that react with autoimmune sera. With such an antiserum (Sm), a protein termed SmN was identified and the gene subsequently cloned (McAllister et al., 1988; Li et al., 1989; Schmauss et al., 1989). Although the sequence of SmN shows it to be highly homologous to the ubiquitous core snRNP protein B and its alternatively spliced form B-prime, SmN is expressed predominantly in brain and especially in central neurons. While the findings of specific interactions between snRNPs and pre-mRNA establish a role of snRNPs in mRNA processing, the functions of individual snRNP proteins are poorly understood. Tissue-specific expression patterns suggest their involvement in tissue-specific mRNA splicing. Mutations in the SNRPN gene might affect alternative splicing of transcripts in the brain and have pleiotropic effects on development of function of the nervous system. As a first step to address this hypothesis, Ozcelik et al. (1992) determined the chromosomal location of the gene for small nuclear ribonucleoprotein polypeptide N (SNRPN). By study of somatic cell hybrids and hybrid cell lines containing specific regions of the chromosomes in question, they were able to map the SNRPN gene to 15q12 and a processed pseudogene, SNRPNP1, to 6pter-p21. Furthermore, they showed that SNRPN maps to the minimal deletion interval that is critical for Prader-Willi syndrome (PWS; 176270). Leff et al. (1992) showed that the mouse Snrpn gene maps to chromosome 7 in a region of homology with human chromosome 15q11-q13. They further demonstrated that the Snrpn gene is maternally imprinted in the mouse. Thus, loss of the paternally derived SNRPN allele may be involved in the PWS phenotype. Cattanach et al. (1992) reported observations indicating that maternal duplication of the central part of mouse chromosome 7, where the Snrpn gene is located, causes an imprinting effect that may correspond to PWS. Paternal duplication was not associated with any detectable effect that might correspond with Angelman syndrome (AS; 105830). Mutirangura et al. (1993) constructed a complete YAC contig of the Prader-Willi/Angelman chromosome region and localized the SNRPN gene to specific YACs within the contig. The small nuclear ribonucleoprotein subunit SmN, thought to be involved in splicing of pre-mRNA, is predominantly expressed in brain. The mouse homolog of the SNRPN gene is functionally imprinted in mouse brain, being expressed only from the paternally derived chromosome. Glenn et al. (1993) demonstrated functional imprinting of the human SNRPN gene using RT-PCR. No expression was observed in cultured skin fibroblasts of patients with Prader-Willi syndrome but was found in all patients with Angelman syndrome and in normal controls. Glenn et al. (1993) also demonstrated a parent-specific DNA methylation imprint within intron 5 of the SNRPN gene, which suggested an epigenetic mechanism by which parent-specific expression of this gene might be inherited. Thus, the authors found that the pattern of imprinting fulfills one major criterion for SNRPN being involved in the pathogenesis of PWS. Reed and Leff (1994) characterized a sequence polymorphism within expressed portions of the human SNRPN gene and showed that the SNRPN gene is monoallelically expressed in fetal brain and heart and in adult brain. Analysis of maternal DNA and of SNRPN cDNA confirmed that the maternal allele is not expressed in fetal brain and heart. Thus, maternal imprinting of SNRPN supports the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype. In 2 sibs with the typical phenotype of PWS but without a cytogenetically detectable deletion in 15q, Ishikawa et al. (1996) demonstrated deletion of SNRPN by fluorescence in situ hybridization. Schulze et al. (1996) presented evidence suggesting that SNRPN is not a major determinant of the Prader-Willi syndrome. They mapped the breakpoint of balanced translocation (9;15)pat associated with most of the PWS features to a region between SNRPN and PAR1 (600161). Methylation and expression studies indicated that the paternal SNRPN allele was unaffected by the translocation, while IPW (601491) and PAR1 were unexpressed. This focused attention on genes distal to the breakpoint as the main candidate for PWS genes and was considered consistent with a cis action of the putative imprinting center (IC) gene located proximal to SNRPN (Sutcliffe et al., 1994; Buiting et al., 1995). Schulze et al. (1996) suggested that further studies of translocational disruption of the imprinted region may establish genotype/phenotype relationships in Prader-Willi syndrome, which they presumed to be a contiguous gene syndrome. Sun et al. (1996) reported a patient with the PWS phenotype and a balanced reciprocal translocation t(15;19)(q12;q13.41), which was paternal in origin. By FISH analysis and examination of DNA by Southern blot hybridization, they found that the translocation breakpoint occurred between exons 0 and 1 of the SNRPN locus, outside of the SmN open reading frame. Sun et al. (1996) reported that the transcriptional activities of ZNF127 (MKRN3; 603856), IPW, PAR1, and PAR5 (600162) were detected with RT-PCR from fibroblasts of this patient, whereas transcription from only the first 2 exons and the last 7 exons of SNRPN was detected with RT-PCR. The complete SNRPN mRNA (10 exons) was not detected. Sun et al. (1996) suggested that the 3 upstream exons (exons -1, 0, and 1) of SNRPN encode an additional independent reading frame, SNURF (SNRPN upstream reading frame). The putative SNURF sequence would be interrupted in this patient, and this disruption may play a role in the etiology of the PWS phenotype. Polycistronic transcripts are common in prokaryotes but rare in eukaryotes. Gray et al. (1999) found that 5 eutherian mammals (cow, rat, mouse, rabbit, and human) have the highly conserved SNURF coding sequence. The vast majority of nucleotide substitutions in SNURF were found to be in the wobble codon position, providing strong evolutionary evidence for selection for protein-coding function. Because SNURF-SNRPN maps to human chromosome 15q11-q13 and is paternally expressed, each cistron is a candidate for a role in the imprinted PWS and PWS mouse models. SNURF encodes a highly basic 71-amino acid protein that is nuclear-localized (as is the product of the SNRPN gene). Because SNURF is the only protein-coding sequence within the imprinting regulatory region in 15q11-q13, it may have provided the original selection for imprinting in this domain. Whereas some human tissues express a minor SNURF-only transcript, mouse tissues express only the bicistronic Snurf-Snrpn transcript. Gray et al. (1999) showed that both SNURF and SNRPN are translated in normal, but not PWS, human and mouse tissues and cell lines. These findings identified SNURF as a protein that is produced along with SNRPN from a bicistronic transcript; polycistronic mRNAs, therefore, are encoded in mammalian genomes where they may form functional operons. Kuslich et al. (1999) likewise identified a de novo balanced translocation in a Prader-Willi syndrome patient: (4;15)(q27;q11.2)pat. The breakpoints lay between SNRPN exons 2 and 3. Parental-origin studies indicated that there was no uniparental disomy and no apparent deletion. The patient expressed ZNF127, SNRPN exons 1 and 2, IPW, and PAR1, but did not express either SNRPN exons 3 and 4 or PAR5, as assayed by RT-PCR, of peripheral blood cells. Kuslich et al. (1999) concluded that this patient and that reported by Sun et al. (1996) supported the contention that an intact genomic region and/or transcription of SNRPN exons 2 and 3 play a pivotal role in the manifestations of the major clinical phenotype in PWS. Dittrich et al. (1996) reported the existence of an imprinting center which maps to a 100-kb region of chromosome 15q11-q13. This imprinting center encodes alternative transcripts of the SNRPN gene. The novel exons lack protein coding potential and are expressed from the paternal chromosome only. They also reported that families with imprinting mutations have mutations in this transcription unit. Deletions and point mutations of the alternative 5-prime exons of SNRPN (referred to as BD transcripts) are associated with a block of the maternal-paternal imprint switch in several families with Angelman syndrome. Deletions of SNRPN exon 1 are associated with a block of the maternal-paternal imprint switch in several families with Prader-Willi syndrome. Based on their studies, Dittrich et al. (1996) proposed a model for imprint switching. In this model the imprint center consists of an imprintor and an imprint switch initiation site. The imprintor encodes the BD transcript. They proposed that the imprintor is transcribed from the paternal chromosome only and that it acts in cis on the switch initiation site (the SNRPN promoter, exon 1, or a site close by), possibly by introducing a change in chromatin structure. Prader-Willi syndrome and Angelman syndrome are neurogenetic disorders caused by the lack of a paternal or a maternal contribution from human 15q11-q13, respectively. They involve oppositely imprinted genes: the paternally expressed PWS gene(s) and the maternally expressed AS gene. Deletions in the transcription unit of the imprinted SNRPN gene occur in patients who have PWS or Angelman syndrome because of a parental imprint switch failure in this chromosomal domain. It has been suggested that the SNRPN exon 1 region, which is deleted in PWS patients, contains an imprint switch element from which the maternal and paternal epigenotypes of the 15q11-q13 domain originate. Using the model organism Drosophila, Lyko et al. (1998) showed that a fragment from this region can function as a silencer in transgenic flies. Repression was detected specifically from this element and could not be observed with control human sequences. Additional experiments allowed the delineation of the silencer to a fragment of 215 bp containing the SNRPN promoter region. These results provide an additional link between genomic imprinting and an evolutionarily conserved silencing mechanism. Lyko et al. (1998) suggested that the identified element participates in the long-range regulation of the imprinted 15q11-q13 domain or locally represses SNRPN expression from the maternal allele. Schweizer et al. (1999) studied the mechanism by which small microdeletions within the 5-prime region of the SNRPN transcription unit affect the transcriptional activity and methylation status of distant imprinted genes throughout 15q11-q13 in cis. They analyzed the chromatin structure of the 150-kb SNRPN transcription unit for DNaseI- and MspI-hypersensitive sites. Using an in vivo approach on lymphoblastoid cell lines from PWS and AS individuals, they discovered that exon 1 of the SNRPN gene is flanked by prominent hypersensitive sites on the paternal allele, but is completely inaccessible to nucleases on the maternal allele. In contrast, they identified several regions of increased nuclease hypersensitivity on the maternal allele, one of which coincides with the minimal microdeletion region for AS, and another that lies in intron 1 immediately downstream of the paternal-specific hypersensitive sites. At several sites, parental origin-specific nuclease hypersensitivity was found to be correlated with hypermethylation on the allele contributed by the other parent. Schweizer et al. (1999) suggested that the differential parental origin-dependent chromatin conformations may govern access of regulatory protein complexes and/or RNAs that mediate interaction of the region with other genes. Bielinska et al. (2000) reported a PWS family in which the father was mosaic for an imprinting center deletion on his paternal chromosome. The deletion chromosome had acquired a maternal methylation imprint in his somatic cells. Identical observations were made in chimeric mice generated from 2 independent embryonic stem cell lines harboring a similar deletion. Bielinska et al. (2000) concluded that the Prader-Willi syndrome imprinting center element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance. To examine the chromatin basis of imprinting in the 15q11-q13 region, Saitoh and Wada (2000) investigated the status of histone acetylation of the SNURF-SNRPN locus, which is a key imprinted gene in PWS. Chromatin immunoprecipitation studies showed that the unmethylated CpG island of the active, paternally derived allele associated with acetylated histones, whereas the methylated maternally derived, inactive allele was specifically hypoacetylated. The body of the SNURF-SNRPN gene was associated with acetylated histones on both alleles. Treatment of PWS cells with the DNA methyltransferase inhibitor 5-azadeoxycytidine induced demethylation of the SNURF-SNRPN CpG island and restored gene expression on the maternal allele. The reactivation was associated with increased H4 acetylation but not with H3 acetylation at the SNURF-SNRPN CpG island. These findings indicated that (1) a significant role for histone deacetylation in gene silencing is associated with imprinting in 15q11-q13, and (2) silenced genes in PWS can be reactivated by drug treatment. Thus, the potential for pharmaceutical treatment of imprinting-related disorders was raised. Several observations had suggested that cis elements within the AS-SRO (shortest region of overlap) and PWS-SRO constitute an imprinting box that regulates the entire domain on both chromosomes. Shemer et al. (2000) showed that a minitransgene composed of 200-bp Snrpn promoter/exon 1 and a 1-kb sequence located approximately 35 kb upstream to the SNRPN promoter confer imprinting as judged by differential methylation, parent-of-origin-specific transcription, and asynchronous replication. Balanced translocations affecting the paternal copy of 15q11-q13 have been proven to be a rare cause of Prader-Willi syndrome (PWS) or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation, t(X;15)(q28;q12), in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85 (605436), as well as IPW (601491) and PAR1 (600161), were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype. The SNRPN promoter is embedded in a CpG island that is maternally methylated, is expressed only from the paternal chromosome, and lies within an imprinting center that is required for switching to and/or maintenance of the paternal epigenotype. In mice and humans, the Snrpn gene, as well as other loci in the region, are subject to genomic imprinting. Bressler et al. (2001) showed that a 0.9-kb deletion of exon 1 of mouse Snrpn did not disrupt imprinting or elicit any obvious phenotype, although it did allow the detection of previously unknown upstream exons. In contrast, a larger, overlapping 4.8-kb deletion caused a partial or mosaic imprinting defect and perinatal lethality when paternally inherited. Gallagher et al. (2002) suggested that the minimal critical region for PWS is approximately 121 kb within the SNRPN locus of more than 460 kb, bordered by a breakpoint cluster region identified in 3 individuals with PWS who had balanced reciprocal translocations and by the proximal deletion breakpoint of a familial deletion found in an unaffected mother, her 3 children with AS, and her father. The subset of SNRPN-encoded snoRNAs within this region comprises the PWCR1/HBII-85 cluster of snoRNAs and the single HBII-438A snoRNA. These are the only known genes within this region, which suggests that loss of their expression may be responsible for much or all of the phenotype of PWS. This hypothesis is challenged by findings in 2 individuals with PWS who had balanced translocations with breakpoints upstream of the proposed minimal critical region but whose cells were reported to express transcripts within it, adjacent to these snoRNAs. By use of real-time quantitative RT-PCR, Gallagher et al. (2002) reassessed expression of these transcripts and of the snoRNAs themselves in fibroblasts of 1 of these patients. They found that the transcripts reported to be expressed in lymphoblast-somatic cell hybrids were not expressed in fibroblasts, and they suggested that the original results were misinterpreted. Most important, they showed that the PWCR1/HBII-85 snoRNAs were not expressed in fibroblasts of this individual. These results were consistent with the hypothesis that loss of expression of the snoRNAs in the proposed minimal critical region confers much or all of the phenotype of PWS. As part of studies of genomic imprinting in the Prader-Willi/Angelman domain, Tsai et al. (2002) inserted an agouti coat color cassette into the downstream open reading frame (ORF) of the Snurf-Snrpn locus in the mouse. The fusion gene was maternally silenced, as is Snurf-Snrpn, and produced a tan abdomen only when inherited paternally in otherwise black mice. A screen for dominant epigenetic or genetic events was performed with ENU mutagenesis, using a strategy whereby variation in abdominal color was scored at weaning. One mouse with maternal origin of the fusion gene had a tan abdomen and had an imprinting defect resulting in loss of both maternal methylation and silencing of the fusion gene. One mouse with paternal origin of the fusion gene was completely yellow and was found to have an ATG-to-AAG mutation in the initiation codon of the upstream ORF encoding Snurf. Northern blotting, immunoblotting, and transfection studies demonstrated that the mutation caused a 15-fold increase in translation of the downstream ORF in 2 fusion constructs, leading the authors to suggest that similar translational control may affect the normal Snurf-Snrpn transcript as well. ### REFERENCES 1. Bielinska, B.; Blaydes, S. M.; Buiting, K.; Yang, T.; Krajewska-Walasek, M.; Horsthemke, B.; Brannan, C. I. : De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch. Nature Genet. 25: 74-78, 2000. Note: Erratum: Nature Genet. 25: 241 only, 2000. PubMed ID : 10802660 2. Bressler, J.; Tsai, T.-F.; Wu, M.-Y.; Tsai, S.-F.; Ramirez, M. A.; Armstrong, D.; Beaudet, A. L. : The SNRPN promoter is not required for genomic imprinting of the Prader-Willi/Angelman domain in mice. Nature Genet. 28: 232-240, 2001. PubMed ID : 11431693 3. Buiting, K.; Saitoh, S.; Gross, S.; Dittrich, B.; Schwartz, S.; Nicholls, R. D.; Horsthemke, B. : Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nature Genet. 9: 395-400, 1995. PubMed ID : 7795645 4. Cattanach, B. M.; Barr, J. A.; Evans, E. P.; Burtenshaw, M.; Beechey, C. V.; Leff, S. E.; Brannan, C. I.; Copeland, N. G.; Jenkins, N. A.; Jones, J. : A candidate mouse model for Prader-Willi syndrome which shows an absence of Snrpn expression. Nature Genet. 2: 270-274, 1992. PubMed ID : 1303278 5. Dittrich, B.; Buiting, K.; Korn, B.; Rickard, S.; Buxton, J.; Saitoh, S.; Nicholls, R. D.; Poustka, A.; Winterpacht, A.; Zabel, B.; Horsthemke, B. : Imprint switching on human chromosome 15 may involve alternative transcripts of the SNRPN gene. Nature Genet. 14: 163-170, 1996. PubMed ID : 8841186 6. Gallagher, R. C.; Pils, B.; Albalwi, M.; Francke, U. : Evidence for the role of PWCR1/HBII-85 C/D box small nucleolar RNAs in Prader-Willi syndrome. Am. J. Hum. Genet. 71: 669-678, 2002. PubMed ID : 12154412 7. Glenn, C. C.; Porter, K. A.; Jong, M. T. C.; Nicholls, R. D.; Driscoll, D. J. : Functional imprinting and epigenetic modification of the human SNRPN gene. Hum. Molec. Genet. 2: 2001-2005, 1993. PubMed ID : 8111367 8. Gray, T. A.; Saitoh, S.; Nicholls, R. D. : An imprinted, mammalian bicistronic transcript encodes two independent proteins. Proc. Nat. Acad. Sci. 96: 5616-5621, 1999. PubMed ID : 10318933 9. Ishikawa, T.; Kibe, T.; Wada, Y. : Deletion of small nuclear ribonucleoprotein polypeptide N (SNRPN) in Prader-Willi syndrome detected by fluorescence in situ hybridization: two sibs with the typical phenotype without a cytogenetic deletion in chromosome 15q. Am. J. Med. Genet. 62: 350-352, 1996. PubMed ID : 8723064 10. Kuslich, C. D.; Kobori, J. A.; Mohapatra, G.; Gregorio-King, C.; Donlon, T. A. : Prader-Willi syndrome is caused by disruption of the SNRPN gene. Am. J. Hum. Genet. 64: 70-76, 1999. PubMed ID : 9915945 11. Leff, S. E.; Brannan, C. I.; Reed, M. L.; Ozcelik, T.; Francke, U.; Copeland, N. G.; Jenkins, N. A. : Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader-Willi syndrome region. Nature Genet. 2: 259-264, 1992. PubMed ID : 1303276 12. Li, S.; Klein, E. S.; Russo, A. F.; Simmons, D. M.; Rosenfeld, M. G. : Isolation of cDNA clones encoding small nuclear ribonucleoparticle-associated proteins with different tissue specificities. Proc. Nat. Acad. Sci. 86: 9778-9782, 1989. PubMed ID : 2532363 13. Lyko, F.; Buiting, K.; Horsthemke, B.; Paro, R. : Identification of a silencing element in the human 15q11-q13 imprinting center by using transgenic Drosophila. Proc. Nat. Acad. Sci. 95: 1698-1702, 1998. PubMed ID : 9465079 14. McAllister, G.; Amara, S. G.; Lerner, M. R. : Tissue-specific expression and cDNA cloning of small nuclear ribonucleoprotein-associated polypeptide N. Proc. Nat. Acad. Sci. 85: 5296-5300, 1988. PubMed ID : 2969109 15. Mutirangura, A.; Jayakumar, A.; Sutcliffe, J. S.; Nakao, M.; McKinney, M. J.; Buiting, K.; Horsthemke, B.; Beaudet, A. L.; Chinault, A. C.; Ledbetter, D. H. : A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11-q13) and refined localization of the SNRPN gene. Genomics 18: 546-552, 1993. PubMed ID : 8307564 16. Ozcelik, T.; Leff, S.; Robinson, W.; Donlon, T.; Lalande, M.; Sanjines, E.; Schinzel, A.; Francke, U. : Small nuclear ribonucleoprotein polypeptide N (SNRPN), an expressed gene in the Prader-Willi syndrome critical region. Nature Genet. 2: 265-269, 1992. PubMed ID : 1303277 17. Reed, M. L.; Leff, S. E. : Maternal imprinting of human SNRPN, a gene deleted in Prader-Willi syndrome. Nature Genet. 6: 163-167, 1994. PubMed ID : 7512861 18. Saitoh, S.; Wada, T. : Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome. Am. J. Hum. Genet. 66: 1958-1962, 2000. PubMed ID : 10775525 19. Schmauss, C.; McAllister, G.; Ohosone, Y.; Hardin, J. A.; Lerner, M. R. : A comparison of snRNP-associated Sm-autoantigens: human N, rat N and human B/B-prime. Nucleic Acids Res. 17: 1733-1743, 1989. PubMed ID : 2522186 20. Schulze, A.; Hansen, C.; Skakkebaek, N. E.; Brondum-Nielsen, K.; Ledbetter, D. H.; Tommerup, N. : Exclusion of SNRPN as a major determinant of Prader-Willi syndrome by a translocation breakpoint. Nature Genet. 12: 452-454, 1996. PubMed ID : 8630505 21. Schweizer, J.; Zynger, D.; Francke, U. : In vivo nuclease hypersensitivity studies reveal multiple sites of parental origin-dependent differential chromatin conformation in the 150 kb SNRPN transcription unit. Hum. Molec. Genet. 8: 555-566, 1999. PubMed ID : 10072422 22. Shemer, R.; Hershko, A. Y.; Perk, J.; Mostoslavsky, R.; Tsuberi, B.; Cedar, H.; Buiting, K.; Razin, A. : The imprinting box of the Prader-Willi/Angelman syndrome domain. Nature Genet. 26: 440-443, 2000. PubMed ID : 11101841 23. Sun, Y.; Nicholls, R. D.; Butler, M. G.; Saitoh, S.; Hainline, B. E.; Palmer, C. G. : Breakage in the SNRPN locus in a balanced 46,XY,t(15;19) Prader-Willi syndrome patient. Hum. Molec. Genet. 5: 517-524, 1996. PubMed ID : 8845846 24. Sutcliffe, J. S.; Nakao, M.; Christian, S.; Orstavik, K. H.; Tommerup, N.; Ledbetter, D. H.; Beaudet, A. L. : Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nature Genet. 8: 52-58, 1994. PubMed ID : 7987392 25. Tsai, T.-F.; Chen, K.-S.; Weber, J. S.; Justice, M. J.; Beaudet, A. L. : Evidence for translational regulation of the imprinted Snurf-Snrpn locus in mice. Hum. Molec. Genet. 11: 1659-1668, 2002. PubMed ID : 12075010 26. Wirth, J.; Back, E.; Huttenhofer, A.; Nothwang, H.-G.; Lich, C.; Gross, S.; Menzel, C,; Schinzel, A.; Kioschis, P.; Tommerup, N.; Ropers, H.-H.; Horsthemke, B.; Buiting, K. : A translocation breakpoint cluster disrupts the newly defined 3-prime end of the SNURF-SNRPN transcription unit on chromosome 15. Hum. Molec. Genet. 10: 201-210, 2001. PubMed ID : 11159938 ### CONTRIBUTORS George E. Tiller - updated : 6/2/2003 Victor A. McKusick - updated : 10/7/2002 Victor A. McKusick - updated : 6/25/2001 George E. Tiller - updated : 4/17/2001 Victor A. McKusick - updated : 7/26/2000 Ada Hamosh - updated : 4/28/2000 Victor A. McKusick - updated : 6/2/1999 Victor A. McKusick - updated : 5/14/1999 Victor A. McKusick - updated : 2/8/1999 Victor A. McKusick - updated : 3/5/1998 Moyra Smith - updated : 10/2/1996 Moyra Smith - updated : 5/14/1996 ### CREATION DATE Victor A. McKusick : 1/26/1993 ### EDIT HISTORY cwells : 6/2/2003 carol : 10/7/2002 tkritzer : 10/7/2002 alopez : 6/28/2001 terry : 6/25/2001 cwells : 4/26/2001 cwells : 4/20/2001 cwells : 4/17/2001 cwells : 4/17/2001 carol : 11/28/2000 terry : 11/22/2000 terry : 11/22/2000 carol : 8/1/2000 terry : 7/26/2000 alopez : 6/9/2000 alopez : 5/1/2000 terry : 4/28/2000 mgross : 10/21/1999 carol : 6/8/1999 jlewis : 6/8/1999 jlewis : 6/8/1999 terry : 6/2/1999 mgross : 5/25/1999 mgross : 5/19/1999 terry : 5/14/1999 carol : 2/14/1999 terry : 2/8/1999 alopez : 3/24/1998 terry : 3/5/1998 terry : 7/7/1997 mark : 11/7/1996 terry : 10/3/1996 terry : 10/2/1996 mark : 10/2/1996 mark : 8/14/1996 carol : 5/14/1996 terry : 4/19/1996 mark : 4/9/1996 terry : 4/5/1996 mimadm : 3/25/1995 terry : 5/5/1994 carol : 3/11/1994 carol : 1/26/1993 Copyright © 1966-2005 Johns Hopkins University
2: | #176270 | GeneTests, Links
| PRADER-WILLI SYNDROME; PWS
#### Alternative titles; symbols PRADER-LABHART-WILLI SYNDROME PRADER-WILLI SYNDROME CHROMOSOME REGION, INCLUDED; PWCR, INCLUDED PRADER-WILLI-LIKE SYNDROME ASSOCIATED WITH CHROMOSOME 6, INCLUDED ### TABLE OF CONTENTS #### DESCRIPTION CLINICAL FEATURES INHERITANCE CYTOGENETICS MAPPING MOLECULAR GENETICS DIAGNOSIS CLINICAL MANAGEMENT POPULATION GENETICS ANIMAL MODEL HISTORY SEE ALSO REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Clinical Synopsis Gene map locus 15q12, 15q11-q13, 15q11 ### TEXT #### DESCRIPTION A number sign (#) is used with this entry because of evidence that Prader-Willi syndrome is in effect a contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN gene (182279), the necdin gene (602117), and possibly other genes. The Prader-Willi syndrome (PWS) is characterized by diminished fetal activity, obesity, muscular hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, and small hands and feet. It can be considered to be an autosomal dominant disorder and is caused by deletion or disruption of a gene or several genes on the proximal long arm of the paternal chromosome 15 or maternal uniparental disomy 15, because the gene(s) on the maternal chromosome(s) 15 are virtually inactive through imprinting. #### CLINICAL FEATURES The original paper by Prader et al. (1956) described the full clinical picture. #### Prenatal Mothers with prior experience of normal pregnancies almost without exception report distinctly delayed onset and reduced fetal activity during the pregnancies involving Prader-Willi children. Obstetricians often fail to detect diminished fetal activity with ultrasound investigation. When reduced fetal activity is observed, prenatal cytogenetic examination produces normal results because cytogeneticists were not instructed to look for the characteristic chromosomal changes of PWS (Schinzel, 1986). Alert clinicians should refer CVS material from pregnancies with fetuses that demonstrate poor activity for molecular diagnosis of the syndrome (see below). Other candidates for prenatal diagnosis of PWS are fetuses of pregnancies in which trisomy 15 or mosaic trisomy 15 was determined from CVS, and in which subsequent amniocyte or fetal blood examinations disclosed a normal diploid karyotype. Theoretically, one-third of trisomy 15 fetuses initially with 2 maternal chromosomes 15 and 1 paternal chromosome 15 should give rise to Prader-Willi syndrome patients exhibiting maternal uniparental disomy(Cassidy et al., 1992; Purvis-Smith et al., 1992; Hall, 1992). #### Perinatal Neonates are profoundly hypotonic, which often causes asphyxia. In addition, there is mild prenatal growth retardation with a mean birth weight of about 6 lbs (2.8 kg) at term, hyporeflexia, poor feeding due to diminished swallowing and sucking reflexes, which in many cases necessitates gavage feeding for about 3 to 4 months. Cryptorchidism occurs with hypoplastic penis and scrotum in boys and hypoplastic labiae in girls (Stephenson, 1980). Chitayat et al. (1989) commented on the normal size of hands and feet at birth and in the first year of life. Miller et al. (1999) described 6 newborns evaluated for hypotonia who were later diagnosed with Prader-Willi syndrome. These newborns lacked the classic neonatal features of the syndrome (peculiar cry, characteristic craniofacial features, and clinical evidence of hypogonadism). The authors suggested that specific genetic testing for PWS be considered for all neonates with undiagnosed central hypotonia even in the absence of the other major features of the syndrome. #### Infancy and Childhood Feeding difficulties generally improve by the age of 6 months. From 12 to 18 months onward, uncontrollable hyperphagia causes major somatic as well as psychologic problems. Diminished growth is observed in the majority of infants (Butler and Meaney, 1987). Small hands with delicate and tapering fingers and small feet (acromicria) are seen in most infants and adolescents; hand and foot sizes correlate well with length, but not with age, and foot size tends to be lower than hand size. However, patients of normal height tend to have normally sized hands (Hudgins and Cassidy, 1991). The face is characterized by a narrow bifrontal diameter, almond-shaped eyes (often in mild upslanted position), strabismus, full cheeks, and diminished mimic activity due to muscular hypotonia. Plethoric obesity becomes the most striking feature. From the age of about 6 years onward, many children present scars from scratching due to itching, and later, almost all show abdominal striae. Depigmentation relative to the familial background is a feature in about three-quarters of the patients. Butler (1989), Hittner et al. (1982), and several authors remarked that this sign is confined to cases with deletions and absent in those with maternal disomy 15. Phelan et al. (1988) presented a black female child with oculocutaneous albinism, PWS, and an interstitial deletion of 15q11.2. Patients with classic albinism (203100) have misrouting of optic fibers, with fibers from 20 degrees or more of the temporal retina crossing at the chiasm instead of projecting to the ipsilateral hemisphere. Misrouting can result in strabismus and nystagmus. Because patients with PWS have hypopigmentation and strabismus, Creel et al. (1986) studied 6 patients, selected for a history of strabismus, with pattern-onset visually evoked potentials on binocular and monocular stimulation. Of the 4 with hypopigmentation, 3 had abnormal evoked potentials indistinguishable from those recorded in albinos. The 2 with normal pigmentation had normal responses. Wiesner et al. (1987) found that 14 of 29 patients with PWS had ocular hypopigmentation. There was possible correlation between hypopigmentation and a deletion of 15q. MacMillan et al. (1972) described 2 unrelated girls with the features of PWS who additionally showed precocious puberty. They suggested that this is a variant and that a hypothalamic disturbance is responsible for this disorder. Hall and Smith (1972) pointed out narrow bifrontal cranial diameter as a feature. Hall (1985) pointed to a possibly increased risk of leukemia in PWS. A frequent feature generally overlooked is thick saliva at the edges of the mouth. Patients tend to be relatively insensitive to pain (including that caused by obtaining blood samples)(Prader, 1991). Eiholzer et al. (1999) presented data on body composition and leptin (164160) levels of 13 young, still underweight children and 10 older overweight children with Prader-Willi syndrome. Both groups showed elevated skinfold standard deviation scores for body mass index and elevated body mass index-adjusted leptin levels, suggesting relatively increased body fat even in underweight children. Leptin production appeared to be intact. The authors concluded that body composition in PWS is already disturbed in infancy, long before the development of obesity. Van Mil et al. (2001) compared body composition in 17 patients with PWS with 17 obese control patients matched for gender and bone age. In children with PWS, adiposity was associated with reduced fat-free mass, and extracellular-to-intracellular water ratio was increased. Both findings are related to growth hormone (GH; 139250) function and physical activity. Bone mineral density, especially in the limbs, tends to be reduced in patients with PWS and is related to growth hormone function. Gunay-Aygun et al. (2001) reviewed the sensitivity of PWS diagnostic criteria and proposed revised criteria for DNA testing. From birth to 2 years any infant with hypotonia and poor suck should have DNA testing for the PWS deletion. From age 2 to 6 years any child with hypotonia and a history of poor suck and global developmental delay should have DNA testing. From 6 years to 12 years any child with history of hypotonia and poor suck, global developmental delay, and excessive eating with central obesity should be tested for PWS. #### Adolescence and Adulthood Greenswag (1987) reported on a survey of 232 adults with PWS, ranging in age from 16 to 64 years. Of 106 patients whose chromosomes were analyzed, 54 had an abnormality of chromosome 15, primarily a deletion. Physical characteristics, health problems, intelligence, psychosocial adjustment, and impact on the family were reviewed. Emotional lability, poor gross motor skills, cognitive impairment, and insatiable hunger were especially remarkable features. Olander et al. (2000) pointed to the occurrence of 3 PWS phenotypes: patients with paternal deletions have the typical PWS phenotype; patients with maternal UPD have a slightly milder phenotype with better cognitive function; and patients with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. They described a patient with the severe phenotype with maternal isodisomy rather than the more common maternal heterodisomy. They concluded that the more severe PWS phenotype was due to trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. In contrast to infants, adults invariably are small compared to their family members (Butler and Meaney, 1987). Due to high caloric intake, alimentary diabetes frequently sets in during or soon after the period of puberty. Puberty itself is diminished in PWS patients of both sexes. Adolescents and young adults often require digitalization because of cardiac insufficiency; however, it has been shown that substantial weight reduction relieves the need of cardiac therapy. Any attempt to reduce food intake in these adolescents often leads to serious psychologic and behavioral problems, and in some children, the situation in their home environment becomes intolerable (Curfs et al., 1991). Patients rarely survive beyond 25 to 30 years of age, the cause of death being diabetes and cardiac failure. However, if strict weight control is achieved, both diabetes and cardiac failure are greatly reduced and survival is either not or only mildly reduced. Johnsen et al. (1967) studied 7 mentally retarded patients, aged 4 to 19 years. Studies showed that fat synthesis from acetate during fasting was 10 times greater in patients than in unaffected sibs, and that hormone-stimulated lipolysis was depressed. These workers suggested that the condition is comparable to the genetic obese-hyperglycemic mouse. Since during fasting substrate continues to be used for new fat and lipolysis is deficient, survival depends on a continuous supply of exogenous calories. The abundant fat, muscle hypotonia, and small feet and hands are exactly the opposite of the sparse fat, muscle hypertrophy, and large hands and feet in Seip syndrome (269700). Hoybye et al. (2002) studied the clinical, genetic, endocrinologic, and metabolic findings in 10 male and 9 female adult PWS patients (mean age, 25 years). The PWS karyotype was demonstrated in 13 patients. The mean BMI was 35.6 kg/m2, and total body fat was increased. Two-thirds were biochemically hypogonadal. Fifty percent had severe GH deficiency. Four were hypertensive. One patient had heart failure and diabetes. Impaired glucose tolerance was seen in 4 patients, elevated homeostasis model assessment index in 9, and modest dyslipidemia in 7. IGF-binding protein-1 (146730) correlated negatively with insulin (176730) levels. Four patients had osteoporosis, and 11 had osteopenia. There was no significant difference between the group with the PWS karyotype and the group without the karyotype in age, BMI, waist-to-hip ratio, percent body fat, insulin values, homeostasis model assessment index, or lipid profile, except for lipoprotein(a) (152200), which was significantly higher in the group with the negative karyotype. Hoybye et al. (2002) concluded that the risk factors found predicting cardiovascular disease were secondary to GHD and emphasized the importance of evaluating treatment of GHD in adults with PWS. Curfs et al. (1991) concluded that PWS patients score better on visual motor discrimination skills than on auditory verbal processing skills. Wise et al. (1991) described 5 patients with PWS who experienced recurrent hyperthermia in infancy. On the basis of these patients and other reports of abnormal temperature regulation in PWS patients, particularly hypothermia with exposure to cold, they concluded that defects in temperature regulation may be a manifestation of hypothalamic dysfunction in PWS. On the other hand, Cassidy and McKillop (1991) concluded on the basis of a survey that clinically significant abnormal temperature control is not a common finding in this disorder. Similarly, Williams et al. (1994) concluded on the basis of a survey that the prevalence of febrile convulsions, fever-associated symptoms, and temperature less than 94 degrees F were not unique to PWS but can occur in any neurodevelopmentally handicapped individual and do not necessarily reflect syndrome-specific hypothalamic abnormalities. Individuals with Prader-Willi syndrome manifest severe skin picking behavior. Bhargava et al. (1996) described 3 adolescent patients in whom an extension of this behavior to rectal picking resulted in significant lower gastrointestinal bleeding and anal rectal disease. Recognition of this behavior is important to avoid misdiagnosing inflammatory bowel disease in PWS patients. Wharton et al. (1997) presented 6 patients with PWS with dramatic acute gastric distention. In 3 young adult women with vomiting and apparent gastroenteritis, clinical course progressed rapidly to massive gastric dilatation and gastric necrosis. One patient died of overwhelming sepsis and disseminated intravascular coagulation. In 2 children, gastric dilatation resolved spontaneously. Gastrectomy was performed in 2 cases; in 1, gastrectomy was subtotal and distal, whereas in the other, gastrectomy was combined with partial duodenectomy and pancreatectomy. All specimens showed ischemic gastroenteritis. There was diffuse mucosal infarction with multifocal transmural necrosis. From a study of 10 African Americans with PWS, Hudgins et al. (1998) pointed out that the clinical features differ from those of white patients. Growth is less affected, hand and foot lengths usually are normal, and the facies are atypical; as a result, PWS may be underdiagnosed in this population. Lindgren et al. (2000) studied the microstructure of eating behavior in patients with PWS and compared it with that of members of obese and normal weight control groups of the same age. PWS patients had a mean age of 10 +/- 4 years, while the control groups were 12 +/- 3 years (normal weight) and 12 +/- 4 years (obese). Subjects with PWS had a longer duration of eating rate compared with members of both obese and normal weight groups. In subjects with PWS, 56% of the eating curves were non-decelerating, compared with 10% of the normal weight group and 30% of the obese group. Lindgren et al. (2000) concluded that the eating behavior found in subjects with PWS might be due to decreased satiation rather than increased hunger. Nagai et al. (2000) reported standard growth curves for height and weight among Japanese children with Prader-Willi syndrome. No difference in height was seen between those with and those without chromosome 15q deletion. Cassidy et al. (1997) personally examined and studied using molecular techniques 54 individuals with PWS to determine whether there are phenotypic differences between patients with the syndrome due to deletion (present in 37) or uniparental disomy (present in 17) as the mechanism. Previously recognized increased maternal age in patients with UPD and increased frequency of hypopigmentation in those with deletion were confirmed. Although the frequency and severity of most other manifestations of PWS did not differ significantly between the 2 groups, those with UPD were less likely to have a 'typical' facial appearance. In addition, this group was less likely to show some of the minor manifestations such as skin picking, skill with jigsaw puzzles, and high pain threshold. Females and those with UPD were also older, on average. Gunay-Aygun et al. (2001) proposed new revised criteria for DNA testing for individuals in adolescence and adulthood. Anyone with cognitive impairment (usually mild mental retardation), excessive eating with central obesity, and hypothalamic hypogonadism, and/or typical behaviors, including temper tantrums and obsessive-compulsive features, should be referred for DNA testing for PWS. Among 25 patients with PWS aged 18 years or older, Boer et al. (2002) found that 7 (28%) had severe affective disorder with psychotic features, with a mean age of onset of 26 years. The 7 affected persons, all aged 28 years or older, included all 5 with disomies of chromosome 15, 1 with a deletion in this chromosome, and 1 with an imprinting center mutation in the same chromosome. They postulated that in PWS, an abnormal pattern of expression of a sex-specific imprinted gene on chromosome 15 is associated with psychotic illness in early adult life. Vogels et al. (2004) detailed the psychopathologic manifestations of 6 adults with PWS and a history of psychotic episodes. Characteristics of the psychotic disorder included early and acute onset, polymorphous and shifting symptoms, psychiatric hospitalization along with precipitating stress factors, and a prodromal phase of physiologic symptoms. To evaluate the risk of cancer in patients with PWS, Davies et al. (2003) conducted a retrospective questionnaire survey of its occurrence among patients registered with the PWS Association compared with cases in the general US population based on the SEER program. The median age of 1,024 PWS patients was 19.0 years (range, 0.1-63 years) with 2 older than age 50. The ratio of observed (8) to expected (4.8) cancers was 1.67 (p = 0.1610; 95% CI = 0.72-3.28). Three myeloid leukemias were confirmed, resulting in a ratio of observed to expected of 40.18 (p = 0.0001; 95% CI = 8.0-117). The authors speculated that a gene within the 15q11-q13 region may be involved in the biology of myeloid leukemia or that secondary manifestations of PWS, such as obesity, may be associated with an increased risk of certain cancers. Wey et al. (2005) described a woman with features consistent with PWS due to a mosaic imprinting defect. Three independent assays revealed a reduced proportion of nonmethylated SNURF-SNRPN alleles in peripheral blood DNA. Microsatellite analysis and FISH revealed apparently normal chromosomes 15 of biparental origin. Wey et al. (2005) estimated that approximately 50% of the patient's blood cells had an imprinting defect. Apart from a rather normal facial appearance, the proband had typical features of PWS in terms of truncal obesity, small hands with tapered fingers, and small feet. Operation for strabismus had been performed. When evaluated at 21 years of age, she presented with the major signs of PWS, except for the relatively normal facial appearance. Wey et al. (2005) suggested that the patient, although presenting with atypical PWS features at birth and in infancy, had progressively acquired more pronounced PWS features during childhood and adolescence. #### Prader-Willi-like Syndrome Associated with Chromosome 6 Fryns et al. (1986) described an 8-month-old girl with a de novo 5q/6q autosomal translocation resulting in loss of the distal part of the long arm of chromosome 6 (6q23.3-qter). Clinical manifestations included abnormal facies with broad, flat nasal bridge, small nose with broad tip, bilateral epicanthus, narrow palpebral fissures, small anteverted ears, and small mouth. Other features included truncal obesity, short hands and feet, and delayed psychomotor development. Prader-Willi syndrome was suspected initially. Villa et al. (1995) reported a 23-month-old boy with mental and psychomotor delay, minor craniofacial abnormalities, and obesity who had a de novo interstitial deletion of chromosome 6q16.2-q21. The authors noted the phenotypic similarities to Prader-Willi syndrome. In a boy with clinical features mimicking Prader-Willi syndrome, but with a normal chromosome 15, Stein et al. (1996) found a de novo interstitial deletion of 6q22.2-q23.1. The boy showed delayed development, hypotonia, seizures, hyperactive behavior, a bicuspid aortic valve with mild aortic stenosis, small hands and feet, hypogonadism, and obesity since about 4 years of age. In a 38-year-old man with moderate to severe intellectual delay, short stature, small hands and feet, small mouth, and obesity, Smith et al. (1999) found a duplication of 6q24.3-q27. The authors noted that the phenotype showed similarities to Prader-Willi syndrome. As reviewed by Gilhuis et al. (2000), several obese patients with cytogenetic alterations in the same region of 6q had been reported; all had in common some clinical features, including obesity, hypotonia, and developmental delays, resembling Prader-Willi syndrome. However, their behavior, facial features, and additional neurologic abnormalities, as well as a lack of cytogenetic changes or imprinting mutations on chromosome 15, clearly distinguished this PWS-like phenotype from PWS patients. Holder et al. (2000) studied a girl with early-onset obesity and a balanced translocation between 1p22.1 and 6q16.2. At 67 months of age she weighed 47.5 kg (+9.3 SD) and was 127.2 cm tall (+3.2 SD); her weight for height was +6.3 SD. The child displayed an aggressive, voracious appetite, and the obesity was thought to be due to high intake, since measured energy expenditure was normal. However, the authors noted that apart from her obesity, there were no features suggestive of PWS. Genetic analysis of the region on chromosome 6 showed that the translocation disrupted the SIM1 gene (603128). Holder et al. (2000) hypothesized that haploinsufficiency of the SIM1 gene may be responsible for the obesity. In a boy with a Prader-Willi-like phenotype, Faivre et al. (2002) identified a deletion of chromosome 6q16.1-q21. Intrauterine growth retardation, oligohydramnios, and a left clubfoot were noted during the third trimester of pregnancy. Later, generalized obesity, slightly dysmorphic facial features, small hands and feet, clumsiness, and mental retardation were observed. Molecular analysis showed that the deletion was paternal in origin and resulted in a deletion of the SIM1 gene. #### INHERITANCE Familial inheritance of PWS has been described frequently. Gabilan (1962) reported a family with affected brother and sister, as well as a second in which the parents of the proband were first cousins, but his patients were not entirely typical. Jancar (1971) reported familial incidence. Hall and Smith (1972) reported 2 affected male maternal first cousins. One was of normal stature and intelligence. DeFraites et al. (1975) observed 5 cases in 3 sibships of an inbred Louisiana Acadian kindred. Clarren and Smith (1977) reported affected sibs and affected first cousins. They found a recurrence risk of 1.6% in sibs of probands. It is clear that chromosomal mechanisms are principally responsible for PWS and that the syndrome is caused by lack of the paternal segment 15q11.2-q12. Basically, there are 2 mechanisms by which such a loss can occur: either through deletion of just the paternal 'critical' segment or through loss of the entire paternal chromosome 15 with presence of 2 maternal homologs (uniparental maternal disomy). The opposite, i.e., maternal deletion or paternal uniparental disomy, causes another characteristic phenotype, the Angelman syndrome (AS; 105830). This indicates that both parental chromosomes are differentially imprinted, and that both are necessary for normal embryonic development. Ming et al. (2000) described 2 cousins with Prader-Willi syndrome resulting from a submicroscopic deletion detected by fluorescence in situ hybridization. Although the karyotype was cytogenetically normal, FISH analysis showed a submicroscopic deletion of SNRPN (182279), but not the closely associated loci D15S10, D15S11, D15S63, and GABRB3 (137192). The affected female and male were offspring of brothers who carried the deletion but were clinically normal, as were also 2 paternal aunts of the probands who likewise had the deletion. The grandmother was deceased and not available for study; the grandfather did not show deletion of SNRPN. DNA methylation analysis of D15S63 was consistent with an abnormality of the imprinting center associated with PWS. Ming et al. (2000) referred to this as grandmatrilineal inheritance, which occurs when a woman with deletion of an imprinted, paternally expressed gene is at risk of having affected grandchildren through her sons. In such an instance, PWS does not become evident as long as the deletion is passed through the female line. #### Occurrence of the Prader-Willi Syndrome The vast majority of PWS cases occur sporadically. These instances include virtually all interstitial deletions, the large majority of de novo unbalanced translocations, all instances of maternal uniparental disomy with normal karyotype or with a de novo rearrangement involving chromosome 15, and almost all cases of maternal uniparental disomy with a familial rearrangement involving chromosome 15. There is no parental age effect whatsoever in the deletion cases. For full discussion on the mode of inheritance, see Cytogenetics, below. #### Recurrence Risk Monozygotic twins are concordantly affected. However, affected siblings and cousins have repeatedly been reported, and even if a publication bias is considered, their incidence is obviously higher than the estimated incidence in the population of about 1 in 25,000 would suggest. Clarren and Smith (1977) reported affected sibs and first cousins. They found a recurrence risk of 1.6% in sibs of probands. Cassidy (1987) stated that the Prader-Willi Syndrome Association maintained a registry of PWS individuals which, as of December 1986, contained 1,595 names of affected persons in the United States and Canada. While in some of these cases the diagnosis had not been fully confirmed, in only 1 family, that reported by Lubinsky et al. (1987), was there a well-documented recurrence. Thus, it is reasonable to assume that the recurrence risk for PWS is less than 1 in 1,000 and that such recurrence is not likely to occur when a 15q interstitial deletion is identified in the proband. (As pointed out by Kennerknecht (1992), the membership of the PWS association is not limited to affected persons; 'two thirds are families and one third professionals'.) Ledbetter et al. (1987) summarized a scientific conference on PWS. Of 195 cases studied by high resolution cytogenetic methods, deletion of chromosome 15 was detected in 116 (59.5%); other chromosome 15 abnormalities were found in 7 additional cases (3.6%). It was suggested that the recurrence risk may be as low as 1 in 1,000. Kennerknecht (1992) used the diagnostic criteria given by Cassidy (1987) to evaluate reported cases of PWS with a view to estimating recurrence risk. Since a deletion at 15q has not been found in familial cases of PWS, except in those where del(15q) is due to familial structural chromosome rearrangement, the recurrence risk with de novo deletion should be nearly zero. In cases with familial translocation, risk estimates depend on the nature of the translocations concerned. If only 1 child is affected and the karyotype is apparently normal, Kennerknecht (1992) estimated an overall recurrence risk of 0.4%. However, if 2 or more sibs are affected, he estimated that the risk to the next sib would be 50%. If every proband were investigated cytogenetically (to ascertain unbalanced chromosome rearrangements), molecularly (with probes to detect invisible deletions and to determine the methylation pattern), and if in each instance of a paternal deletion an examination of the father was carried out, then the few instances with a high recurrence risk could be ascertained before a second child was born. #### Mutagenic Factors Strakowski and Butler (1987) found an increased incidence of paternal periconceptional employment in hydrocarbon-exposing occupations. Among 81 patients with PWS, Cassidy et al. (1989) compared the frequency of possible periconceptional occupational hydrocarbon exposure in those fathers who demonstrated a 15q deletion with the frequency in those who did not. There was no statistically significant difference between the cytogenetically different groups. In both groups, approximately half the fathers had been employed in hydrocarbon-exposing jobs. The data provided additional support for the possibility that hydrocarbon exposure is causally related to the disorder and further suggested lack of etiologic heterogeneity between the cytogenetically different groups. #### CYTOGENETICS Deletions account for 70 to 80% of cases; the majority are interstitial deletions, many of which can be visualized by prometaphase banding examination. A minority consist of unbalanced translocations, mostly de novo, which are easily detected by routine chromosome examination. The remainder of cases are the result of maternal uniparental disomy. In most of these latter cases, cytogenetic examinations yield normal results. However, in a few cases, either balanced translocations, familial or de novo, or supernumerary small marker chromosomes, are observed. #### Deletions Butler et al. (1986) found an interstitial deletion of chromosome 15 (breakpoints q11 and q13) in 21 of 39 cases and an apparently normal karyotype in the remainder. By studying chromosome 15 heteromorphisms, the del(15q) was demonstrably paternal in origin in all cases, although both parents were normal and all deletions were de novo events. Paternal age was not increased. The exclusively paternal origin of deletions was subsequently confirmed cytogenetically and by molecular marker analysis (Magenis et al., 1990; Zori et al., 1990; Robinson et al., 1991). Examination of other series of patients by different groups resulted in the figures that two-thirds to three-fourths of PWS patients have a deletion of 15q11-q13. In less than 10%, this is due to an unbalanced translocation while the remainder have interstitial deletions. To analyze the mechanism underlying the interstitial de novo deletions at 15q11-q13 that underlie approximately 70% of PWS cases, Carrozzo et al. (1997) genotyped 10 3-generation families of PWS-deletion patients using microsatellite markers flanking the common deletion region. By FISH and/or other molecular techniques, each patient was known to be deleted for the interval from D15S11 to GABRB3. In 5 of 7 cases, a different grandparental origin was identified for the alleles flanking the deletion, a finding significantly different from the expected frequency in light of the close position of the markers. This finding was considered highly suggestive of an unequal crossover occurring in the paternal meiosis at the breakpoint as the mechanism leading to deletion. The authors noted that asymmetric exchanges between nonsister chromatids in meiosis I have previously been demonstrated and are the basis of a number of genetic diseases. When the related sequences are part of tandemly arrayed homologous genes, nonhomologous recombination may lead to the formation of chimeric genes, such as those of Lapore hemoglobin and of the red-green pigment genes involved in abnormalities of color vision. In other instances, the deletion/duplication event may arise from the unequal recombination between repetitive elements interspersed throughout a genomic region. A misalignment between Alu-repetitive sequences has been demonstrated in duplications of the LDL-receptor gene (606945; Lehrman et al., 1987) and the HPRT gene (308000; Marcus et al., 1993). Duplications of 15q11-q13 have been reported in only a few instances (Clayton-Smith et al., 1993), and it is unclear whether any of these represent the reciprocal event of deletion by unequal crossingover. The paucity of duplication cases compared with deletions of this region may mean that the duplications occur much less frequently or that a milder phenotype causes them to be ascertained much less often. In 2 PWS families studied by Carrozzo et al. (1997), the data were consistent with an intrachromosomal mechanism being responsible for the deletion. One of the few precedents for intrachromosomal recombination leading to human disease is provided by the recombination that occurs between the small intronless gene within intron 22 of the factor VIII gene (306700), and a copy of gene A (FSA; 305423) located 500 kb telomeric to the F8 gene, a recombination that causes severe hemophilia (Lakich et al., 1993). This rearrangement arises almost exclusively in male meioses, indicating that it is intrachromosomal. Carrozzo et al. (1997) suggested that the in-cis mechanism leading to the deletions in PWS patients may be related either to an exchange of chromosomal material between sister chromatids or to the formation of an intrachromosomal loop, either during meiosis or as a somatic event, followed by an excision of the chromosomal material lying between the recombining regions. #### Maternal Uniparental Disomy Nicholls et al. (1989), studying cases of PWS in which no deletion was cytologically evident using RFLP analysis, were the first to demonstrate maternal uniparental disomy (UPD) in 2 families. Two different, apparently intact, maternal chromosomes were present ('heterodisomy'), and, as with deletion cases of PWS, there was an absence of paternal genes from the 15q11-q13 segment. Robinson et al. (1991) used cytogenetic and molecular techniques to examine 37 patients with features of PWS. Clinical features in 28 of the patients were thought to fulfill diagnostic criteria for typical PWS. In 21 of these, a deletion of the 15q11.2-q12 region could be identified molecularly, including several cases in which the cytogenetic results were inconclusive. Five cases of maternal heterodisomy and 2 of isodisomy for 15q11-q13 were observed. All 9 patients who did not fulfill clinical criteria for typical PWS showed normal maternal and paternal inheritance of chromosome 15 markers; however, one of these carried a ring-15 chromosome. Thus, all typical PWS cases showed either a deletion or maternal uniparental disomy of 15q11.2-q12. As the disomy patients did not show any additional or more severe features than did the typical deletion patients, it is likely that there is only one imprinted region on chromosome 15. A significantly increased mean maternal age was found in the disomy cases, suggesting an association between increased maternal age and nondisjunction. Mascari et al. (1992) demonstrated maternal uniparental disomy for chromosome 15 in 18 of 30 patients (60%) without a cytogenetic deletion. Furthermore, they confirmed the observation of Robinson et al. (1991) that the phenomenon was associated with advanced maternal age. In another 8 patients (27%), they identified large molecular deletions. The remaining 4 patients (13%) had evidence of normal biparental inheritance for chromosome 15; 3 of these patients were the only ones in the study which had some atypical clinical features. All told, they estimated that about 20% of cases of PWS result from maternal uniparental disomy and that, by the combined use of cytogenetic and molecular techniques, the genetic basis of PWS can be identified in at least 95% of patients. Mitchell et al. (1996) compared 79 cases of PWS with UPD and 43 cases with deletions. Although there were no major clinical differences between the 2 classes of patients analyzed as a whole, mean maternal and paternal age were significantly higher in the UPD patients. The UPD group had a predominance of males, yet a gender bias was not seen in the deletion group. Hypopigmentation was found in 77% of the deletion group compared to only 39% of the UPD children. When the groups were analyzed by gender, females with UPD tended to be less severely affected than female deletion patients. Mutirangura et al. (1993) demonstrated maternal heterodisomy in 10 PWS patients. Since the markers used were 13 cM from the centromere, heterodisomy indicated that maternal meiosis I nondisjunction was primarily involved in the origin of UPD. In contrast, 2 paternal disomy cases of Angelman syndrome (AS) showed isodisomy for all markers tested along the length of chromosome 15. This suggested a paternal meiosis II nondisjunction event (without crossing over) or, more likely, monosomic conception (due to maternal nondisjunction) followed by chromosome duplication. The latter mechanism would indicate that at least some instances of uniparental disomy in PWS and AS initiate as reciprocal products of maternal nondisjunction events. Robinson et al. (1993) reported data indicating that the majority (82%) of maternal nondisjunction events leading to UPD and causing PWS involve a meiosis I error, whereas most paternal UPD Angelman syndrome cases are meiosis II or, more likely, mitotic errors. Robinson et al. (1993) made the interesting statement that the proportion of UPD cases among all PWS patients in Switzerland is higher than in the United States, which could reflect the higher mean maternal age at birth in Switzerland versus the United States. #### Rescuing of Trisomy 15 Maternal nondisjunction does not itself directly lead to uniparental disomy but must also involve a further nondisjunction event to produce a euploid embryo. Purvis-Smith et al. (1992) have confirmed such an origin of uniparental disomy 15 resulting from 'correction' of an initial trisomy 15. Routine chorionic villus sampling performed for advanced maternal age led to detection of placental mosaicism for trisomy 15. Follow-up studies on amniotic fluid indicated a normal 46,XY karyotype with no evidence of trisomy 15, and the pregnancy continued to term. At birth, the baby was found to have PWS. Molecular analysis indicated that the mother was the sole contributor of the chromosome 15 pair in the child. Centromere/short-arm heteromorphisms were different in the 2 chromosome 15 homologs, consistent with meiosis I error. Cassidy et al. (1992) reported a similar case that supported the idea that maternal disomy can result from a 'corrected' trisomy 15 and that maternal age was a predisposing factor to nondisjunction. Thus, in any case in which trisomy or mosaic trisomy 15 has been prenatally determined through CVS examination, a molecular study should follow to exclude uniparental (paternal or) maternal disomy. This type of examination should also be considered in case of pregnancies of translocation carrier parents involving chromosome 15. Devriendt et al. (1997) proposed partial zygotic trisomy rescue as a mechanism for mosaicism for a de novo jumping translocation of distal chromosome 15q, resulting in partial trisomy for 15q24-qter in a patient with PWS. A maternal uniparental heterodisomy for chromosome 15 was present in all cells and was responsible for the PWS phenotype. The translocated 15q segment was of paternal origin and was present as a jumping translocation, involving chromosomes 14q, 4q, and 16p. The recipient chromosomes were cytogenetically intact. Devriendt et al. (1997) reported that mental retardation was more marked in their patient than is usually observed in PWS, and proposed that this was due to partial trisomy for distal 15q. #### Multiple Affected Relatives There are several mechanisms that explain the simultaneous occurrence of affected first- and second-degree relatives in PWS families. These include translocations that give rise to maternal nondisjunction and hence effective maternal uniparental disomy for the PWS region and translocations which give rise to paternally derived deletions. The first report of involvement of a D group translocation in PWS (later identified as a 15-15 translocation) dates back to 1963 (Buehler et al., 1963). Additional translocations were found subsequently, and after the introduction of chromosome banding it became obvious that at least one chromosome 15 was involved in all instances (Zuffardi et al., 1978; Kucerova et al., 1979; Guanti, 1980). However, the situation was further complicated by cases in which not only the proband had a translocation involving chromosome 15, but the mother and 2 normal sibs showed the seemingly identical translocation as well (Smith and Noel, 1980). In addition, there were a few cases that did not show a translocation involving chromosome 15, but had a small supernumerary chromosome, presumably an isochromosome for the short arm of an acrocentric (Fleischer-Michaelsen et al., 1979; Fujita et al., 1980; Wisniewski et al., 1980). Smith and Noel (1980) described a family in which a Prader-Willi girl had the same balanced 4;15 translocation as her mother and other phenotypically normal family members. A second such family was observed by Smith et al. (1983). Nicholls et al. (1989) reported a similar family and demonstrated that the Prader-Willi proband had inherited the maternal translocation chromosome plus the normal maternal homolog, but no paternal 15. Therefore, having a balanced translocation involving chromosome 15 predisposes to PWS offspring via nondisjunction, and this is a much more frequent cause than spontaneous nondisjunction, which may arise from chromosomally normal individuals. The opposite, i.e., Angelman syndrome, could also occur with paternal translocation carriers. The simplest instance is that of a balanced rearrangement with a breakpoint in 15q13 in related male carriers. Fernandez et al. (1987) reported a family with a 15;22 translocation carrier father who had 2 children with PWS because of an unbalanced segregation. Hulten et al. (1991) described a family in which a balanced translocation involving 15q13 was segregating. Females with the translocation appeared to have an increased risk of having children with AS, whereas male carriers of the translocation had an increased risk of having children with PWS. Ledbetter et al. (1980) pointed out that apparent balanced translocations involving chromosome 15 have been found. The defect may be an alteration in gene expression, i.e., a regulatory defect. Ledbetter et al. (1981), assuming a small deletion of proximal 15q as the cause of the clinical features in the translocated cases, studied 45 persons with the clinical diagnosis of PWS. Of the 45, 25 had an abnormality of chromosome 15 (which in 23 was an interstitial deletion affecting the q11-q12 region). No relatives of probands showed chromosomal changes. Orstavik et al. (1992) described 3 sibs thought to have the Prader-Willi syndrome but with no abnormality in the 15q11-q13 region detectable by cytogenetic or molecular genetic methods. One of the sibs, a boy, was born at 32 weeks by cesarean section. He was extremely hypotonic and died at 7 days of age from respiratory distress. The other sibs, a 12-year-old brother and a 7-year-old sister, had an accessory nipple and seemingly typical PWS. A paternally inherited submicroscopic deletion was suggested as one possibility. A very small deletion was later molecularly detected in affected members of this family (Tommerup, 1993). Ishikawa et al. (1987) described 2 sisters with PWS. No interstitial deletion of 15q was detected in either; 1 sister had a possibly unrelated partial deletion of one X chromosome. No molecular investigations were performed in this family. Lubinsky et al. (1987) reported the cases of 2 brothers and 2 sisters in a single sibship with PWS but apparently normal chromosomes. Results of chromosome studies in the parents and surviving sibs were normal. The diagnosis was made clinically on the basis of history, behavior, and physical findings in 3 of the sibs. The fourth child had died at the age of 10 months with a history and clinical findings typical of the first phase of PWS. Again, no molecular or fluorescence in situ hybridization (FISH) studies were performed. It seems likely that an undetected structural chromosome rearrangement is the cause for this multiple occurrence of PWS. McEntagart et al. (2000) described a brother and sister with PWS in whom there was no microscopically visible deletion in 15q11-q13 or maternal disomy. Methylation studies at D15S63 and at the SNRPN locus confirmed the diagnosis of PWS. Molecular studies revealed biparental inheritance in both sibs with the exception of 2 markers where no paternal contribution was present, indicating a deletion of the imprinting center. Family studies indicated that the father of the sibs carried the deletion which he had inherited from his mother. Recurrence risk of PWS in his offspring was 50%. #### Co-Occurrence of Prader-Willi and Angelman Syndromes Hasegawa et al. (1984) studied a family in which 2 cousins were claimed to have the Prader-Willi syndrome and found a reciprocal translocation t(14;15)(q11.2;q13) in a single parent of each cousin and in their common grandmother. The affected cousins had the same unbalanced translocation including monosomy of the 15pter-q13 segment. Schinzel et al. (1992) pointed out that the unbalanced karyotype with deletion of 15q11-q13 came from the mother in the case of the proband who had been described to have classic Prader-Willi syndrome and from the father in the case of the cousin; the mother of the proband and the father of the cousin were sister and brother. However, the proband was not hypotonic and had seizures. Schinzel et al. (1992) suggested that the diagnosis in the proband actually may have been Angelman syndrome, consistent with the finding that there has been no reported instance of a patient in which absence of the paternal segment 15q11-q13 does not cause PWS, while the absence of the maternal segment leads to AS. Another mechanism by which the Prader-Willi syndrome and Angelman syndrome can occur in cousins was reported by Smeets et al. (1992). Two female first cousins were offspring of brothers, both of whom had a familial translocation between chromosome 6 and 15, t(6;15)(p25.3;q11.1). The cousin with the Prader-Willi syndrome had the karyotype 45,XX,-6,-15+t(6;15)(p25.3;q13); DNA studies indicated that there was a large paternally derived deletion of all loci from the Prader-Willi chromosomal region tested. The cousin with Angelman syndrome had the karyotype 45,XX,-6,-15,+t(6;15)(p25.3;q11.1) and DNA studies indicated that she had uniparental heterodisomy, having inherited both the (6;15) translocation and the normal chromosome 15 from her father, but no chromosome 15 from her mother. In an editorial, Hall (1992) suggested that the cousin with Angelman syndrome had started out life as a trisomy and survived only through the loss of extra chromosomal material. Greenstein (1990) presented a kindred in which both the Prader-Willi and the Angelman syndromes were found; the inheritance pattern was consistent with genetic imprinting. #### Marker Chromosomes Finally, additional small marker chromosomes representing isochromosomes or isodicentric chromosomes from the short arms of acrocentrics have repeatedly been observed (Fleischer-Michaelsen et al., 1979; Fujita et al., 1980; Wisniewski et al., 1980) before Robinson et al. (1993) demonstrated maternal uniparental disomy 15 in a Prader-Willi child mosaic for such a marker and paternal UPD 15 in an Angelman patient also mosaic for a small metacentric marker chromosome. Investigation of PWS and AS patients with a small inv dup(15) chromosome attributes the abnormal phenotype to uniparental disomy rather than to the extra chromosome (Robinson et al., 1993). The small chromosome may represent either the remnant of the missing parental chromosome 15 or could be associated with nondisjunction. Park et al. (1998) described an example of maternal disomy and Prader-Willi syndrome consistent with gamete complementation. They considered that the probable event was adjacent-1 segregation of a paternal t(3;15)(p25;q11.2) with simultaneous maternal meiotic nondisjunction for chromosome 15. The patient, a 17-year-old white male with PWS, had 47 chromosomes with a supernumerary, paternal der(15) consisting of the short arm and the proximal long arm of chromosome 15 fused to distal 3p. The t(3;15) was present in the balanced state in the patient's father and a sister. Fluorescence in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion in the PWS region on the normal pair of 15s present in the patient. Maternal disomy was confirmed by 2 methods. #### MAPPING Kirkilionis et al. (1991) constructed a long-range restriction map of the PWS region, 15q11.1-q12, using a combination of pulsed-field gel techniques and rare cutting restriction enzymes. A preliminary YAC contig map was reported by Kuwano et al. (1992), which also localized many common proximal and distal deletion breakpoints to two YACs. Ozcelik et al. (1992) refined the localization of the small nuclear ribonucleoprotein N gene (SNRPN; 182279) within the minimum deletion region. FISH ordering of reference markers in this region was also reported by Knoll et al. (1993) who placed D15S63 in the minimum PWS deletion region between D15S13 and D15S10. Mutirangura et al. (1993) published a complete YAC contig of the PWS/AS critical region and discussed the potential role of uniparental disomy (UPD) in PWS and AS. Buiting et al. (1993) constructed a YAC restriction map of the entire minimum PWS critical region defined by the shortest region of overlap between two key PWS deletion patients. This region is 320 kb and includes D15S63 and SNRPN. #### MOLECULAR GENETICS Latt et al. (1987) isolated probes from the proximal region of the long arm of chromosome 15 that are useful in the study of PWS. Buiting et al. (1992) isolated a putative gene family and candidate genes by microdissection and microcloning from the 15q11-q13 region. One microclone, designated MN7, detected multiple loci in 15q11-q13 and 16p11.2. There were 4 or 5 different MN7 copies spread over a large distance within 15q11-q13. The presence of multiple copies of the MN7 gene family in proximal 15q may be related to the instability of this region and thus to the etiology of PWS and Angelman syndrome. Using restriction digests with the methyl-sensitive enzymes HpaII and HhaI and probing Southern blots with several genomic and cDNA probes, Driscoll et al. (1992) systematically scanned segments of 15q11-q13 for DNA methylation differences between patients with PWS (20 deletion cases and 20 cases of uniparental disomy) and those with AS (26 deletion cases and 1 case of uniparental disomy). They found that the sequences identified by the cDNA DN34, which is highly conserved in evolution, demonstrate distinct differences in DNA methylation of the parental alleles at the D15S9 locus. Clayton-Smith et al. (1993) used DN34 to perform methylation analysis of 2 first-cousin males, one with AS and the other with PWS. The methylation pattern varied according to the parent of origin, providing further evidence for the association of methylation with genomic imprinting. Thus, DNA methylation can be used as a reliable postnatal diagnostic tool. Dittrich et al. (1992) found that an MspI/HpaII restriction site at the D15S63 locus in 15q11-q13 is methylated on the maternally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this difference, they devised a rapid diagnostic test for patients suspected of having PWS or AS. The human homolog for the mouse pink-eyed dilution locus (p locus) was found to be equivalent to the D15S12 locus which maps within the PWS/AS deletion region (Rinchik et al., 1993). Mutations in both copies of the P gene were found in a patient with type II oculocutaneous albinism, and it is suggested that deletion of 1 copy of this gene is the cause of hypopigmentation in PWS and AS. The SNRPN gene was shown by RT-PCR to be expressed in normal and AS individuals, but not in fibroblasts from either deletion or maternal UPD PWS patients who lack a paternal copy of this gene (Glenn et al., 1993). Parent-specific DNA methylation was also identified for the SNRPN gene. Reed and Leff (1994) showed that in the human, as in the mouse, there is maternal imprinting of SNRPN, thus supporting the hypothesis that paternal absence of SNRPN is responsible for the PWS phenotype. See SNRPN (182279) for discussion of evidence indicating that this is a candidate gene in PWS and suggesting that PWS may be caused, in part, by defects in mRNA processing. In 2 sibs with the typical phenotype of PWS but without a cytogenetically detectable deletion in 15q, Ishikawa et al. (1996) demonstrated deletion of SNRPN by FISH. A DNA transcript, OP2, was identified just centromeric to D15S10 by Woodage et al. (1994). Multiple expressed genes were identified by Sutcliffe (1994) in the region between SNRPN and D15S10. They showed that at least 4 genes are expressed only on the paternal chromosome including SNRPN, PAR1 (600161), PAR5 (600162), and PAR7. A PWS patient with a small paternal deletion showed no expression of these genes, even though the deletion occurs proximal to but not including these maternally imprinted genes, implying a common element involved in regulation of these genes. Wevrick et al. (1994) identified another expressed gene in the region, designated IPW (601491) for 'imprinted gene in the Prader-Willi syndrome region,' that is expressed only from the paternal chromosome 15. DNA replication was shown by FISH to be asynchronous between maternal and paternal alleles within 15q11-q13 (Knoll et al., 1993). Loci in the PWS-critical region were shown to be early replicating on the paternal chromosome, and alleles within the AS critical region were early replicating on the maternal chromosome. A mosaic replication pattern with maternal and paternal alleles alternatively expressed was noted at the P locus, and is consistent with the presence of hypopigmentation in both PWS and AS due to decreased product. Schulze et al. (1996) reported a boy with PWS who had a rare translocation and a normal methylation pattern at SNRPN. Although the boy fulfilled the diagnostic criteria for PWS defined by Holm et al. (1993), he had a normal methylation pattern due to the position of the translocation breakpoint. Cassidy (1997) provided a comprehensive review of the clinical and molecular aspects of Prader-Willi syndrome. Cassidy and Schwartz (1998) provided a similar review of both Prader-Willi syndrome and Angelman syndrome. PWS and AS are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2 to 4% of patients, this loss of function is the result of an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Buiting et al. (1998) described the molecular analysis of 13 PWS patients and 17 AS patients who had an imprinting defect but no IC deletion. Furthermore, heteroduplex and partial sequence analyses did not reveal any point mutations in the known IC elements. All of these patients represented sporadic cases, and some shared the paternal PWS or maternal AS 15q11-q13 haplotype with an unaffected sib. In each of the 5 PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and 4 cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggested that the grandmaternal imprint was not erased in the father's germline. In 7 informative AS patients reported by Buiting et al. (1998) and in 3 previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding was not compatible with an imprint-switch failure, but it suggested that a paternal imprint developed either in the maternal germline or postzygotically. Buiting et al. (1998) concluded that (1) the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error; (2) these cases have a low recurrence risk; and (3) the paternal imprint may be the default imprint. Buiting et al. (2003) described a molecular analysis of 51 patients with PWS and 85 patients with AS. A deletion of an IC was found in 7 patients with PWS (14%) and 8 patients with AS (9%). Sequence analysis of 32 PWS patients and 66 AS patients, neither with an IC deletion, did not reveal any point mutation in the critical IC elements. The presence of a faint methylated band in 27% of patients with AS and no IC deletion suggested that these patients were mosaic for an imprinting defect that occurred after fertilization. In patients with AS, the imprinting defect occurred on the chromosome that was inherited from either the maternal grandfather or grandmother; however, in all informative patients with PWS and no IC deletion, the imprinting defect occurred on the chromosome inherited from the paternal grandmother. These data suggested that this imprinting defect resulted from a failure to erase the maternal imprint during spermatogenesis. Microdeletions of the imprinting center in 15q11-q13 have been identified in several families with PWS or Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in this region of 15q during gametogenesis. Ohta et al. (1999) identified a large series of cases of familial PWS, including 1 case with a deletion of only 7.5 kb, that narrowed the PWS critical region to less than 4.3 kb spanning the SNRPN gene CpG island and exon 1. The identification of a strong DNase I hypersensitive site, specific for the paternal allele, and 6 evolutionarily conserved (human-mouse) sequences that are potential transcription factor binding sites is consistent with a conclusion that this region defines the SNRPN gene promoter. These findings suggested that promoter elements at SNRPN play a key role in the initiation of imprint switching during spermatogenesis. Ohta et al. (1999) also identified 3 patients with sporadic PWS who had an imprinting mutation (IM) and no known detectable mutation in the IC. An inherited 15q11-q13 mutation or a trans-factor gene mutation are unlikely; thus, the disease in these patients may arise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental gametogenesis. These studies allowed a better understanding of the novel mechanism of human disease, since the epigenetic effect of an imprinting mutation in parental germline determines the phenotypic effect in the patient. To elucidate the mechanism underlying the deletions that lead to PWS and Angelman syndrome, Amos-Landgraf et al. (1999) characterized the regions containing 2 proximal breakpoint clusters and a distal cluster. Analysis of rodent-human somatic cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences, termed 'END' repeats, at or near the breakpoints. END-repeat units are derived from large genomic duplications of the HERC2 gene (605837) (Ji et al., 1999). Many copies of the HERC2 gene are transcriptionally active in germline tissues. Amos-Landgraf et al. (1999) postulated that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, they proposed that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process. To identify additional imprinted genes that could contribute to the PWS phenotype and to understand the regional control of imprinting in 15q11-q13, Lee and Wevrick (2000) constructed an imprinted transcript map of the PWS-AS deletion interval. They found 7 new paternally expressed transcripts localized to a domain of approximately 1.5 Mb surrounding the SNRPN-associated imprinting center, which already included 4 imprinted, paternally expressed genes. All other tested new transcripts in the deletion region were expressed from both alleles. A domain of exclusive paternal expression surrounding the imprinting center suggested strong regional control of the imprinting process. Bielinska et al. (2000) reported a PWS family in which the father was mosaic for an imprinting center deletion on his paternal chromosome. The deletion chromosome had acquired a maternal methylation imprint in his somatic cells. Identical observations were made in chimeric mice generated from 2 independent embryonic stem cell lines harboring a similar deletion. Bielinska et al. (2000) concluded that the Prader-Willi syndrome imprinting center element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance. Boccaccio et al. (1999) and Lee et al. (2000) independently cloned and characterized MAGEL2 (605283), a gene within the PWS deletion region. They demonstrated that the MAGEL2 gene is transcribed only from the paternal allele. Balanced translocations affecting the paternal copy of 15q11-q13 have been proven to be a rare cause of PWS or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation t(X;15)(q28;q12) in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene (182279) and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85 (605436), as well as IPW (601491) and PAR1 (600161), were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype. Meguro et al. (2001) determined the allelic expression profiles of 118 cDNA clones using monochromosomal hybrids retaining either a paternal or maternal human chromosome 15. There was a preponderance of unusual transcripts lacking protein-coding potential that were expressed exclusively from the paternal copy of the critical interval. This interval also encompassed a large direct repeat (DR) cluster displaying a potentially active chromatin conformation of paternal origin, as suggested by enhanced sensitivity to nuclease digestion. Database searches revealed an organization of tandemly repeated consensus elements, all of which possessed well-defined C/D box sequences characteristic of small nucleolar RNAs (snoRNAs). Southern blot analysis further demonstrated a considerable degree of phylogenetic conservation of the DR locus in the genomes of all mammalian species tested. The authors suggested that there may be a potential direct contribution of the DR locus, representing a cluster of multiple snoRNA genes, to certain phenotypic features of PWS. Fulmer-Smentek and Francke (2001) explored whether differences in histone acetylation exist between the 2 parental alleles of SNRPN and other paternally expressed genes in the region by using a chromatin immunoprecipitation assay with antibodies against acetylated histones H3 (see 601058) and H4 (see 142750). SNRPN exon 1, which is methylated on the silent maternal allele, was associated with acetylated histones on the expressed paternal allele only. SNRPN intron 7, which is methylated on the paternal allele, was not associated with acetylated histones on either allele. The paternally expressed genes NDN, IPW, PWCR1, and MAGEL2 were not associated with acetylated histones on either allele. Treatment of the lymphoblastoid cells with trichostatin A, a histone deacetylase inhibitor, did not result in any changes to SNRPN expression or association of acetylated histones with exon 1. Treatment with 5-aza-deoxycytidine, which inhibits DNA methylation, resulted in activation of SNRPN expression from the maternal allele, but was not accompanied by acetylation of histones. The authors hypothesized that histone acetylation at this site may be important for regulation of SNRPN and of other paternally expressed genes in the region, and that histone acetylation may be a secondary event in the process of gene reactivation by CpG demethylation. The Prader-Willi syndrome/Angelman syndrome region on chromosome 15q11-q13 exemplifies coordinate control of imprinted gene expression over a large chromosomal domain. Establishment of the paternal state of the region requires the PWS imprinting center (PWS-IC); establishment of the maternal state requires the AS-IC. Cytosine methylation of the PWS-IC, which occurs during oogenesis in mice, occurs only after fertilization in humans, so this modification cannot be the gametic imprint for the PWS/AS region in humans. Xin et al. (2001) demonstrated that the PWS-IC shows parent-specific complementary patterns of histone H3 (see 601128) lysine-9 (lys9) and H3 lysine-4 (lys4) methylation. H3 lys9 is methylated on the maternal copy of PWS-IC and H3 lys4 is methylated on the paternal copy. Xin et al. (2001) suggested that H3 lys9 methylation is a candidate maternal gametic imprint for this region, and they showed how changes in chromatin packaging during the life cycle of mammals provide a means of erasing such an imprint in the male germline. Bittel et al. (2003) performed cDNA microarray analysis of 73 genes/transcripts from the 15q11-q13 region in actively growing lymphoblastoid cell lines established from 9 young adult males: 6 with PWS (3 with deletion and 3 with UPD) and 3 controls. They detected no difference in expression of genes with known biallelic expression located outside the 15q11-q13 region in all cell lines studied. When comparing UPD cell lines with controls, there was no difference in expression levels of biallelically expressed genes from within 15q11-q13 (e.g., OCA2 203200). Two genes previously identified as maternally expressed, UBE3A (601623) and ATP10C (605855), showed a significant increase in expression in UPD cell lines compared with those from control and PWS deletion patients. The results suggested that differences in expression of candidate genes may contribute to phenotypic differences between the deletion and UPD types of PWS. #### DIAGNOSIS Seven clinicians experienced with PWS, in consultation with national and international experts, proposed 2 scoring systems as diagnostic criteria: one for children aged 0-36 months and another for children aged 3 years to adults (Holm et al., 1993). The American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfe outlined approaches to the laboratory diagnosis of PWS and Angelman syndrome. White et al. (1996) exploited the allele-specific replication differences that had been observed in imprinted chromosomal regions to obtain a diagnostic test for detecting uniparental disomy. They used FISH of D15S9 and SNRPN (182279) on interphase nuclei to distinguish between Angelman and Prader-Willi syndrome patient samples with uniparental disomy of 15q11-q13 and those with biparental inheritance. They found that the familial recurrence risks are low when the child has de novo uniparental disomy and may be as high as 50% when the child has biparental inheritance. The frequency of interphase cells with asynchronous replication was significantly lower in patients with uniparental disomy than in patients with biparental inheritance. Within the sample population of patients with biparental inheritance, those with altered methylation and presumably imprinting center mutations could not be distinguished from those with no currently detectable mutation. White et al. (1996) considered the test cost-effective because it could be performed on interphase cells from the same hybridized cytologic preparation in which a deletion was included, and additional specimens were not required to determine the parental origin of chromosome 15. Kubota et al. (1996) noted that neither FISH nor uniparental disomy (UPD) analysis with microsatellite markers will detect rare PWS patients with imprinting mutations, including small deletions or point mutations in the imprinting center region. They reported that as an initial screening test, methylation analysis has the advantage of detecting all of the major classes of molecular defects involved in PWS (deletions, uniparental disomy, and imprinting mutations) without the need for parental blood. Kubota et al. (1996) reported that in 67 patients examined clinically, the methylation results for PW71 were consistent with the clinical diagnosis. They concluded that SNRPN methylation analysis, similar to PW71 methylation analysis, constitutes a reliable diagnostic test for PWS. They emphasized the importance of conventional cytogenetic analysis in parallel with DNA methylation analysis. They noted that a few patients with signs of PWS have balanced translocations within or distal to SNRPN and normal methylation patterns. They noted also that conventional cytogenetic analysis is important to rule out other cytogenetic anomalies in patients who may have similar clinical manifestations but who do not have PWS. Since the SNRPN gene is not expressed in any patient with PWS regardless of the underlying cytogenetic or molecular cause, Wevrick and Francke (1996) tested for expression of the SNRPN gene and a control gene in 9 patients with PWS and 40 control individuals by PCR analysis of reverse transcribed mRNA from blood leukocytes. SNRPN expression could readily be detected in blood leukocytes by PCR analysis in all control samples but not in samples from known PWS patients. Four suspected PWS cases were negative for SNRPN expression and were found to have chromosome 15 rearrangements, while the diagnosis of PWS was excluded in 7 other patients with normal SNRPN expression based on clinical, molecular, and cytogenetic findings. Thus, Wevrick and Francke (1996) concluded that the SNRPN-expression test is rapid and reliable in the molecular diagnosis of PWS. The diagnostic criteria arrived at by a consensus group (Holm et al., 1993) were presented in a table by Schulze et al. (1996). In a point system, 1 point each was allowed for each of 5 major criteria, such as feeding problems in infancy and failure to thrive, and one-half point each for 7 minor criteria, such as hypopigmentation. A minimum of 8.5 points was considered necessary for the diagnosis of PWS. Hordijk et al. (1999) reported a boy with a PWS-like phenotype who was found to have maternal heterodisomy for chromosome 14. The authors noted that while previous reports of this phenotype had been associated with a Robertsonian translocation involving chromosome 14, in this case the karyotype was normal. Hordijk et al. (1999) concluded that patients with a PWS-like phenotype and normal results of DNA analysis for PWS should be reexamined for uniparental disomy for maternal chromosome 14. Whittington et al. (2002) compared clinical and genetic laboratory diagnoses of PWS. The genetic diagnosis was established using the standard investigation of DNA methylation of SNRPN, supplemented with cytogenetic studies. The 5 clinical features floppy at birth, weak cry or inactivity, poor suck, feeding difficulties, and hypogonadism were present in 100% of persons with positive genetic findings, the absence of any 1 predicting a negative genetic finding. The combination of poor suck at birth, weak cry or inactivity, decreased vomiting, and thick saliva correctly classified 92% of all cases. Whittington et al. (2002) hypothesized that these criteria ('core criteria') invariably present when genetic findings are positive and are necessary accompaniments of the genetics of PWS. No subset of clinical and behavioral criteria was sufficient to predict with certainty a positive genetic diagnosis, but the absence of any 1 of the core criteria predicted a negative genetic finding. #### CLINICAL MANAGEMENT The suggestion of a hypothalamic defect located in the ventromedial or ventrolateral nucleus is plausible, but no such lesion has been reported, nor was such found on careful search in a typical case (Warkany, 1970). Hamilton et al. (1972) showed that the hypogonadism is the hypogonadotropic type and the result of hypothalamic dysfunction. Treatment with clomiphene citrate raised plasma luteinizing hormone, testosterone, and urinary gonadotropin levels to normal and resulted in normal spermatogenesis and physical signs of puberty. Vagotomy has been successful in correcting obesity in experimental obesity produced by hypothalamic lesions (Hirsch, 1984). Fonkalsrud and Bray (1981) performed truncal vagotomy without pyloroplasty in a 17-year-old boy who had maintained a weight of approximately 264 lb (120 kg) for several years. Initially, he lost weight satisfactorily but by 11 months postoperative he had regained most of the weight. Prader (1991) reported a 17-year-old boy weighing 264 lb (120 kg) who had developed diabetes, required digitalization for cardiac failure, and presented with intolerable behavior problems. Strict dietary control in combination with psychotherapy in a foster environment resulted in a weight reduction to 143 lb (65 kg), cessation of hyperglycemia and glucosuria, and cardiac normalization. Carrel et al. (1999) presented the results of a randomized controlled study of growth hormone treatment in children with Prader-Willi syndrome. They showed that growth hormone treatment accelerated growth, decreased percent body fat, and increased fat oxidation, but did not significantly increase resting energy expenditure. Improvements in respiratory muscle strength, physical strength, and agility also were observed, leading the authors to suggest that growth hormone treatment may have value in reducing disability in children with PWS. Lindgren et al. (1999) measured resting ventilation, airway occlusion pressure, and respiratory response to CO(2) in 9 children, aged 7 to 14 years, before and 6 to 9 months after the start of growth hormone therapy. Treatment resulted in a significant increase in all 3 measurements. Studies had shown that GH (139250) therapy with doses of GH typically used for childhood growth improves growth, body composition, physical strength and agility, and fat utilization in children with PWS. However, these measurements remained far from normal after up to 2 years of GH therapy. Carrel et al. (2002) assessed the effects of 24 additional months of GH treatment at varying doses on growth, body composition, strength and agility, pulmonary function, resting energy expenditure, and fat utilization in 46 children with PWS, who had previously been treated with GH therapy for 12 to 24 months. During months 24 to 48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and resting energy expenditure occurred with higher GH therapy doses, but not with the lowest dose. Bone mineral density continued to improve at all doses of GH (P less than 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. They authors concluded that salutary and sustained GH-induced changes in growth, body composition, bone mineral density, and physical function in children with PWS can be achieved with daily administration of GH doses greater than or equal to 1 mg/m2. With regard to genetic counseling, the type of cytogenetic aberration and molecular results determine the recurrence risk. Prenatal molecular investigation from chorionic villi should be recommended in every case despite very low recurrence risk. Prenatal ultrasonographic studies of fetal activity may be useful for a first screening since Prader-Willi fetuses will show diminished fetal movement during the second trimester (Schinzel, 1986). Furthermore, a molecular examination for uniparental disomy is indicated in any pregnancy in which a CVS examination disclosed (mosaic) trisomy 15 and a subsequent cytogenetic examination from amniocytes or fetal blood revealed a normal diploid karyotype. To determine whether ghrelin (605353), a GH (139250) secretagogue with orexigenic properties, is elevated in PWS, Delparigi et al. (2002) measured fasting plasma ghrelin concentration, body composition, and subjective ratings of hunger in 7 subjects with PWS and 30 healthy subjects who had fasted overnight. The mean plasma ghrelin concentration was higher in PWS than in the reference population and this difference remained significant after adjustment for percentage of body fat. A positive correlation was found between plasma ghrelin and subjective ratings of hunger. The authors concluded that ghrelin is elevated in subjects with PWS. They also suggested that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS. Haqq et al. (2003) measured fasting serum ghrelin levels in 13 children with PWS with an average age of 9.5 years and body mass index (BMI) of 31.3 kilograms per square meter. The PWS group was compared with 4 control groups: normal weight controls, obese children, and children with melanocortin-4 receptor (155541) mutations and leptin (164160) deficiency. Ghrelin levels in children with PWS were significantly elevated (3-4 fold) compared with BMI-matched obese controls. The authors concluded that elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS. Treatment with octreotide, a somatostatin (182450) agonist, decreases ghrelin concentrations in healthy and acromegalic adults and induces weight loss in children with hypothalamic obesity. To investigate whether the high fasting ghrelin concentrations of children with PWS could be suppressed by short-term octreotide administration, Haqq et al. (2003) treated 4 subjects with PWS with octreotide (5 microg/kg-d) for 5 to 7 days and studied ghrelin concentration, body composition, resting energy expenditure, and GH markers. Octreotide treatment decreased mean fasting plasma ghrelin concentration by 67% (P less than 0.05). Meal-related ghrelin suppression was still present after intervention but was blunted. Body weight, body composition, leptin, insulin (176730), resting energy expenditure, and GH parameters did not change. However, one subject's parent noted fewer tantrums over denial of food during octreotide intervention. The authors concluded that short-term octreotide treatment markedly decreased fasting ghrelin concentrations in children with PWS but did not fully ablate the normal meal-related suppression of ghrelin. #### POPULATION GENETICS In a review, Butler (1990) estimated the frequency of PWS at about 1 in 25,000 and suggested that it is the most common syndromal cause of human obesity. In a comprehensive survey of PWS in North Dakota, Burd et al. (1990) identified 17 affected persons, from which they derived a prevalence rate of 1 per 16,062. Whittington et al. (2001) identified all definite or possible PWS cases in the Anglia and Oxford Health Region of the U.K. (population approximately 5 million people). From a total of 167 people referred with possible PWS, 96 were classified as having PWS on genetic and/or clinical grounds. From this, Whittington et al. (2001) estimated a lower limit of population prevalence of 1 in 52,000 with a proposed true prevalence of 1 in 45,000; a lower limit of birth incidence of 1 in 29,000 was also estimated. #### ANIMAL MODEL Nakatsu et al. (1992) found that the mouse homolog of a human gene within the PWCR is tightly linked to the p locus, which is the site of mutations affecting pigmentation and is often associated with neurologic abnormalities as well. The p locus is located on mouse chromosome 7 near a chromosomal region associated with imprinting effects. Nakatsu et al. (1992) suggested that the hypopigmentation in both PWS and Angelman syndrome may result from an imprinting effect on the human cognate of the mouse p locus. Although representing only indirectly an animal model in the usual sense, studies focusing on the effects of imprinted genes on brain development by examining the fate of androgenetic (Ag; duplicated paternal genome) and parthenogenetic/gynogenetic (Pg/Gg; duplicated maternal genome) cells in chimeric mouse embryos (Keverne et al., 1996) sheds interesting light on the pathogenesis of the distinctive neuropsychologic features of PWS and Angelman syndrome. Keverne et al. (1996) observed striking cell-autonomous differences in the role of the 2 types of uniparental cells in brain development. Ag cells with a duplicated paternal genome contributed substantially to the hypothalamic structures and not the cerebral cortex. By contrast, Pg/Gg cells with a duplicated maternal genome contributed substantially to the cortex, striatum, and hippocampus but not to the hypothalamic structures. Furthermore, growth of the brain was enhanced by Pg/Gg and retarded by Ag cells. Keverne et al. (1996) proposed that genomic imprinting may represent a change in strategy controlling brain development in mammals. In particular, genomic imprinting may have facilitated a rapid nonlinear expansion of the brain, especially the cortex, during development over evolutionary time. It is noteworthy that Ag cells were seen predominantly in the medial preoptic area and hypothalamus, regions of the brain concerned with neuroendocrine function and primary motivated behavior, including feeding and sexual behavior, which are disturbed in PWS. Contrariwise, MRI shows that the sylvian fissures are anomalous in Angelman patients, who are severely mentally retarded with speech and movement disorders, findings not inconsistent with the distribution of Pg cells. Yang et al. (1998) created 2 deletion mutations in mice to understand PWS and the mechanism of the 'imprinting center,' or IC, which maps in part to the promoter and first exon of the SNRPN gene (182279). Mice harboring an intragenic deletion of Snrpn were phenotypically normal, suggesting that mutations of SNRPN are not sufficient to induce PWS. Mice with a larger deletion involving both Snrpn and the putative PWS-IC lacked expression of the imprinted genes Zfp127 (mouse homolog of ZNF127; 176270), Ndn (602117), and lpw, and manifested several phenotypes common to PWS infants. Mice heterozygous for the paternally inherited IC-deletion died as neonates, 72% within 48 hours. At birth, the heterozygous mutant mice were present in the expected mendelian ratio. On the day of birth, the affected mice appeared normal but underweight. There was little hypotonia, but one consistently observed difference was that mutant mice were unable to support themselves on their hind feet, resting on their knees instead. No genital or gonadal hypoplasia was observed at the time of birth. Gabriel et al. (1999) reported the characterization of a transgene insertion into mouse chromosome 7C, which resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicated that the transgene-induced mutation had generated a complete deletion of the PWS/AS homologous region but had not deleted flanking loci. Because the intact chromosome 7, opposite the deleted homolog, maintained the correct imprint in somatic cells of PWS and AS mice and established the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism. This heritable-deletion mouse model could be particularly useful for the identification of the etiologic genes and mechanisms, phenotypic basis, and therapeutic approaches for PWS. Muscatelli et al. (2000) also produced mice deficient for necdin (602117), and suggested that postnatal lethality associated with loss of the paternal gene may vary dependent on the strain. Viable necdin mutants showed a reduction in both oxytocin (167050)-producing and luteinizing hormone-releasing hormone (LHRH; 152760)-producing neurons in hypothalamus, increased skin scraping activity, and improved spatial learning and memory. The authors proposed that underexpression of necdin is responsible for at least a subset of the multiple clinical manifestations of PWS. #### HISTORY Langdon-Down (1828-1896), who described 'mongolism' (Down syndrome), also described PWS (Down, 1887) about 70 years before Prader et al. (1956), and called it polysarcia (see account by Brain, 1967). The patient was a mentally subnormal girl who, when 13 years old, was 4 feet 4 inches tall (1.32 m) and weighed 196 lbs (84 kg). At 25 years of age she weighed 210 lbs (95.4 kg). 'Her feet and hands remained small, and contrasted remarkably with the appendages they terminated. She had no hair in the axillae, and scarcely any on the pubis. She had never menstruated, nor did she exhibit the slightest sexual instinct.' ### SEE ALSO Bray et al. (1983); Burke et al. (1987); Butler et al. (1982); Butler et al. (1982); Butler and Palmer (1983); Butler and Palmer (1983); Carpenter (1994); Cassidy (1987); Cassidy et al. (1984); Charrow et al. (1983); Donlon et al. (1986); Duckett et al. (1984); Dunn (1968); Fraccaro et al. (1983); Fryns (1988); Fuhrmann-Rieger et al. (1984); Futterweit et al. (1986); Gabilan and Royer (1968); Gregory et al. (1990); Gregory et al. (1991); Hawkley and Smithies (1976); Hoefnagel et al. (1967); Holm et al. (1981); Katcher et al. (1977); Kousseff (1982); Labidi and Cassidy (1986); Laurance (1967); Laurance et al. (1981); Ledbetter et al. (1982); Mattei et al. (1983); Mattei et al. (1984); Michaelsen et al. (1979); Nicholls et al. (1989); Niikawa and Ishikiriyama (1985); Orenstein et al. (1980); Qumsiyeh et al. (1992); Reed and Butler (1984); Ridler et al. (1971); Rivera et al. (1990); Robinson et al. (1993); Robinson et al. (1993); Robinson et al. (1993); Seyler et al. (1979); Smith et al. (1991); Trent et al. (1991); Veenema et al. (1984); Zellweger and Schneider (1968) ### REFERENCES 1. 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Whittington, J. E.; Holland, A. J.; Webb, T.; Butler, J.; Clarke, D.; Boer, H. : Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region. (Letter) J. Med. Genet. 38: 792-798, 2001. PubMed ID : 11732491 194. Wiesner, G. L.; Bendel, C. M.; Olds, D. P.; White, J. G.; Arthur, D. C.; Ball, D. W.; King, R. A. : Hypopigmentation in the Prader-Willi syndrome. Am. J. Hum. Genet. 40: 431-442, 1987. PubMed ID : 3578281 195. Williams, M. S.; Rooney, B. L.; Williams, J.; Josephson, K.; Pauli, R. : Investigation of thermoregulatory characteristics in patients with Prader-Willi syndrome. Am. J. Med. Genet. 49: 302-307, 1994. PubMed ID : 8209890 196. Wirth, J.; Back, E.; Huttenhofer, A.; Nothwang, H.-G.; Lich, C.; Gross, S.; Menzel, C,; Schinzel, A.; Kioschis, P.; Tommerup, N.; Ropers, H.-H.; Horsthemke, B.; Buiting, K. : A translocation breakpoint cluster disrupts the newly defined 3-prime end of the SNURF-SNRPN transcription unit on chromosome 15. Hum. Molec. Genet. 10: 201-210, 2001. PubMed ID : 11159938 197. Wise, M. S.; Zoghbi, H.; Edwards, M.; Byrd, L. K.; Guttmacher, A. E.; Greenberg, F. : Hyperthermia in infants with Prader-Willi syndrome. (Abstract) Am. J. Med. Genet. 41: 528 only, 1991. 198. Wisniewski, L. P.; Witt, M. E.; Ginsberg-Fellner, F.; Wilner, J.; Desnick, R. J. : Prader-Willi syndrome and a bisatellited derivative of chromosome 15. Clin. Genet. 18: 42-47, 1980. PubMed ID : 7418253 199. Woodage, T.; Lindeman, R.; Deng, Z. M.; Fimmel, A.; Smith, A.; Trent, R. J. : Physical mapping studies at D15S10: implications for candidate gene identification in the Angelman syndrome/Prader-Willi syndrome chromosome region of 15q11-q13.. Genomics 19: 170-172, 1994. PubMed ID : 8188222 200. Xin, Z.; Allis, C. D.; Wagstaff, J. : Parent-specific complementary patterns of histone H3 lysine 9 and H3 lysine 4 methylation at the Prader-Willi syndrome imprinting center. Am. J. Hum. Genet. 69: 1389-1394, 2001. PubMed ID : 11592036 201. Yang, T.; Adamson, T. E.; Resnick, J. L.; Leff, S.; Wevrick, R.; Francke, U.; Jenkins, N. A.; Copeland, N. G.; Brannan, C. I. : A mouse model for Prader-Willi syndrome imprinting-centre mutations. Nature Genet. 19: 25-31, 1998. PubMed ID : 9590284 202. Zellweger, H.; Schneider, H. J. : Syndrome of hypotonia-hypomentia-hypogonadism-obesity (HHHO) or Prader-Willi syndrome. Am. J. Dis. Child. 115: 588-598, 1968. PubMed ID : 5645106 203. Zori, R.; Williams, C.; Mattei, J. F.; Moncla, A. : Parental origin of del(15)(q11-q13) in Angelman and Prader-Willi syndromes.. Am. J. Med. Genet. 37: 294-295, 1990. PubMed ID : 2248305 204. Zuffardi, O.; Buhler, E. M.; Fraccaro, M. : Chromosome 15 and Prader-Willi syndrome. (Abstract) Clin. Genet. 14: 315-316, 1978. ### CONTRIBUTORS Victor A. McKusick - updated : 4/4/2005 John A. Phillips, III - updated : 10/15/2004 Natalie E. Krasikov - updated : 10/1/2004 John A. Phillips, III - updated : 8/16/2004 Natalie E. Krasikov - updated : 3/5/2004 Victor A. McKusick - updated : 6/30/2003 John A. Phillips, III - updated : 4/8/2003 Victor A. McKusick - updated : 2/28/2003 John A. Phillips, III - updated : 2/6/2003 John A. Phillips, III - updated : 11/11/2002 Michael J. Wright - updated : 10/22/2002 Victor A. McKusick - updated : 2/27/2002 Ada Hamosh - updated : 2/13/2002 Ada Hamosh - updated : 1/29/2002 Victor A. McKusick - updated : 12/20/2001 George E. Tiller - updated : 5/29/2001 George E. Tiller - updated : 4/25/2001 George E. Tiller - updated : 4/17/2001 Victor A. McKusick - updated : 4/12/2001 George E. Tiller - updated : 3/5/2001 Sonja A. Rasmussen - updated : 12/12/2000 Ada Hamosh - updated : 12/5/2000 Victor A. McKusick - updated : 10/23/2000 George E. Tiller - updated : 9/25/2000 Victor A. McKusick - updated : 8/17/2000 Ada Hamosh - updated : 7/5/2000 Ada Hamosh - updated : 4/28/2000 Victor A. McKusick - updated : 4/25/2000 Victor A. McKusick - updated : 4/10/2000 Armand Bottani - updated : 3/14/2000 Michael J. Wright - updated : 2/10/2000 Victor A. McKusick - updated : 1/12/2000 Victor A. McKusick - updated : 9/15/1999 Sonja A. Rasmussen - updated : 6/30/1999 Victor A. McKusick - updated : 5/14/1999 Victor A. McKusick - updated : 2/18/1999 Victor A. McKusick - updated : 9/2/1998 Victor A. McKusick - updated : 7/20/1998 Michael J. Wright - updated : 6/16/1998 Victor A. McKusick - updated : 5/27/1998 Victor A. McKusick - updated : 4/28/1998 Victor A. McKusick - updated : 1/13/1998 Michael J. Wright - updated : 11/20/1997 Victor A. McKusick - updated : 11/4/1997 Victor A. McKusick - updated : 8/20/1997 Iosif W. Lurie - updated : 1/8/1997 Moyra Smith - updated : 1/3/1997 Mark H. Paalman - updated : 11/9/1996 Alan F. Scott - updated : 12/13/1995 Orest Hurko - updated : 9/22/1995 Albert Schinzel - updated : 3/2/1994 ### CREATION DATE Victor A. McKusick : 6/2/1986 ### EDIT HISTORY wwang : 4/15/2005 wwang : 4/7/2005 terry : 4/4/2005 alopez : 10/15/2004 carol : 10/1/2004 alopez : 8/16/2004 carol : 3/5/2004 carol : 11/17/2003 ckniffin : 11/14/2003 tkritzer : 10/3/2003 tkritzer : 10/1/2003 tkritzer : 7/15/2003 tkritzer : 7/8/2003 terry : 6/30/2003 tkritzer : 4/15/2003 tkritzer : 4/14/2003 terry : 4/8/2003 tkritzer : 3/5/2003 terry : 2/28/2003 cwells : 2/6/2003 alopez : 11/11/2002 tkritzer : 10/23/2002 terry : 10/22/2002 ckniffin : 6/5/2002 cwells : 3/22/2002 cwells : 3/20/2002 terry : 2/27/2002 alopez : 2/14/2002 terry : 2/13/2002 alopez : 1/31/2002 terry : 1/29/2002 cwells : 1/9/2002 terry : 12/20/2001 mcapotos : 6/21/2001 cwells : 6/4/2001 cwells : 5/29/2001 cwells : 5/1/2001 cwells : 4/26/2001 cwells : 4/25/2001 mcapotos : 4/24/2001 mcapotos : 4/17/2001 cwells : 4/17/2001 cwells : 4/17/2001 terry : 4/12/2001 mgross : 4/11/2001 cwells : 3/7/2001 cwells : 3/5/2001 cwells : 3/5/2001 carol : 12/26/2000 mcapotos : 12/13/2000 mcapotos : 12/12/2000 mgross : 12/6/2000 terry : 12/5/2000 mcapotos : 11/6/2000 terry : 10/23/2000 terry : 10/6/2000 alopez : 9/25/2000 mcapotos : 8/30/2000 mcapotos : 8/29/2000 terry : 8/17/2000 carol : 7/5/2000 carol : 7/5/2000 alopez : 6/9/2000 alopez : 5/1/2000 terry : 4/28/2000 terry : 4/25/2000 terry : 4/10/2000 carol : 3/15/2000 terry : 3/14/2000 alopez : 2/10/2000 mgross : 2/3/2000 terry : 1/12/2000 mgross : 10/21/1999 terry : 9/30/1999 jlewis : 9/28/1999 terry : 9/15/1999 carol : 6/30/1999 carol : 6/30/1999 carol : 6/30/1999 kayiaros : 6/29/1999 alopez : 6/3/1999 mgross : 6/1/1999 mgross : 5/26/1999 terry : 5/14/1999 carol : 2/22/1999 terry : 2/18/1999 alopez : 9/8/1998 terry : 9/2/1998 carol : 7/22/1998 terry : 7/20/1998 carol : 7/2/1998 terry : 6/17/1998 terry : 6/16/1998 terry : 5/27/1998 carol : 5/19/1998 alopez : 4/29/1998 terry : 4/28/1998 mark : 1/16/1998 terry : 1/13/1998 alopez : 12/5/1997 alopez : 12/3/1997 alopez : 12/3/1997 alopez : 11/25/1997 terry : 11/20/1997 jenny : 11/12/1997 terry : 11/4/1997 dholmes : 9/17/1997 dholmes : 9/17/1997 dholmes : 8/29/1997 terry : 8/25/1997 terry : 8/20/1997 terry : 8/20/1997 alopez : 7/30/1997 jenny : 7/9/1997 terry : 3/12/1997 mark : 3/6/1997 joanna : 2/21/1997 jenny : 1/21/1997 jamie : 1/8/1997 jenny : 1/8/1997 terry : 1/6/1997 terry : 1/3/1997 terry : 1/3/1997 mark : 11/9/1996 mark : 10/23/1996 terry : 10/7/1996 mark : 9/10/1996 terry : 9/3/1996 mark : 8/14/1996 terry : 7/22/1996 mark : 6/17/1996 terry : 6/11/1996 terry : 4/30/1996 mark : 4/9/1996 terry : 4/5/1996 mark : 3/30/1996 terry : 3/21/1996 joanna : 12/20/1995 joanna : 12/13/1995 mark : 12/13/1995 mark : 6/11/1995 davew : 8/15/1994 jason : 6/16/1994 warfield : 4/21/1994 Copyright © 1966-2005 Johns Hopkins University
3: | *601623 | GeneTests, Links
| UBIQUITIN-PROTEIN LIGASE E3A; UBE3A
#### Alternative titles; symbols HUMAN PAPILLOMAVIRUS E6-ASSOCIATED PROTEIN; E6AP ### TABLE OF CONTENTS #### CLONING GENE STRUCTURE GENE FUNCTION CYTOGENETICS MOLECULAR GENETICS BIOCHEMICAL FEATURES ANIMAL MODEL ALLELIC VARIANTS View List REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q11-q13 ### TEXT #### CLONING E6AP was initially identified as a cellular protein that mediates the in vitro association of the human papillomavirus E6 protein with p53 (191170), leading to the ubiquitin-dependent degradation of p53 (Huibregtse et al., 1991, Scheffner et al., 1990). Scheffner et al. (1993) found that E6AP is an E3 ubiquitin-protein ligase. Huibregtse et al. (1993) cloned the E6AP gene and studied the expressed protein's association with p53 and E6. The 865-amino acid E6AP protein has a native molecular mass of approximately 100 kD. To determine possible epigenetic effects on expression within duplicated 15q11-q13 regions, Herzing et al. (2002) utilized RNA-FISH to directly observe gene expression. RNA-FISH, unlike RT-PCR, is polymorphism-independent and detects relative levels of expression at each allele. Unamplified, gene-specific RNA signals were detected using cDNA probes. Subsequent DNA-FISH confirmed RNA signals and assigned parental origin by colocalization of genomic probes. SNRPN (182279) and NDN (602117) expression was detected primarily from paternal alleles. However, maternal-UBE3A signals were consistently larger than paternal signals in normal fibroblasts, neural-precursor cells, on one or both maternal alleles in a cell line carrying a maternal interstitial duplication, and on both alleles of a maternally derived marker(15) chromosome. Excess total maternal-UBE3A RNA was confirmed by Northern blot analysis of cell lines carrying 15q11-q13 duplications or triplications. The authors concluded that: UBE3A is imprinted in fibroblasts, lymphoblasts and neural-precursor cells; allelic imprint status is maintained in the majority of cells upon duplication both in cis and in trans; and alleles on specific types of duplications may exhibit an increase in expression levels/loss of expression constraints. #### GENE STRUCTURE The UBE3A gene encodes a member of a family of functionally related proteins defined by a conserved C-terminal 350-amino acid 'hect' domain. Hect E3 proteins appear to be important in substrate recognition and in ubiquitin transfer (see 600012). Yamamoto et al. (1997) found that the coding region of the UBE3A gene is composed of 10 exons and spans at least 60 kb; the 5-prime untranslated region (UTR) is composed of at least 4 exons. Several UBE3A mRNAs, identified by RT-PCR, encode protein isoforms differing at their N termini. Each of the mRNAs was expressed in all cell lines tested. Kishino and Wagstaff (1998) found that the UBE3A gene has at least 16 exons, including 6 exons that encode the 5-prime UTR. The gene spans approximately 120 kb, with transcription oriented from telomere to centromere. Kishino and Wagstaff (1998) identified additional alternatively spliced forms of UBE3A mRNA. #### PSEUDOGENES Kishino and Wagstaff (1998) mapped 2 processed UBE3A pseudogenes to chromosomes 2 and 21. #### GENE FUNCTION Vu and Hoffman (1997) and Rougeulle et al. (1997) showed that imprinting of the UBE3A gene is restricted to brain. Its expression is biallelic in fibroblasts, lymphoblasts, heart, kidney, and other tissues. This finding is consistent with the clinical manifestations of Angelman syndrome and the postmortem findings, both of which suggest that the brain is the major organ affected in this disorder. Albrecht et al. (1997) used mice with partial paternal uniparental disomy (UPD) encompassing Ube3a to differentiate maternal and paternal expression. They found by in situ hybridization that expression of Ube3a in Purkinje cells, hippocampal neurons, and mitral cells of the olfactory bulb in UPD mice was markedly reduced compared to non-UPD littermates. In contrast, expression of Ube3a in other regions of the brain was reduced only moderately or not at all in UPD mice. The major phenotypic features of AS correlate with the loss of maternal-specific expression of Ube3a in hippocampus and cerebellum as revealed in this mouse model. Yamasaki et al. (2003) analyzed Ube3a imprinting status in embryonic mouse cortical cell cultures. RT-PCR and immunofluorescence were performed to determine the allelic expression of the gene. The sense transcript was expressed maternally in neurons but biallelically in glial cells in the embryonic brain, whereas the antisense transcript was expressed only in neurons and only from the paternal allele. Yamasaki et al. (2003) concluded that reciprocal imprinting of sense and antisense transcripts present only in neurons suggests a neuron-specific imprinting mechanism that is related to the lineage determination of neural stem cells. #### CYTOGENETICS As diagrammed by Matsuura et al. (1997) in their Figure 1, UBE3A was found to lie in the Angelman syndrome (AS; 105830) region of proximal chromosome 15q defined by the breakpoint of an interstitial deletion on the centromeric side and the breakpoint in a familial t(14;15) on the telomeric side. The region is telomeric to the Prader-Willi syndrome (176270) region which contains the SNRPN gene. RT-PCR analysis of UBE3A for imprinted expression in cultured human fibroblasts and lymphoblasts from AS and PWS patients with large deletions using primers in exons 9 and 10 indicated biallelic expression, suggesting that UBE3A was an unlikely candidate locus for AS. Kishino et al. (1997) found an inversion that causes AS when transmitted maternally and which disrupted the UBE3A gene. #### MOLECULAR GENETICS Kishino et al. (1997) found 2 mutations in nondeletion/nonuniparental disomy/nonimprinting mutations (NDUI) AS patients that were predicted to eliminate UBE3A function. Matsuura et al. (1997) identified 4 mutations in the UBE3A gene in AS patients, including a de novo frameshift mutation and a de novo nonsense mutation in exon 3 and 2 missense mutations of less certain significance. The de novo truncating mutations indicated that UBE3A is the AS gene and suggested the possibility of a maternally expressed gene product in addition to the biallelically expressed transcript. The authors commented that intragenic mutation of UBE3A in Angelman syndrome was the first example of a genetic disorder of the ubiquitin-dependent proteolytic pathway in mammals. It may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products. Precedent for the production of imprinted and nonimprinted transcripts from a single locus exist for insulin-like growth factor-2 (IGF2; 147470), where 4 promoters, 3 imprinted and 1 biallelically expressed, account for differential expression. Malzac et al. (1998) identified UBE3A coding-region mutations detected by SSCP analysis in 13 AS individuals or families. In 2 cases, an identical de novo 5-bp duplication in exon 16 was found. Among the other 11 unique mutations, 8 were small deletions or insertions predicted to cause frameshifts, 1 was a mutation to a stop codon, 1 was a missense mutation, and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein, which functions in E2 binding and ubiquitin transfer. Eight of the cases were familial, and 5 were sporadic. In 2 familial cases and 1 sporadic case, mosaicism for UBE3A mutations was detected: in the mother of 3 AS sons, in the maternal grandfather of 2 AS first cousins, and in the mother of an AS daughter. The frequency with which they detected mutations was 5 (14%) of 35 in sporadic cases and 8 (80%) of 10 in familial cases. Fung et al. (1998) found a functionally insignificant 14-bp deletion in the 3-prime untranslated region of the UBE3A1 gene. The allelic variant was identified in the search for a mutation in a patient with what was thought to be atypical Angelman syndrome. The patient had mental retardation, lack of speech, ataxia, and a 'happy disposition.' A fair complexion, strabismus, and disrupted sleep were also observed. She was considered to be atypical since she was very short in stature and did not have a prominent mandible. In addition, her ataxia was less severe than is typically seen in Angelman syndrome, she did not exhibit inappropriate laughter, and she had normal occiput formation as well as a normal EEG at age 2 years and 6 months. The 14-bp deletion was found in the patient, her normal sib, and her unaffected mother. Fang et al. (1999) sequenced the major coding exons of the UBE3A gene in 56 index patients with a clinical diagnosis of Angelman syndrome (105830) and a normal DNA methylation pattern. Disease-causing mutations were identified in 17 of the 56 patients (30%), including 13 truncating mutations, 2 missense mutations, 1 single amino acid deletion, and 1 stop codon mutation which predicted an elongated protein. Mutations were identified in 6 of 8 families (75%) with more than 1 affected individual, and in 11 of 47 isolated cases (23%); no mutation was found in 1 family with 2 sibs, 1 with typical and 1 with atypical phenotype. Mutations were de novo in 9 of the 11 isolated cases. An amino acid polymorphism, ala178 to thr, was identified, and a 3-bp length polymorphism was found in the intron upstream of exon 8. In all informative cases, phenotypic expression was consistent with imprinting, with a normal phenotype when the mutation was on the paternal chromosome and an Angelman syndrome phenotype when the mutation was on the maternal chromosome. Rapakko et al. (2004) performed conformation-sensitive gel electrophoresis (CSGE) mutation analysis of the UBE3A coding region in 9 patients with Angelman syndrome who had shown a normal biparental inheritance and methylation pattern of 15q11-q13. They identified disease-causing mutations in 5 of them, including 2 missense mutations: thr106 to pro (601623.0006) and ile130 to thr (601623.0007). Two patients shared a frameshift deletion of 4 nucleotides in exon 16: 3093delAAGA (601623.0008); the fifth patient's mutation was a frameshift resulting from 1930delAG in exon 9 (601623.0009). CSGE was found to be a sensitive and simple screening method for mutations in UBE3A. #### BIOCHEMICAL FEATURES Huang et al. (1999) determined that the crystal structure of the catalytic hect domain of E6AP revealed a bilobal structure with a broad catalytic cleft at the junction of the 2 lobes. The cleft consists of conserved residues whose mutation interferes with ubiquitin-thioester bond formation and is the site of Angelman syndrome mutations. The crystal structure of E6AP hect domain bound to the UBCH7 ubiquitin-conjugating (E2) enzyme (603721) revealed the determinants of the E2-E3 specificity and provided insights into the transfer of ubiquitin from the E2 to the E3. #### ANIMAL MODEL Jiang et al. (1998) generated transgenic mice with the maternal or paternal UBE3A genes knocked out and compared them with their wildtype (m+/p+) littermates. Mice with paternal deficiency (m+/p-) were essentially similar to wildtype mice. The phenotype of mice with maternal deficiency (m-/p+) resembles that of human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. The absence of detectable expression of UBE3a in hippocampal neurons and Purkinje cells in m-/p+ mice, indicating imprinting with silencing of the paternal allele, correlated well with the neurologic and cognitive impairments. Long-term potentiation in the hippocampus was severely impaired. The cytoplasmic abundance of p53 was found to be greatly increased in Purkinje cells and in a subset of hippocampal neurons in m-/p+ mice, as well as in a deceased AS patient. Jiang et al. (1998) suggested that failure of Ube3a to ubiquitinate target proteins and promote their degradation could be a key aspect of the pathogenesis of AS. ### ALLELIC VARIANTS (selected examples) #### .0001 ANGELMAN SYNDROME [UBE3A, 5-BP DUP] In a nondeletion/non-UPD/nonimprinting mutation (NDUI) Angelman syndrome (105830) patient, Kishino et al. (1997) found heterozygosity for a 5-bp de novo tandem duplication of the UBE3A gene that resulted in a frameshift and premature termination of translation. #### .0002 ANGELMAN SYNDROME [UBE3A, IVS9, A-G, -8] In 2 brothers with Angelman syndrome (105830), Kishino et al. (1997) found an A-to-G transition in the UBE3A gene that created a new 3-prime splice junction 7-bp upstream from the normal splice junction. The mutation was predicted to cause a frameshift and premature termination of translation. SSCP analysis of products derived with primers flanking exon 10 showed an abnormal band that was also present in their normal mother but not in their father. The normal phenotype of the mother was presumably a consequence of her having inherited the mutation from her father. #### .0003 ANGELMAN SYNDROME [UBE3A, 2-BP DEL, 1344GT] Matsuura et al. (1997) studied 10 patients meeting standard clinical diagnostic criteria for Angelman syndrome (105830) and 1 with possible Angelman syndrome, all having a normal methylation pattern at SNRPN (182279). One of the 11 patients was found to have a 2-bp deletion (1344delAG), resulting in a frameshift mutation and truncation of the protein 23 codons downstream. This mutation was not present in either parent. Fung et al. (1998) found this mutation in a patient with typical Angelman syndrome. Restriction analysis of parental amplicons with XbaI and EcoRI demonstrated that the allele was not carried by either parent. Nonpaternity was excluded on the basis of genotyping with 5 highly polymorphic markers. #### .0004 ANGELMAN SYNDROME [UBE3A, ARG417TER ] In a patient with Angelman syndrome (105830), Matsuura et al. (1997) identified an arg417-to-ter (R417X) nonsense mutation. This mutation resulted in loss of a TaqI restriction enzyme site. An analysis of the family revealed that this was a de novo mutation. #### .0005 ANGELMAN SYNDROME [UBE3A, TRP768TER ] In a family of mixed Ashkenazi and Iraqi Jewish descent, Tsai et al. (1998) observed 2 children affected with Angelman syndrome (105830). Sequence analysis for the 10 major coding exons of UBE3A identified a nonsense mutation in exon 15. The mutation was a G-to-A substitution at nucleotide 2304, which caused a nonsense mutation (trp768 to ter) at the protein level. The mother was heterozygous for the mutation. #### .0006 ANGELMAN SYNDROME [UBE3A, THR106PRO ] In a patient with Angelman syndrome (105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) identified a 902A-C transversion in exon 9 of the UBE3A gene, resulting in a thr106-to-pro amino acid substitution (T106P). The patient's mother was mosaic for the mutation. #### .0007 ANGELMAN SYNDROME [UBE3A, ILE130THR ] In a patient with Angelman syndrome (105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) identified a 975T-C transition in exon 9 of the UBE3A gene, resulting in an ile130-to-thr amino acid substitution (I130T). #### .0008 ANGELMAN SYNDROME [UBE3A, 4-BP DEL, 3093AAGA] In 2 patients with Angelman syndrome (105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) identified a 4-bp deletion in exon 16 of the UBE3A gene, 3093delAAGA, that resulted in frameshift and a truncated protein. #### .0009 ANGELMAN SYNDROME [UBE3A, 2-BP DEL, 1930AG] In a patient with Angelman syndrome (105830) who had shown a normal biparental inheritance and methylation pattern of 15q11-q13, Rapakko et al. (2004) found a 2-bp deletion in exon 9 of the UBE3A gene, 1930delAG, that resulted in frameshift and a truncated protein. #### .0010 ANGELMAN SYNDROME [UBE3A, 4-BP DUP, EX10, GAGG ] In 2 first cousins with Angelman syndrome (105830), Molfetta et al. (2003) identified a duplication of GAGG in exon 10 of the UBE3A gene, which caused a frameshift and truncation of the protein. The mutation was inherited from their asymptomatic mothers. Molfetta et al. (2004) reported that these first cousins presented discordant phenotypes. The proband had typical AS features, whereas her cousin had a more severe phenotype with asymmetric spasticity, which originally led to the diagnosis of cerebral palsy, and severe brain malformations on MRI. Because the cousins' grandfather had transmitted the mutation to only 2 of 8 sibs, Molfetta et al. (2004) raised the hypothesis of mosaicism for this mutation. ### REFERENCES 1. Albrecht, U.; Sutcliffe, J. S.; Cattanach, B. M.; Beechey, C. V.; Armstrong, D.; Eichele, G.; Beaudet, A. L. : Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons. Nature Genet. 17: 75-78, 1997. PubMed ID : 9288101 2. Fang, P.; Lev-Lehman, E.; Tsai, T.-F.; Matsuura, T.; Benton, C. S.; Sutcliffe, J. S.; Christian, S. L.; Kubota, T.; Halley, D. J.; Meijers-Heijboer, H.; Langlois, S.; Graham, J. M., Jr.; Beuten, J.; Willems, P. J.; Ledbetter, D. H.; Beaudet, A. L. : The spectrum of mutations in UBE3A causing Angelman syndrome. Hum. Molec. Genet. 8: 129-135, 1999. PubMed ID : 9887341 3. Fung, D. C. Y.; Yu, B.; Cheong, K. F.; Smith, A.; Trent, R. J. : UBE3A 'mutations' in two unrelated and phenotypically different Angelman syndrome patients. Hum. Genet. 102: 487-492, 1998. PubMed ID : 9600250 4. Herzing, L. B. K.; Cook, E. H.; Ledbetter, D. H. : Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications. Hum. Molec. Genet. 11: 1707-1718, 2002. PubMed ID : 12095913 5. Huang, L.; Kinnucan, E.; Wang, G.; Beaudenon, S.; Howley, P. M.; Huibregtse, J. M.; Pavletich, N. P. : Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2-E3 enzyme cascade. Science 286: 1321-1326, 1999. PubMed ID : 10558980 6. Huibregtse, J. M.; Scheffner, M.; Howley, P. M. : A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 10: 4129-4135, 1991. PubMed ID : 1661671 7. Huibregtse, J. M.; Scheffner, M.; Howley, P. M. : Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Molec. Cell. Biol. 13: 775-784, 1993. PubMed ID : 8380895 8. Jiang, Y.; Armstrong, D.; Albrecht, U.; Atkins, C. M.; Noebels, J. L.; Eichele, G.; Sweatt, J. D.; Beaudet, A. L. : Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21: 799-811, 1998. PubMed ID : 9808466 9. Kishino, T.; Lalande, M.; Wagstaff, J. : UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genet. 15: 70-73, 1997. PubMed ID : 8988171 10. Kishino, T.; Wagstaff, J. : Genomic organization of the UBE3A/E6-AP gene and related pseudogenes. Genomics 47: 101-107, 1998. PubMed ID : 9465301 11. Malzac, P.; Webber, H.; Moncla, A.; Graham, J. M., Jr.; Kukolich, M.; Williams, C.; Pagon, R. A.; Ramsdell, L. A.; Kishino, T.; Wagstaff, J. : Mutation analysis of UBE3A in Angelman syndrome patients. Am. J. Hum. Genet. 62: 1353-1360, 1998. PubMed ID : 9585605 12. Matsuura, T.; Sutcliffe, J. S.; Fang, P.; Galjaard, R.-J.; Jiang, Y.; Benton, C. S.; Rommens, J. M.; Beaudet, A. L. : De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genet. 15: 74-77, 1997. PubMed ID : 8988172 13. Molfetta, G. A.; Munoz, M. V. R.; Santos, A. C.; Silva, W. A., Jr.; Wagstaff, J.; Pina-Neto, J. M. : Discordant phenotypes in first cousins with UBE3A frameshift mutation. Am. J. Med. Genet. 127A: 258-262, 2004. 14. Molfetta, G. A.; Silva, W. A., Jr.; Pina-Neto, J. M. : Clinical, cytogenetical, and molecular analyses of Angelman syndrome. Genet. Counsel. 14: 45-56, 2003. 15. Rapakko, K.; Kokkonen, H.; Leisti, J. : UBE3A gene mutations in Finnish Angelman syndrome patients detected by conformation sensitive gel electrophoresis. Am. J. Med. Genet. 126A: 248-252, 2004. 16. Rougeulle, C.; Glatt, H.; Lalande, M. : The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. (Letter) Nature Genet. 17: 14-15, 1997. PubMed ID : 9288088 17. Scheffner, M.; Huibregtse, J. M.; Vierstra, R. D.; Howley, P. M. : The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75: 495-505, 1993. PubMed ID : 8221889 18. Scheffner, M.; Werness, B. A.; Huibregtse, J. M.; Levine, A. J.; Howley, P. M. : The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63: 1129-1136, 1990. PubMed ID : 2175676 19. Tsai, T.-F.; Raas-Rothschild, A.; Ben-Neriah, Z.; Beaudet, A. L. : Prenatal diagnosis and carrier detection for a point mutation in UBE3A causing Angelman syndrome. (Letter) Am. J. Hum. Genet. 63: 1561-1563, 1998. PubMed ID : 9792887 20. Vu, T. H.; Hoffman, A. R. : Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. (Letter) Nature Genet. 17: 12-13, 1997. PubMed ID : 9288087 21. Yamamoto, Y.; Huibregtse, J. M.; Howley, P. M. : The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing. Genomics 41: 263-266, 1997. PubMed ID : 9143503 22. Yamasaki, K.; Joh, K.; Ohta, T.; Masuzaki, H.; Ishimaru, T.; Mukai, T.; Niikawa, N.; Ogawa, M.; Wagstaff, J.; Kishino, T. : Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a. Hum. Molec. Genet. 12: 837-847, 2003. PubMed ID : 12668607 ### CONTRIBUTORS George E. Tiller - updated : 2/21/2005 Carol A. Bocchini - updated : 11/3/2004 Victor A. McKusick - updated : 4/14/2004 George E. Tiller - updated : 6/18/2003 Wilson H. Y. Lo - updated : 4/7/2000 Ada Hamosh - updated : 11/11/1999 Victor A. McKusick - updated : 2/17/1999 Victor A. McKusick - updated : 12/8/1998 Clair A. Francomano - updated : 6/26/1998 Victor A. McKusick - updated : 6/23/1998 Rebekah S. Rasooly - updated : 5/19/1998 Victor A. McKusick - updated : 8/28/1997 ### CREATION DATE Victor A. McKusick : 1/10/1997 ### EDIT HISTORY wwang : 3/2/2005 terry : 2/21/2005 carol : 11/3/2004 alopez : 4/16/2004 terry : 4/14/2004 cwells : 6/18/2003 alopez : 7/11/2002 alopez : 7/11/2002 alopez : 7/11/2002 alopez : 5/3/2001 terry : 4/30/2001 carol : 7/6/2000 terry : 4/7/2000 mgross : 12/2/1999 alopez : 11/12/1999 terry : 11/11/1999 mgross : 2/26/1999 mgross : 2/22/1999 terry : 2/17/1999 dkim : 12/11/1998 terry : 12/8/1998 carol : 6/26/1998 carol : 6/25/1998 terry : 6/23/1998 psherman : 5/20/1998 psherman : 5/19/1998 jenny : 9/1/1997 terry : 8/28/1997 mark : 6/27/1997 mark : 6/27/1997 mark : 6/27/1997 mark : 1/15/1997 jenny : 1/14/1997 mark : 1/10/1997 Copyright © 1966-2005 Johns Hopkins University
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| IMPRINTED IN PRADER-WILLI SYNDROME; IPW
### TABLE OF CONTENTS #### TEXT REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q11-q13 ### TEXT The Prader-Willi syndrome (176270) is a neurologic behavioral disorder that is usually associated with microscopically detectable cytogenetic deletion of the paternal 15q11-q13 chromosome region. Cases have also been associated with uniparental maternal disomy, submicroscopic deletions, or chromosomal rearrangements involving chromosome 15. By direct selection of expressed sequences from the PWS smallest region of deletion overlap, Wevrick et al. (1994) isolated a gene they showed to be expressed exclusively from the paternal allele in lymphoblasts and fibroblasts. The gene, designated 'imprinted gene in the Prader-Willi syndrome region' (IPW), is spliced and polyadenylated but encodes a polypeptide of only 45 amino acids. They showed that the transcript is cytoplasmic, as is the imprinted H19 gene (103280) on chromosome 11, and that it is widely expressed in adult and fetal tissues. By YAC contig analysis, Wevrick et al. (1994) placed IPW about 150 kb distal to SNRPN (182279) and about 50 kb proximal to the breakpoint of a translocation defining the distal end of the PWS critical region and the proximal end of the Angelman syndrome (105830) region. The authors observed that PWS patients with 15q11-q13 deletions do not express IPW, whereas expression was normal in Angelman syndrome patients. Wevrick et al. (1994) speculated that the IPW may function as an RNA (not unlike the XIST (314670) and H19 transcripts) and that it may play a role in the imprinting process. Wevrick and Francke (1997) cloned a mouse gene, designated Ipw, that has sequence similarity to a part of IPW and is located in the conserved homologous region of mouse chromosome 7. The Ipw cDNA also contains no long open reading frame, is alternatively spliced, and contains multiple copies of a 147 bp repeat, arranged in a head-to-tail orientation, that are interrupted by the insertion of an intracisternal A particle sequence. Ipw is expressed predominantly in brain. They could show that expression of Ipw in an interspecies F1 animal was limited to the paternal allele. Because of all of these striking similarities, Wevrick and Francke (1997) proposed that Ipw is the murine homolog of IPW, a prime candidate for involvement in the cause of Prader-Willi syndrome. Balanced translocations affecting the paternal copy of 15q11-q13 are a rare cause of Prader-Willi syndrome (PWS) or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation, t(X;15)(q28;q12), in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene (182279) and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85 (605436), as well as IPW and PAR1 (600161), were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype. ### REFERENCES 1. Wevrick, R.; Francke, U. : An imprinted mouse transcript homologous to the human imprinted in Prader-Willi syndrome (IPW) gene. Hum. Molec. Genet. 6: 325-332, 1997. PubMed ID : 9063754 2. Wevrick, R.; Kerns, J. A.; Francke, U. : Identification of a novel paternally expressed gene in the Prader-Willi syndrome region. Hum. Molec. Genet. 3: 1877-1882, 1994. PubMed ID : 7849716 3. Wirth, J.; Back, E.; Huttenhofer, A.; Nothwang, H.-G.; Lich, C.; Gross, S.; Menzel, C,; Schinzel, A.; Kioschis, P.; Tommerup, N.; Ropers, H.-H.; Horsthemke, B.; Buiting, K. : A translocation breakpoint cluster disrupts the newly defined 3-prime end of the SNURF-SNRPN transcription unit on chromosome 15. Hum. Molec. Genet. 10: 201-210, 2001. PubMed ID : 11159938 ### CONTRIBUTORS George E. Tiller - updated : 4/17/2001 Victor A. McKusick - updated : 2/26/1997 ### CREATION DATE Mark H. Paalman : 11/7/1996 ### EDIT HISTORY cwells : 4/26/2001 cwells : 4/20/2001 cwells : 4/17/2001 cwells : 4/17/2001 mark : 2/26/1997 terry : 2/24/1997 mark : 11/8/1996 mark : 11/7/1996 Copyright © 1966-2005 Johns Hopkins University
5: | #105830 | GeneTests, Links
| ANGELMAN SYNDROME; AS
#### Alternative titles; symbols HAPPY PUPPET SYNDROME ANGELMAN SYNDROME CHROMOSOME REGION, INCLUDED; ANCR, INCLUDED ### TABLE OF CONTENTS #### TEXT ANIMAL MODEL SEE ALSO REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Clinical Synopsis Gene map locus Xq28, 15q11-q13 ### TEXT A number sign (#) is used with this entry because of evidence that the cause of the syndrome resides in the E6-associated protein ubiquitin-protein ligase gene (UBE3A; 601623). Additionally, patients with a clinical diagnosis of Angelman syndrome but who show features of Rett syndrome (312750) have been reported who have mutations in the MECP2 gene (300005). Bower and Jeavons (1967) coined the name 'happy puppet' syndrome for a condition with features of severe motor and intellectual retardation, ataxia, hypotonia, epilepsy, absence of speech, and unusual facies characterized by a large mandible and open-mouthed expression revealing the tongue. They reported 2 patients. The French refer to the syndrome as that of the 'marionette joyeuse' (Halal and Chagnon, 1976) or 'pantin hilare' (Pelc et al., 1976). Williams and Frias (1982) suggested use of the eponym Angelman syndrome because the term 'happy puppet' may appear derisive and even derogatory to the patient's family. (Harry Angelman pronounces his name as though it means 'male angel;' in other words, he uses a 'long a' and a 'soft g.') Angelman (1965) had reported 3 'puppet children,' as he called them. Berg and Pakula (1972) reported a case and reviewed those reported by Angelman (1965) and Bower and Jeavons (1967). All of the patients demonstrated excessive laughter, an occipital groove, a great facility for protruding the tongue (tongue thrusting), abnormal choroidal pigmentation, and characteristic electroencephalogram (EEG) discharges. Of the 3 patients reported by Angelman (1965), at least 1 developed optic atrophy. Two patients showed jerky movements and had trouble walking. The walking problem may be due to poor balance. One, a 9-year-old boy who was noticed as an infant to be 'floppy,' could take only a few steps without support. Both patients had major convulsions and showed periods of flapping their arms up and down with the elbows flexed. The EEG pattern seen in these 2 cases and in the cases of Bower and Jeavons (1967) consisted of high amplitude bilateral spike-and-wave activity which was symmetrical, synchronous, and most often monorhythmic, having a slow wave component at 2 cycles per sec. Normal karyotype was found in the 5 patients studied. Viani et al. (1995) found electroencephalographic evidence of transient myoclonic status epilepticus in 9 of 18 Angelman patients. This may account for recurrent jerky abnormal movements that have been previously observed in these patients. In addition, 7 patients had partial seizures with eye deviation and vomiting similar to those of childhood occipital epilepsies. The patient reported by Berg and Pakula (1972) had an unaffected sib who, however, showed abnormal EEG patterns. Williams and Frias (1982) demonstrated unilateral cerebellar atrophy by computerized axial tomography in 1 patient. Angelman (1965) emphasized the abnormal cranial shape and suggested that the depressed occiput may reflect a cerebellar abnormality. Boyd et al. (1988) pointed out the usefulness of the electroencephalogram in the early diagnosis of Angelman syndrome. Dorries et al. (1988) described 7 cases and concluded that the diagnosis is difficult in the first years of life. Robb et al. (1989) reviewed the clinical features in 36 children. Episodes of paroxysmal laughter was a feature, and tongue thrusting was common. The movement disorder consisted of a wide-based, ataxic gait with frequent jerky limb movements and flapping of the hands. Scheffer et al. (1990) pointed out the possible confusion with Rett syndrome (312750). Fryburg et al. (1991) described the clinical features in 4 patients diagnosed at less than 2 years of age. One of their patients had oculocutaneous albinism, and all were hypopigmented compared to their first-degree relatives. All 4 had choroidal pigment hypoplasia, severe to profound global developmental delay and microcephaly of postnatal onset, seizures, hypotonia, hyperreflexia, and hyperkinesis. Clayton-Smith (1993) reported on observations concerning 82 affected individuals. All of them had absent speech or spoke less than 6 words. Thirty-nine percent were hypopigmented compared to the family. Frequent smiling was present in 96%. King et al. (1993) concluded from the study of 6 individuals with AS that hypopigmentation characterized by light skin, reduced retinal pigment, low hairbulb tyrosinase activity, and incomplete melanization of melanosomes is part of the phenotype of AS, and is similar to that found in Prader-Willi syndrome (PWS; 176270). Reish and King (1995) established the diagnosis of Angelman syndrome in a 50-year-old woman. She had been healthy without seizures and had a history of pelvic fracture resulting from her unbalanced gait. She was born to a 40-year-old mother. Her height was 148 cm and her IQ was measured at less than 20. She did not speak and had frequent bursts of laughter. Reish and King (1995) demonstrated a 15q11.2-q12 deletion by karyotypic examination and fluorescence in situ hybridization (FISH). Buntinx et al. (1995) compared the main manifestations of Angelman syndrome in 47 patients at different ages. Most patients between the ages of 2 and 16 years showed at least 8 of the major characteristics of the syndrome (bursts of laughter, happy disposition, hyperactivity, micro- and brachycephaly, macrostomia, tongue protrusion, prognathism, widely spaced teeth, puppetlike movements, wide-based gait) in addition to mental retardation and absence of speech. Most patients (80.8%) had epileptic seizures, starting after the age of 10 months. In children under the age of 2 years, bursts of laughter was found in 42.8% and macrostomia in only 13.3%, but protruding tongue was a constant feature. In patients over 16 years of age, protruding tongue was found in 38.8%, whereas prognathism and macrostomia were almost constant findings. A cytogenetic deletion was found in 61% and a molecular deletion in 73% of the patients. No case of paternal disomy was found. Buntinx et al. (1995) found no differences between patients with or without deletion. The diagnosis of Angelman syndrome may be hampered in young children because of the absence of some typical manifestations and in older patients because of the changing behavioral characteristics. Angelman syndrome is not typically mendelian. The disorder could represent a dominant mutation. However, paternal age was not remarkable in the patients of Williams and Frias (1982). Pashayan et al. (1982) reported Angelman syndrome in 2 brothers, and Kuroki et al. (1980) reported 2 affected sisters. Pashayan et al. (1982) found reports of 27 sporadic cases with a sex ratio of M1:F1. Dijkstra et al. (1986) reported brother and sister with the Angelman syndrome. Hersh et al. (1981) reported affected monozygotic twins. Fisher et al. (1987) reported affected brother and sister. Baraitser et al. (1987) reported 7 cases of Angelman syndrome from 3 families: 2 brothers in the first family, 3 sisters in the second, and 2 brothers in the third. The EEG changes were striking in all 7 patients. Willems et al. (1987) reported what they believed to be the fourth family with affected sibs out of a total of 52 cases in the literature. This suggests a low but not negligible recurrence risk. Robb et al. (1989) observed 3 sibships with more than 1 affected sib: 3 affected sisters, 2 affected brothers, and 2 affected sisters. Clayton-Smith et al. (1992) studied 11 patients and their parents from 5 families using high resolution chromosome analysis and molecular probes from the region 15q11-q13. No deletions were detected. All sets of sibs inherited the same maternal chromosome 15, whereas in 3 families sibs inherited different paternal 15s. Polymorphic DNA markers gave the same conclusion. Thus, autosomal recessive inheritance is very unlikely and maternal transmission of a mutation within 15q11-q13 is much more tenable. Magenis et al. (1987) described 2 unrelated girls with a deletion of the proximal part of 15q. The girls showed none of the typical features of the Prader-Willi syndrome, a disorder with which this deletion is sometimes associated. The clinical features were more like those of Angelman syndrome; specifically, ataxia-like incoordination, frequent, unprovoked and prolonged bouts of laughter, and a facial appearance compatible with that diagnosis. Magenis et al. (1988) studied 15q deletion in 6 Angelman syndrome patients and an equal number of Prader-Willi syndrome patients. In all patients, band 15q11 appeared to be deleted; however, the deletion appeared larger in the patients with Angelman syndrome and also included band q12. Magenis et al. (1988) suggested that genes in band 15q12 are responsible for the greater severity of mental retardation and speech in Angelman syndrome and that these genes also suppress or alter the presumed hypothalamic abnormality that results in the uncontrolled appetite and obesity of Prader-Willi syndrome. Magenis et al. (1990) did high-resolution cytogenetic studies of 7 patients with Prader-Willi syndrome and 10 patients with Angelman syndrome. The same proximal band was deleted (15q11.2) in both syndromes. In general, the deletion in patients with Angelman syndrome was larger, though variable, and included bands q12 and part of q13. Magenis et al. (1990) confirmed the maternal origin of the deleted chromosome, contrasting with the predominant paternal origin of the deletion in patients with Prader-Willi syndrome. All 4 of the patients described by Fryburg et al. (1991) had deletions in the 15q11.2-q13 region. Parental chromosomes were available for study in 3 of these cases; in all 3 the deleted chromosome 15 was maternally derived. By molecular analyses, Donlon (1988) and Knoll et al. (1989) showed that similar deletions of 15q11.2 were present in patients with the Prader-Willi syndrome and the Angelman syndrome. He proposed a hypothesis to explain the seemingly paradoxical findings. Whereas the deleted chromosome is of paternal origin in the Prader-Willi syndrome, it is the maternal chromosome that is partially deleted in Angelman syndrome (Williams et al., 1988). Otherwise, the deletions in Angelman syndrome and the Prader-Willi syndrome are indistinguishable cytogenetically or by molecular genetic methods. This has been interpreted as indicating imprinting of chromosomes, i.e., changes in the chromosome according to the parent of origin, with resulting consequences for early development. Using RFLPs, Knoll et al. (1989) demonstrated maternal inheritance of the deleted chromosome 15 in 4 Angelman syndrome patients. Knoll et al. (1990) studied DNA of 19 patients, including 2 sib pairs, using 4 DNA markers specific to 15q11-q13. Three classes were identified: in class I, deletion of 2 markers was detected; in class II, deletion of 1 marker; and in class III, including both sib pairs, no deletion was detected. High resolution cytogenetic data were available on 16 of the patients, and complete concordance between the presence of a cytogenetic deletion and a molecular deletion was observed. No submicroscopic deletions were detected by the DNA studies. DNA samples from the parents of 10 patients with either a class I or a class II deletion were available for study. In 7 of the 10 families, RFLPs were informative as to the parental origin of the deletion, and in all, the deleted chromosome was of maternal origin. Knoll et al. (1991) concluded, however, that uniparental disomy (UPD) may be infrequent in Angelman syndrome: by qualitative hybridization with chromosome 15q11-q13-specific DNA markers, they examined the DNA from 10 AS patients (at least 7 of whom were familial cases) with no cytogenetic or molecular deletion of chromosome 15q11-q13. In each case, 1 maternal copy and 1 paternal copy of 15q11-q13 was observed. Malcolm et al. (1991) found evidence of uniparental paternal disomy in 2 patients. Engel (1991), who introduced the concept of uniparental disomy in 1980 (Engel, 1980), took Knoll et al. (1991) to task for their conclusion that uniparental disomy may be rare in this disorder and urged further studies. Paternal uniparental disomy was demonstrated by Freeman et al. (1993) in a child with a balanced 15;15 translocation. DNA polymorphisms demonstrated that the patient was homozygous at all loci for which the father was heterozygous, suggesting that the structural rearrangement was an isochromosome 15q and not a Robertsonian translocation. Engel (1993) reviewed the possible mechanisms for uniparental disomy. One possibility is gamete complementation, i.e., the gamete from one parent containing both chromosomes of the pair and that from the other parent containing neither. When gamete complementation is the mechanism, the centromeres of the resulting pair will be heterodisomic if resulting from a meiosis 1 error, and isodisomic if resulting from a meiosis 2 error. Beyond that, meiosis 1 UPD, depending on crossing-over and segregation, may be wholly heterodisomic (holo-heterodisomy) or partially isodisomic (mero-isodisomy); meiosis 2 UPD should always result in an element of isodisomy embodied in the 2 segments of the nonseparated chromatids left unaffected by crossing-over. This unaffected segment, of course, tends to be juxtacentromeric. Gametic complementation UPD was reported by Wang et al. (1991), who found paternal heterodisomy for chromosome 14 in a 45,XX,t(13q14q)der pat proposita, whose 2 parents were balanced heterozygotes for a translocation involving chromosome 14. This situation is analogous to the effects of biparental translocation as in the mouse experiments of Cattanach and Kirk (1985). A second mechanism of UPD is so-called trisomy rescue or correction. It is expected that the remaining pair, after loss of the extra homolog, will be biparental in two-thirds of cases and uniparental in one-third of cases. In such instances, as in gamete complementation, isodisomy may or may not be present. Cases of UPD in Prader-Willi syndrome whose chromosomal 15 maternal disomy could be traced to a placental mosaicism for trisomy 15 documented at the time of choriocentesis (chorion villus sampling) performed for advanced maternal age were reported by Cassidy et al. (1992) and Purvis-Smith et al. (1992). A third situation is akin to the second; the abnormal initial zygotic situation is monosomy rather than trisomy and the abnormality is 'corrected' through duplication of the single available homolog. The case of cystic fibrosis with maternal chromosome 7 isodisomy and growth delay reported by Spence et al. (1988) may have been of this type, although there is at least one other explanation. Donnai (1993) pointed out that Robertsonian translocations, occurring with a frequency of about 1 in 10,000 live births, may be an important cause of UPD; such has been demonstrated to be the case for 13/15, 13/14, 14/14, and 22/22 translocations. Dysmorphologic features and/or mental retardation are clinical clues for uniparental disomy in apparently balanced offspring of translocation carriers. Among abortion products of balanced Robertsonian translocation carriers, an excess of 'normal balanced' conceptions has been noted. Robertsonian translocations involving chromosomes 13 and/or 21 are frequently ascertained through a trisomic child. Among those ascertained through a mentally retarded but nontrisomic proband, there appears to be overrepresentation of translocations involving chromosome 14. Since nonmosaic trisomy 14 is nonviable, such a conception would survive a pregnancy only by reducing to disomy. In line with other reports, Smith et al. (1992) found the deletion of band 15q12 to be of maternal origin in all of 25 cases. The parental origin was determined using cytogenetic markers in 13 of the cases, by the pattern of inheritance of RFLPS in 9, and by both techniques in 3. Tonk et al. (1992) found cytogenetic deletion of 15q12 in 3 cases of AS and by heteromorphism studies showed that the deleted chromosome was maternal in all 3. Meijers-Heijboer et al. (1992) reported findings in an usually large pedigree with segregation of AS through maternal inheritance and apparent asymptomatic transmission through several male ancestors. Deletion and paternal disomy at 15q11-q13 were excluded; however, the genetic defect was located in this region because they found a maximum lod score of 5.40 for linkage to GABRB3 (137192) and the DNA marker D15S10. The size of the pedigree allowed calculation of an odds ratio in favor of genomic imprinting of 9.25 x 10(5). After discovering 2 unrelated patients with a small deletion of proximal 15q, Pembrey et al. (1988, 1989) reassessed 10 further patients. Four showed a deletion within 15q11-q13, 1 showed an apparent pericentric inversion with breakpoints at 15q11 and q13 inherited from the mother, and 5 showed no discernible abnormality. Of the 5 children without discernible chromosome change, 1 had a definitely affected sib and 1 had a possibly affected sib. Of the 4 sets of parents studied, 3 had normal chromosomes, and in 1 the mother had a deletion of 15q11.2 but not 15q12. Kaplan et al. (1987) also described deletion in 15q11-q12 in a child with Angelman syndrome. By flow karyotype analysis on lymphoblastoid cell lines, Cooke et al. (1988, 1989) confirmed the presence of a de novo 15q deletion in a child with Angelman syndrome. The deleted segment represented 6.1 to 9.5% of chromosome 15, or approximately 6-9.3 million basepairs. Cytogenetic evidence suggested that the deleted chromosome was derived from the smaller chromosome 15 homolog of the mother. Like Pembrey et al. (1989), Fryns et al. (1989) found a visible chromosomal change in half of the patients they studied. No deletion was found in 2 affected sisters. In 6 out of 8 children, aged 3 to 10 years, Dickinson et al. (1988) found an association of striking deficiency of choroidal pigment with normal foveal reflexes. All 6 had light blue irides with normal iris architecture. All were isolated cases born to healthy, unrelated parents. The presence or absence of 15q microdeletions did not correlate with the ocular findings. Imaizumi et al. (1990) described 6 patients, including 2 sibs, with Angelman syndrome. The 4 sporadic cases showed a microdeletion in the proximal part of 15q. The affected sibs had no visible deletion. No clinical difference between the sporadic cases and the sib cases was discerned. Using 2 DNA probes that detect a molecular deletion in most patients with Prader-Willi syndrome, they found by densitometry that 2 patients had only 1 copy of each probe, whereas the other 4, including the sibs, had 2 copies of each sequence. Thus, the segment causing Angelman syndrome may be different from that causing Prader-Willi syndrome, although closely adjacent. Williams et al. (1990) studied 6 persons with Angelman syndrome and de novo deletions of 15q11-q13. In 4 of the patients, cytogenetic studies were informative of parental origin; in all, the deletion was inherited from the mother. Genomic imprinting was suggested. Malcolm et al. (1990) studied 37 typical cases. A 15q11-q13 deletion was observed in 18 of 24 isolated cases. No deletion was observed in 13 cases from 6 families with more than 1 affected child. In 11 cases it was possible to elucidate the parental origin of the deleted chromosome and these were shown to be predominantly maternal. Greenstein (1990) presented a kindred in which both the Prader-Willi and Angelman syndromes were found; the inheritance pattern was consistent with genetic imprinting. Hulten et al. (1991) reported an extraordinary family showing segregation of a balanced translocation t(15;22)(q13;q11) and 2 cases of Prader-Willi syndrome and 1 of Angelman syndrome. It appeared that the females carrying the balanced translocation had a high risk of having children with AS, while their brothers had a high risk of having children with PWS. Wagstaff et al. (1992) presented observations on a family demonstrating that nondeletion, nonuniparental disomy can result from a genetic alteration in 15q11-q13, when transmitted by the mother, and that the loci responsible for PWS and AS, although closely linked, are distinct. In the instructive family they described, 3 sisters had given birth to 4 AS offspring who had no evidence of deletion or paternal disomy. Wagstaff et al. (1992) showed that the inferred mutation had been transmitted by the grandfather to 3 of his offspring without phenotypic effects. Wagstaff et al. (1993) indicated that this was the first instance in which the origin of a new mutation in nondeletion AS could be pinpointed. A sister of the grandfather had transmitted the same AS-associated haplotype to 4 of her children, all of whom were phenotypically normal. Therefore, either there was germline mosaicism in the grandfather, with the mutation transmitted to at least 3 of his 5 children, or the grandfather inherited a new AS mutation from his father. Hamabe et al. (1991) described transmission of a submicroscopic deletion in a 3-generation family which resulted in AS only upon maternal transmission of the deletion. No clinical phenotype was associated with paternal transmission. Greger et al. (1993) cloned and sequenced the breakpoint of this submicroscopic deletion. Among other things, their findings suggested that the imprinted gene responsible for the PWS phenotype is proximal to that responsible for the AS phenotype. In studies reported by Robinson et al. (1993), most cases of paternal UPD(15) leading to Angelman syndrome were meiosis II errors or, more likely, mitotic errors. On the other hand, in more than 82% of cases of maternal UPD(15) leading to Prader-Willi syndrome, the extra chromosome was due to a meiosis I nondisjunction event. A similar observation has been made for trisomy 21: the majority (78%) of maternal errors leading to trisomy 21 are attributable to meiosis I events, whereas most paternal errors are attributed to either meiosis II or mitotic events (40% and 33%, respectively) (Antonarakis et al., 1993). In summary, Angelman syndrome results from a lack of maternal contribution from chromosome 15q11-q13, arising from de novo deletion in most cases or from uniparental disomy in rare cases. Most families are associated with a low recurrence risk. With the exception of the family reported by Hamabe et al. (1991)(see earlier), no deletion has been found in the minority of families with more than one child affected. The mode of inheritance in these families is autosomal dominant modified by imprinting. Sporadic cases with no observable deletion pose a counseling dilemma. Chan et al. (1993) presented a series of 93 Angelman syndrome patients, showing the relative contribution of the various genetic mechanisms. Sporadic cases accounted for 81 AS patients, while 12 cases came from 6 families. Deletions in 15q11-q13 were detected in 60 cases by use of a set of highly polymorphic (CA)n repeat markers and conventional RFLPs. In 10 sporadic cases and in all 12 familial cases, no deletion was detectable. In addition, 2 cases of de novo deletions occurred in a chromosome 15 carrying a pericentric inversion. In one of these the AS child had a cousin with Prader-Willi syndrome arising from a de novo deletion in an inverted chromosome 15 inherited from his father. The other case arose from a maternal balanced t(9;15)(p24;q15) translocation. There were 3 cases of uniparental disomy. In the familial cases, all affected sibs inherited the same maternal chromosome 15 markers for the region 15q11-q13. Cytogenetic analysis detected only 42 of the 60 deletion cases. Cytogenetic analysis is still essential, however, to detect chromosomal abnormalities other than deletions such as inversions and balanced translocations, both of which have an increased risk for deletions. Beuten et al. (1996) reported an extraordinary, highly inbred, extended Dutch kindred in which 3 cases, 2 males and 1 female with Angelman syndrome, occurred in 3 separate sibships in the kindred sharing common ancestral couples through all 6 parents. High resolution chromosome analysis combined with DNA analysis using 14 marker loci from the 15q11-q13 region failed to detect a deletion in any of the 3 patients. Paternal uniparental disomy of chromosome 15 was detected in 1 case, while the other 2 patients had abnormal methylation of D15S9, D15S63, and SNRPN (182279). Although the 3 patients were distantly related, the chromosome 15q11-q13 haplotypes were different, again suggesting that independent mutations gave rise to AS in this family. On the basis of molecular and cytogenetic findings, Saitoh et al. (1994) classified 61 Angelman syndrome patients into 4 groups: familial cases without deletion, familial cases with submicroscopic deletion, sporadic cases with deletion, and sporadic cases without deletion. Among 53 sporadic cases, 37 (70%) had molecular deletion, which commonly extended from D15S9 to D15S12, although not all deletions were identical. Of 8 familial cases, 3 sibs from 1 family had a molecular deletion involving only 2 loci, D15S10 and GABRB3, which defined the critical region for AS phenotypes. The deletion, both in sporadic and familial cases, was exclusively maternal in origin, consistent with the genomic imprinting hypothesis. Among sporadic and familial cases without deletion, no uniparental disomy was found. Of 23 patients with a normal karyotype, 10 (43%) showed a molecular deletion. Except for hypopigmentation of skin or hair, neurologic signs and facial characteristics were not distinctive in a particular group. Familial cases with submicroscopic deletion were not associated with hypopigmentation, suggesting that a gene for hypopigmentation is located outside the critical region of AS and is not imprinted. Bundey et al. (1994) reported a boy with ataxia, mental retardation, infantile autism, and seizures, who had an extensive interstitial duplication of 15q11-q13, including the critical regions for the Prader-Willi and Angelman syndromes, on the maternally derived chromosome. Analysis by FISH and conventional Southern blot analysis, as well as genotyping for (CA)n repeat markers by PCR amplification, demonstrated duplication of all markers from D15S11 to D15S24. Among the duplicated genes were GABRA5 (137142) and GABRB3 (137192), and the authors speculated that these duplications may have contributed to the phenotype. Clayton-Smith et al. (1993) had earlier reported a patient with a less extensive duplication, which included the Angelman critical region, who had ataxia and moderate developmental delay, particularly of language, but neither epilepsy nor behavior problems. Before the study of Buxton et al. (1994), the AS region had been narrowed to approximately 1.5 Mb, as defined by an affected family carrying a small inherited deletion (Kuwano et al., 1992) and another patient with an unbalanced translocation (Reis et al., 1993). Buxton et al. (1994) identified an individual with typical features of AS who had a deletion of the maternal chromosome shown to be less than 200 kb. Unlike the usual cause of loss of maternal genetic material through deletion of 15q11-q13 or paternal uniparental disomy of chromosome 15, Burke et al. (1996) reported a case of Angelman syndrome resulting from an unbalanced cryptic translocation with a breakpoint at 15q11.2. The proband was diagnosed clinically as having Angelman syndrome but no cytogenetic deletion was detected. Fluorescence in situ hybridization detected a deletion of D15S11, with an intact GABRB3 locus. Subsequent studies of the proband's mother and sister detected a cryptic reciprocal translocation between chromosomes 14 and 15 with the breakpoint being between SNRPN (182279) and D15S10. The proband was found to have inherited an unbalanced form, being monosomic from 15pter through SNRPN and trisomic for 14pter-q11.2. DNA methylation studies showed that the proband had a paternal-only DNA methylation pattern at SNRPN, D15S63, and ZNF127 (MKRN3; 603856). The mother and unaffected sister, both having the balanced translocation, demonstrated normal DNA methylation patterns at all 3 loci. These data suggested to Burke et al. (1996) that the gene for AS most likely lies proximal to D15S10, in contrast to the previously published position, although a less likely possibility is that the maternally inherited imprinting center acts in trans in the unaffected balanced translocation carrier sister. Clayton-Smith and Pembrey (1992) provided a review. Smith et al. (1996) reviewed the clinical features of 27 Australian patients with AS, all with a DNA deletion involving 15q11-q13 and spanning markers from D15S9 to D15S12 (approximately 3.5 Mb of DNA). There were 9 males and 18 females, all sporadic, ranging in age from 3 to 34 years, and all ataxic, severely retarded, and lacking in recognizable speech. Head circumference at birth was normal in all but skewed in distribution, with 62.5% at the tenth centile. Epilepsy was present in 96% with onset during the third year of life in 20 of 26 patients. Hypopigmentation was present in 19 (73%). One patient had ocular cutaneous albinism. A happy disposition was noted in infancy in 95% and they all had a large, wide mouth. The American Society of Human Genetics/American College of Medical Genetics Test and Technology Transfe reviewed diagnostic testing for Prader-Willi syndrome and Angelman syndrome. Kishino et al. (1997) and Matsuura et al. (1997) demonstrated that the gene for E6-AP ubiquitin-protein ligase is one cause of Angelman syndrome. Matsuura et al. (1997) identified de novo truncating mutations in patients with Angelman syndrome, indicating that UBE3A is the AS gene and suggesting the possibility of a maternally expressed gene product in addition to the biallelically expressed transcript of the UBE3A gene. Kishino et al. (1997) found novel UBE3A mutations in nondeletion/nonuniparental disomy/nonimprinting mutation AS patients. These mutations also were predicted to cause a frameshift and premature termination of translation. This suggested that AS is the first recognized example of genetic disorder of the ubiquitin-dependent proteolytic pathway in mammals. It also may represent an example of a human genetic disorder associated with a locus producing functionally distinct imprinted and biallelically expressed gene products. Precedent for the production of imprinted and nonimprinted transcripts from a single locus exists for insulin growth factor-2 (IGF2; 147470), where 4 promoters, 3 imprinted and 1 biallelically expressed, account for differential expression. Among 22 institutionalized adults selected for criteria suggestive of Angelman syndrome, Sandanam et al. (1997) found deletion in the 15q11-q13 region in 11 (9 males and 2 females). The mean age at last review was 31.5 years (range 24 to 36 years). Clinical assessment documented findings of large mouth and jaw with deep set eyes and microcephaly in 9 patients (2 having a large head size for height). No patient was hypopigmented; 1 patient was fair. Outbursts of laughter occurred in all patients, but infrequently in 7 of 11 (64%), and a constant happy demeanor was present in 5 of 11 (46%). All had epilepsy, with improvement in 5 (46%), no change in 4 (36%), and deterioration in 2 (18%). The EEG was abnormal in 10 of 10 patients. Ocular abnormalities were reported in 3 of 8 patients (37.5%), with keratoconus present in 2, and 4 of 11 (36%) developed kyphosis. Two had never walked. All 9 who walked were ataxic with an awkward, clumsy, heavy, and/or lilting gait. No patient had a single word of speech, but 1 patient could use sign language for 2 needs, food and drink. The findings of Sandanam et al. (1997) supported the concept that AS resulting from deletion is a severe neurologic syndrome in adulthood. Minassian et al. (1998) found severe intractable epilepsy in patients with maternally inherited chromosome 15q11-q13 deletions but relatively mild epilepsy in patients with uniparental disomy methylation imprinting abnormalities or mutations in the UBE3A gene. As indicated earlier, Angelman syndrome most frequently results from large de novo deletions of 15q11-q13. The deletions are exclusively of maternal origin, and a few cases of paternal uniparental disomy of chromosome 15 have been identified as the cause of AS. The findings indicate that AS is caused by absence of a maternal contribution to the imprinted 15q11-q13 region. Cases of AS resulting from translocations or pericentric inversions had been observed to be associated with deletions, and no confirmed reports of balanced rearrangements had been reported in AS until the patient described by Greger et al. (1997). Their patient had a paracentric inversion with a breakpoint located approximately 25 kb proximal to the reference marker D15S10. This inversion was inherited from a phenotypically normal mother. No deletion was evident by molecular analysis in this case, by use of cloned fragments mapped to within approximately 1 kb of the inversion breakpoint. Among the possible explanations for the AS phenotype put forth by Greger et al. (1997) was the possibility that the inversion disrupted the UBE3A gene. Trent et al. (1997) reported 2 families that further defined the Angelman syndrome critical region. The first analysis, of a 5-year-old girl with typical features of AS, her 14-year-old brother, and an 11-year-old male cousin with less typical clinical features, showed that the 3 shared a common segment of the same grandpaternal chromosome defined by markers D15S122 to GABRB3. The typically affected 5-year-old girl had in addition a maternal recombination between markers D15S210 and D15S113. Trent et al. (1997) proposed that the 3 affected individuals shared a mutation involving the UBE3A gene and that the severe phenotype in the 5-year-old girl was the result of the recombination event, affecting a 5-prime regulatory or controlling region. Trent et al. (1997) analyzed a second family in which a mother and son had a deletion extending from D15S986 telomeric of the UBE3A gene. These individuals had mental retardation, but no other features of AS. Trent et al. (1997) concluded that together, these 2 families identified a region between D15S210 and D15S986, which contains a potential regulatory or controlling region for the UBE3A gene. Approximately 6% of AS patients have a paternal imprint on the maternal chromosome. In a few cases, this is due to an inherited microdeletion in the 15q11-q13 imprinting center (IC) that blocks the paternal-to-maternal imprint switch in the maternal germline. Burger et al. (1997) determined the segregation of 15q11-q13 haplotypes in 9 families with AS and with an imprinting defect. One family, with 2 affected sibs, had a microdeletion affecting the IC transcript. In the other 8 patients, no mutation was found at that locus. In 2 families, the patient and a healthy sib shared the same maternal alleles. In 1 of these families and in 2 others, grandparental DNA samples were available, and the chromosomes with the imprinting defect were found to be of grandmaternal origin. These findings suggested that germline mosaicism or de novo mutations account for a significant fraction of imprinting defects among patients who have an as-yet-undetected mutation in a cis-acting element. Alternatively, Burger et al. (1997) suggested that these data might indicate that some imprinting defects are caused by a failure to maintain or to reestablish the maternal imprint in the maternal germline or by a failure to replicate the imprint postzygotically. Depending on the underlying cause of the imprinting defect, different recurrence risks need to be considered. Stalker and Williams (1998) addressed the challenges of genetic counseling in this disorder with multiple causes. Most cases result from typical large de novo deletions of 15q11-q13 and are expected to have a low (less than 1%) risk of recurrence. AS due to paternal uniparental disomy, which occurs in the absence of a parental translocation, is likewise expected to have a recurrence risk of less than 1%. Parental transmission of a structurally or functionally unbalanced chromosome complement can lead to 15q11-q13 deletions or to UPD and will result in case-specific recurrence risks. In instances where there is no identifiable large deletion or UPD, the risk of recurrence may be as high as 50% as a result of either a maternally inherited imprinting center mutation or a mutation in the UBE3A gene. Individuals with AS who have none of the above abnormalities comprise a significant proportion of cases, and some may be at a 50% recurrence risk. Misdiagnoses can be represented in this group as well. In light of the many conditions that are clinically similar to AS, it is essential to address the possibility of diagnostic uncertainty and potential misdiagnosis before providing genetic counseling. Stalker and Williams (1998) presented an algorithmic chart summarizing the different causal classes of AS for consideration in determining recurrence risks. PWS and AS are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2 to 4% of patients, this loss of function is the result of an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Buiting et al. (1998) described the molecular analysis of 13 PWS patients and 17 AS patients who had an imprinting defect but no IC deletion. Furthermore, heteroduplex and partial sequence analyses did not reveal any point mutations in the known IC elements. All of these patients represented sporadic cases, and some shared the paternal PWS or maternal AS 15q11-q13 haplotype with an unaffected sib. In each of the 5 PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and 4 cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggested that the grandmaternal imprint was not erased in the father's germline. In 7 informative AS patients reported by Buiting et al. (1998) and in 3 previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding was not compatible with an imprint-switch failure, but it suggested that a paternal imprint developed either in the maternal germline or postzygotically. Buiting et al. (1998) concluded that (1) the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error; (2) these cases have a low recurrence risk; and (3) the paternal imprint may be the default imprint. In several patients with Angelman syndrome or Prader-Willi syndrome, microdeletions upstream of the SNRPN gene have been identified, defining an imprinting center that appears to control the imprint switch process in the male and female germlines. Ohta et al. (1999) identified 2 large families segregating an Angelman syndrome imprinting mutation; one of these families was originally described in the first genetic linkage study of Angelman syndrome that mapped the AS gene to 15q11-q13 (Wagstaff et al., 1993). Identification of the imprinting mutation demonstrates that the original linkage was for the imprinting center at 15q11-q13. Affected patients in these 2 Angelman syndrome families had either a 5.5- or a 15-kb microdeletion, one of which narrowed the shortest region of deletion overlap to 1.15 kb in all 8 cases. This small region defined a component of the imprinting center involved in Angelman syndrome, i.e., the paternal-to-maternal switch element. The presence of an inherited imprinting mutation in multiple unaffected members of these 2 families, who are at risk for transmitting the mutation to affected children or children of their daughters, raised important genetic counseling issues. Imprinting in 15q11-q13 is controlled by a bipartite imprinting center (IC), which maps to the SNURF-SNRPN locus. Deletions of the exon 1 region impair the establishment or maintenance of the paternal imprint and can cause Prader-Willi syndrome. Deletions of a region 35 kb upstream of exon 1 impair maternal imprinting and can cause Angelman syndrome. In all sibs affected by Angelman syndrome, an inherited imprinting center deletion had been identified. Buiting et al. (2001) reported 2 sibs with Angelman syndrome who did not have a deletion of the imprinting center but instead had a 1-to-1.5 Mb inversion separating the 2 imprinting center elements. The inversion was transmitted silently through a male germline but impaired maternal imprinting after transmission through the female germline. The findings suggested that the close proximity of the 2 imprinting center elements and their correct orientation, or both, are necessary for the establishment of a maternal imprint. Fridman et al. (1998) studied a patient with an overgrowth syndrome and the chromosome constitution 45,XY,t(15q15q) with molecular methods including methylation analysis with an SNRPN probe, microsatellite analyses of D15S11, GABRB3 and D15S113 loci, and FISH using SNRPN and GABRB3 probes. The results were consistent with the diagnosis of Angelman syndrome due to paternal isodisomy. This was the fourth reported case of translocation 15q15q with paternal uniparental disomy. The findings suggested that some patients with clinical features of AS have hyperphagia and obesity with overgrowth as features. They discussed possible explanations such as homozygosity due to paternal isodisomy for sequence variation (mutation) in one of the genes involved in the pathogenesis of Prader-Willi syndrome. They pointed out that hyperphagia and obesity may occur specifically in association with AS in the context of certain genetic backgrounds, as mice with paternal UPD for the Ube3a region have a postnatal onset of severe obesity (Cattanach et al., 1997). Moncla et al. (1999) compared 20 nondeletion AS patients with 20 age-matched 15q11-q12 deletion AS patients. A less severe phenotype with regard to both physical anomalies and neurologic manifestations was found to be associated with nondeletion AS. The nondeletion cases included patients with paternal uniparental disomy, imprinting mutations, and UBE3A mutations. The clinical severity scale from more to less severe was deletion cases to UBE3A mutation cases to imprinting mutations and/or UPD cases. The molecular cases, however, have a potential high risk for recurrence. Cassidy and Schwartz (1998) gave a comprehensive review of molecular and clinical aspects of both Prader-Willi syndrome and Angelman syndrome. Gillessen-Kaesbach et al. (1999) described 7 patients who lacked most of the features of Angelman syndrome: severe mental retardation, postnatal microcephaly, macrostomia and prognathia, absence of speech, ataxia, and a happy disposition. They presented, however, with obesity, muscular hypotonia, and mild mental retardation. Based on the latter findings, the patients were initially suspected of having Prader-Willi syndrome. DNA methylation analysis of SNRPN and D15S63, however, revealed the pattern of Angelman syndrome, i.e., the maternal band was faint or absent. Cytogenetic studies and microsatellite analysis demonstrated apparently normal chromosomes 15 of biparental origin. Gillessen-Kaesbach et al. (1999) concluded these patients had an imprinting defect and a previously unrecognized form of AS. They suggested that the mild phenotype may have been due to an incomplete imprinting defect or by cellular mosaicism. Molfetta et al. (2004) reported 2 first cousins with AS who had inherited the same UBE3A frameshift mutation (601623.0010) from their asymptomatic mothers but presented discordant phenotypes. The proband had typical AS features, whereas her cousin had a more severe phenotype with asymmetric spasticity that originally led to the diagnosis of cerebral palsy. Brain MRI showed mild cerebral atrophy in the proband and severe malformation in her cousin. Because the mutation was transmitted from the cousins' grandfather to only 2 of 8 sibs, Molfetta et al. (2004) raised the possibility of mosaicism. To elucidate the mechanism underlying the deletions that lead to Prader-Willi syndrome and Angelman syndrome, Amos-Landgraf et al. (1999) characterized the regions containing 2 proximal breakpoint clusters and a distal cluster. Analysis of rodent-human somatic cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences, termed 'END' repeats, at or near the breakpoints. END-repeat units are derived from large genomic duplications of the HERC2 gene (605837) (Ji et al., 1999). Many copies of the HERC2 gene are transcriptionally active in germline tissues. Amos-Landgraf et al. (1999) postulated that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, they proposed that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process. Lossie and Driscoll (1999) described a pregnancy in a 15-year-old female with AS who had been reported by Williams et al. (1989). Williams et al. (1989) had raised the possibility that the proband's mother, who had normal intelligence, was mosaic for a submicroscopic deletion of 15q11-q13, because she displayed brachycephaly, hearing loss, an enlarged foramen magnum, and mild ataxia. However, extensive cytogenetic and molecular analyses of peripheral blood and skin fibroblasts failed to reveal any abnormality in 15q11-q13 in the mother. The daughter had classic AS features, with severe mental retardation, AS-specific behavior, complete lack of speech, and a movement disorder characterized by ataxia. She showed microbrachycephaly with a head circumference of less than -2 standard deviations, relative prognathism, a protruding tongue, excessive drooling, and an inappropriately happy affect with excessive laughter. Menarche began at 11.5 years. Head CT and MRI were remarkable only for an enlarged foramen magnum. The pregnancy was terminated at 15 to 16 weeks gestation. The fetus had inherited large deletions of maternal 15q11-q13 and demonstrated paternal-only DNA methylation imprints along 15q11-q13. UBE3A was paternally expressed in eye tissue from the fetus. These results indicated that females with AS are fully capable of reproduction and that UBE3A is not imprinted in fetal eye. In 25 patients with Angelman syndrome, Fridman et al. (2000) detected 21 with deletion and 4 with paternal UPD, 2 isodisomies originating by postzygotic error, and 1 meiotic stage II nondisjunction event. By comparison of the clinical data from these and published UPD patients with data from patients with deletions, they observed the following: the age at diagnosis was higher in the UPD group, microcephaly was more frequent among deletion patients, UPD children started walking earlier, epilepsy started later in UPD patients, weight above the 75th centile was reported mainly in UPD patients, and complete absence of speech was more common in the deletion patients. UPD patients had somewhat better verbal development and occipital frontal circumference in the upper normal range. In a study of 45 Finnish Angelman patients, Kokkonen and Leisti (2000) found 2 affected sibs, a 16-year-old boy and a 5-year-old girl, in whom the diagnosis was made at 8 years and at 3 months of age, respectively. Both parents and an 18-year-old brother were healthy. The 2 sibs were found to have del(15)(q11q13); the mother's chromosomes 15 were structurally normal, whereas the patients and their unaffected brother shared an identical maternally derived haplotype outside the deletion region. These findings were suggestive of maternal germline mosaicism of del(15)(q11q13). Tekin et al. (2000) described a patient with clinical features of Angelman syndrome in whom FISH analysis revealed mosaicism for a deletion in the AS critical region, but whose methylation study results were normal. The authors recommended that FISH studies for detection of mosaicism be done in patients with clinical findings of AS even if methylation studies are normal. Pointing out that the diagnosis of Angelman syndrome can be confirmed by genetic laboratory in about 80% of cases but remains clinical in the remaining instances, Williams et al. (2001) reviewed several mimicking conditions, including microdeletions or microduplications. Single gene conditions include methylenetetrahydrofolate reductase deficiency (236250), Rett syndrome (312750), alpha-thalassemia retardation syndrome (ATRX; 301040), and Gurrieri syndrome (601187). There are, in addition, symptom complexes, including cerebral palsy (see 603513), autism spectrum disorder (209850), and pervasive developmental delay (PDD), that can suggest Angelman syndrome. Watson et al. (2001) studied 47 patients (25 female and 22 male) with a clinical diagnosis of Angelman syndrome and no molecular abnormality of 15q11-q13. They screened for mutations in the MECP2 gene (300005) and identified causative mutations in 4 females and 1 male. Following the diagnosis it was possible to elicit a history of regression in 3 of the patients, who by then were showing features suggestive of Rett syndrome (312750). In the remaining 2 patients the clinical phenotype was still considered to be Angelman-like. Lossie et al. (2001) studied 104 patients with a classic AS phenotype from 93 families. Twenty of the 104 patients (22%) had normal DNA methylation at 15q11-q13 and of these, 7 of 16 (44%) sporadic patients had mutations within the UBE3A gene. Lossie et al. (2001) identified 4 phenotypic patient groups based on molecular analysis: those with deletions, UPD and imprinting defects, UBE3A mutations, and those with unknown etiology. Patients with deletions were the most severely affected, while those with UPD and imprinting defects were the least severely affected. Patients with UPD and imprinting defects and UBE3A mutations were taller and heavier than those with deletions or of unknown etiology. Those with UPD and imprinting defects were the least likely to have microcephaly. Seizures began earlier in patients with deletions or AS of unknown etiology, and those with deletions were more likely to require anticonvulsive medication. Hall (2002) reported an apparently unique response by Angelman syndrome individuals to the vibrating tuning fork when it was held up to their ears. The response was a wide smile, often with an outburst of laughter, followed by a tendency to lean toward the vibrating tuning fork. In 6 consecutive Angelman individuals ranging in ages from 18 months to 43 years, they demonstrated a positive 'tuning fork response.' The 2 oldest individuals, aged 17 and 43 years, tended to be somewhat less demonstrative with mostly smiles and a more controlled laugh. Parents had observed their affected children as liking sound. This feature was manifested by their lying down or leaning against appliances that made a noise as if it relaxed them or made them feel good. Hall (2002) raised the possibility of the potential use of sound in intervention strategies for these individuals. Hall and Cadle (2002) described a 12-month-old child, later confirmed to have Angelman syndrome, who had a positive tuning fork response. The authors suggested that this test, if found to be positive in Angelman syndrome children at ages 2 to 12 months, may aid in the often difficult first-year diagnosis. Cox et al. (2002) reported 2 children who were conceived by intracytoplasmic sperm injection (ICSI) and who developed Angelman syndrome. Molecular studies, including DNA methylation and microsatellite and quantitative Southern blot analysis, revealed a sporadic imprinting defect in both patients. In germ cells and the early embryo, the mammalian genome undergoes widespread epigenetic reprogramming. Animal studies had suggested that this process is vulnerable to external factors. The authors discussed the possibility that ICSI may interfere with the establishment of the maternal imprint in the oocyte or pre-embryo. Orstavik et al. (2003) described a third case of imprinting defect in a girl with Angelman syndrome who was conceived by ICSI. Biparental origin of normal chromosomes 15 and absence of the common large deletion of 15q11-q13 was found. Methylation-specific Southern blot analysis and methylation-specific PCR for the SNRPN locus showed the presence of a normal unmethylated paternal band and the complete absence of a methylated maternal band, indicating that the patient had an imprinting defect. Among 1,272 patients suspected of having Angelman syndrome, Burger et al. (2002) found 1 with an isolated deletion of the UBE3A gene on the maternally inherited chromosome. Initial DNA methylation testing at the SNURF-SNRPN locus revealed a normal pattern in the patient. The deletion was only detected through allelic loss at 3 microsatellite loci, and confirmed with FISH using BAC probes derived from those 3 loci. The deletion extended approximately 570 kb, encompassing the UBE3A locus, and was familial: it was present in the mother, the maternal grandfather, and his sister. Haplotype studies suggested that the proband's great-grandfather, who was deceased, already carried the deletion, and that it causes Angelman syndrome when inherited through female germline, but not Prader-Willi syndrome when paternally inherited. The findings support the hypothesis that the functional loss of maternal UBE3A is sufficient to cause Angelman syndrome and that the deletion does not contain genes or other structures that are involved in the pathogenesis of Prader-Willi syndrome. The case also emphasized that methylation tests can fail to detect some familial Angelman syndrome cases with a recurrence risk of 50%. Angelman syndrome deletions and rearrangements tend to occur at specific 'hotspots' or breakpoint (BP) clusters in proximal 15q (see Pujana et al., 2002): 2 proximal clusters, referred to as BP1 and BP2, are the breakpoints for class I and class II patients, respectively. The most common distal breakpoint, BP3, is located between markers D15S12 and D15S24. Two other breakpoint regions called BP4 and BP5 have been mapped distal to BP3, between markers D15S24 and D15S144. Gimelli et al. (2003) reported that some mothers of AS patients with deletions of the 15q11-q13 region have a heterozygous inversion involving the region that is deleted in the affected offspring. The inversion was detected in the mothers of 4 of 6 AS cases with the breakpoint 2-3 (BP2/3) 15q11-q13 deletion, but not in 7 mothers of AS cases due to paternal UPD 15. Variable inversion breakpoints were identified within breakpoint segmental duplications in the inverted AS mothers, as well as in AS deleted patients. The BP2-BP3 chromosome 15q11-q13 inversion was detected in 4 of 44 control subjects. Gimelli et al. (2003) hypothesized that the BP2/3 inversion may be an intermediate state that facilitates the occurrence of 15q11-q13 BP2/3 deletions in the offspring. Varela et al. (2004) analyzed the phenotypic and behavioral variability in 49 AS patients with different classes of deletions and 9 patients with UPD. All BP1-BP3 (class I) patients had complete absence of vocalization, compared to only 62% of BP2-BP3 (class II) patients (p = 0.03); and the age of sitting without support was lower in BP2-BP3 patients (p = 0.04). Patients with deletions had a higher incidence of swallowing disorders and hypotonia compared to UPD patients (p = 0.015 and 0.031, respectively). UPD patients also showed significantly better physical growth, fewer or no seizures, a lower incidence of microcephaly, less ataxia, and higher cognitive skills. Varela et al. (2004) suggested that because of their milder or less typical phenotype, AS patients with UPD may remain undiagnosed, leading to overall underdiagnosis of the disease. #### ANIMAL MODEL Cattanach et al. (1992) described a putative mouse model of Prader-Willi syndrome (176270), occurring with maternal duplication (partial maternal disomy) for the region of mouse chromosome 7 homologous to human 15q11-q13. Cattanach et al. (1997) showed that mice with paternal duplication for the same region exhibited characteristics of Angelman syndrome. An elevated frequency of postnatal loss was observed among the mice. Although of normal weight at birth, the mice exhibited a reduced growth rate over the first 4 to 5 weeks. Subsequently, however, their growth rate increased so that by early adulthood (8 weeks) their body weights were similar to those of their sibs. Animals kept to later ages continued to increase in weight and by 6 months they were grossly obese. Despite this, tail and femur lengths were significantly shorter than those of sibs, suggesting a smaller overall skeletal size. Most males proved to be fertile, but, perhaps because of the developing obesity, females were often infertile. Neurobehavioral differences were also suggested: at 10 to 14 days of age, the mice with the paternal duplication displayed a mild gait ataxia with slight eversion of the hind limbs; at 16 to 18 days they showed abnormal limb clasping when suspended briefly by the tail and exhibited a startle reflex when dropped onto their feet from a height of about 10 cms; after weaning (3 to 16 weeks) they showed marked behavioral hyperactivity relative to their normal sibs in the open field testing. Neuropathologic examinations revealed that total brain weight was diminished by about 10%. Electrocorticographic recordings on paternally duplicated mice showed a striking diffuse cortical excitability disturbance that was identical in all animals. The gross obesity of a 6 month old AS mouse was pictured. Cattanach et al. (1997) noted that both PWS and AS patients may exhibit hypopigmentation and early feeding difficulties, and that a late-onset obesity, rather than the early-onset obesity of PWS, may be seen in a subset of AS patients (Clayton-Smith, 1992; Smith et al., 1996). Jiang et al. (1998) generated transgenic mice with the maternal or paternal UBE3A genes knocked out and compared them with their wildtype (m+/p+) littermates. Mice with paternal deficiency (m+/p-) were essentially similar to wildtype mice. The phenotype of mice with maternal deficiency (m-/p+) resembles that of human AS with motor dysfunction, inducible seizures, and a context-dependent learning deficit. The absence of detectable expression of UBE3a in hippocampal neurons and Purkinje cells in m-/p+ mice, indicating imprinting with silencing of the paternal allele, correlated well with the neurologic and cognitive impairments. 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L. : Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21: 799-811, 1998. PubMed ID : 9808466 61. Kaplan, L. C.; Wharton, R.; Elias, E.; Mandell, F.; Donlon, T.; Latt, S. A. : Clinical heterogeneity associated with deletions in the long arm of chromosome 15: report of 3 new cases and their possible genetic significance. Am. J. Med. Genet. 28: 45-53, 1987. PubMed ID : 3674117 62. King, R. A.; Wiesner, G. L.; Townsend, D.; White, J. G. : Hypopigmentation in Angelman syndrome. Am. J. Med. Genet. 46: 40-44, 1993. PubMed ID : 8494033 63. Kishino, T.; Lalande, M.; Wagstaff, J. : UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genet. 15: 70-73, 1997. PubMed ID : 8988171 64. Knoll, J. H. M.; Glatt, K. A.; Nicholls, R. D.; Malcolm, S.; Lalande, M. : Chromosome 15 uniparental disomy is not frequent in Angelman syndrome. Am. J. Hum. Genet. 48: 16-21, 1991. PubMed ID : 1985457 65. Knoll, J. H. M.; Nicholls, R. D.; Magenis, R. E.; Glatt, K.; Graham, J. M., Jr.; Kaplan, L.; Lalande, M. : Angelman syndrome: three molecular classes identified with chromosome 15q11q13-specific DNA markers. Am. J. Hum. Genet. 47: 149-155, 1990. PubMed ID : 1971993 66. Knoll, J. H. M.; Nicholls, R. D.; Magenis, R. E.; Graham, J. M., Jr.; Lalande, M.; Latt, S. A. : Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am. J. Med. Genet. 32: 285-290, 1989. PubMed ID : 2564739 67. Kokkonen, H.; Leisti, J. : An unexpected recurrence of Angelman syndrome suggestive of maternal germ-line mosaicism of del(15)(q11q13) in a Finnish family. Hum. Genet. 107: 83-85, 2000. PubMed ID : 10982040 68. Kuroki, Y.; Matsui, I.; Yamamoto, Y.; Ieshima, A. : The 'happy puppet' syndrome in two siblings. Hum. Genet. 56: 227-229, 1980. PubMed ID : 7450780 69. Kuwano, A.; Mutirangura, A.; Dittrich, B.; Buiting, K.; Horsthemke, B.; Saitoh, S.; Niikawa, N.; Ledbetter, S. A.; Greenberg, F.; Chinault, A. C.; Ledbetter, D. H. : Molecular dissection of the Prader-Willi/Angelman syndrome region (15q11-13) by YAC cloning and FISH analysis. Hum. Molec. Genet. 1: 417-425, 1992. PubMed ID : 1363801 70. Lossie, A. C.; Driscoll, D. J. : Transmission of Angelman syndrome by an affected mother. Genet. Med. 1: 262-266, 1999. PubMed ID : 11258627 71. Lossie, A. C.; Whitney, M. M.; Amidon, D.; Dong, H. J.; Chen, P.; Theriaque, D.; Hutson, A.; Nicholls, R. D.; Zori, R. T.; Williams, C. A.; Driscoll, D. J. : Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J. Med. Genet. 38: 834-845, 2001. PubMed ID : 11748306 72. Magenis, R. E.; Brown, M. G.; Lacy, D. A.; Budden, S.; LaFranchi, S. : Is Angelman syndrome an alternate result of del(15)(q11q13)? Am. J. Med. Genet. 28: 829-838, 1987. PubMed ID : 3688021 73. Magenis, R. E.; Toth-Fejel, S.; Allen, L. J.; Black, M.; Brown, M. G.; Budden, S.; Cohen, R.; Friedman, J. M.; Kalousek, D.; Zonana, J.; Lacy, D.; LaFranchi, S.; Lahr, M.; Macfarlane, J.; Williams, C. P. S. : Comparison of the 15q deletions in Prader-Willi and Angelman syndromes: specific regions, extent of deletions, parental origin, and clinical consequences. Am. J. Med. Genet. 35: 333-349, 1990. PubMed ID : 2309780 74. Magenis, R. E.; Toth-Fejel, S.; Allen, L. J.; Cohen, R.; Lahr, M.; Macfarlane, J.; Black, M.; Lacy, D.; Brown, M. : Angelman happy puppet and Prader Willi syndromes: do they share an identical deletion? (Abstract) Am. J. Hum. Genet. 43: A113, 1988. 75. Malcolm, S.; Clayton-Smith, J.; Nichols, M.; Robb, S.; Webb, T.; Armour, J. A. L.; Jeffreys, A. J.; Pembrey, M. E. : Uniparental paternal disomy in Angelman's syndrome. Lancet 337: 694-697, 1991. PubMed ID : 1672177 76. Malcolm, S.; Webb, T.; Rutland, P.; Middleton-Price, H. R.; Pembrey, M. E. : Molecular genetic studies of Angelman's syndrome. (Abstract) J. Med. Genet. 27: 205, 1990. PubMed ID : 2325098 77. Matsuura, T.; Sutcliffe, J. S.; Fang, P.; Galjaard, R.-J.; Jiang, Y.; Benton, C. S.; Rommens, J. M.; Beaudet, A. L. : De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genet. 15: 74-77, 1997. PubMed ID : 8988172 78. Meijers-Heijboer, E. J.; Sandkuijl, L. A.; Brunner, H. G.; Smeets, H. J. M.; Hoogeboom, A. J. M.; Deelen, W. H.; van Hemel, J. O.; Nelen, M. R.; Smeets, D. F. C. M.; Niermeijer, M. F.; Halley, D. J. J. : Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome. J. Med. Genet. 29: 853-857, 1992. PubMed ID : 1362220 79. Minassian, B. A.; DeLorey, T. M.; Olsen, R. W.; Philippart, M.; Bronstein, Y.; Zhang, Q.; Guerrini, R.; Van Ness, P.; Livet, M. O.; Delgado-Escueta, A. V. : Angelman syndrome: correlations between epilepsy phenotypes and genotypes. Ann. Neurol. 43: 485-493, 1998. PubMed ID : 9546330 80. Molfetta, G. A.; Munoz, M. V. R.; Santos, A. C.; Silva, W. A., Jr.; Wagstaff, J.; Pina-Neto, J. M. : Discordant phenotypes in first cousins with UBE3A frameshift mutation. Am. J. Med. Genet. 127A: 258-262, 2004. 81. Moncla, A.; Malzac, P.; Voelckel, M.-A.; Auquier, P.; Girardot, L.; Mattei, M.-G.; Philip, N.; Mattei, J.-F.; Lalande, M.; Livet, M.-O. : Phenotype-genotype correlation in 20 deletion and 20 non-deletion Angelman syndrome patients. Europ. J. Hum. Genet. 7: 131-139, 1999. PubMed ID : 10196695 82. Moore, J. R.; Jeavons, P. M. : The 'happy puppet' syndrome: two new cases and a review of five previous cases. Neuropaediatrie 4: 172-179, 1973. 83. Ohta, T.; Buiting, K.; Kokkonen, H.; McCandless, S.; Heeger, S.; Leisti, H.; Driscoll, D. J.; Cassidy, S. B.; Horsthemke, B.; Nicholls, R. D. : Molecular mechanism of Angelman syndrome in two large families involves an imprinting mutation. Am. J. Hum. Genet. 64: 385-396, 1999. PubMed ID : 9973277 84. Orstavik, K. H.; Eiklid, K.; van der Hagen, C. B.; Spetalen, S.; Kierulf, K.; Skjeldal, O.; Buiting, K. : Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic sperm injection. (Letter) Am. J. Hum. Genet. 72: 218-219, 2003. PubMed ID : 12549484 85. Pashayan, H. M.; Singer, W.; Bove, C.; Eisenberg, E.; Seto, B. : The Angelman syndrome in two brothers. Am. J. Med. Genet. 13: 295-298, 1982. PubMed ID : 7180875 86. Pelc, S.; Levy, J.; Point, G. : 'Happy puppet' syndrome ou syndrome du 'pantin hilare.'. Helv. Paediat. Acta 31: 183-188, 1976. PubMed ID : 955942 87. Pembrey, M.; Fennell, S. J.; van den Berghe, J.; Fitchett, M.; Summers, D.; Butler, L.; Clarke, C.; Griffiths, M.; Thompson, E.; Super, M.; Baraitser, M. : The association of Angelman's syndrome with deletions within 15q11-13. J. Med. Genet. 26: 73-77, 1989. PubMed ID : 2918545 88. Pembrey, M.; Fennell, S. J.; van den Berghe, J.; Fitchett, M.; Summers, D.; Butler, L.; Clarke, C.; Griffiths, M.; Thompson, E.; Super, M.; Baraitser, M. : The association of Angelman syndrome and deletions within 15q11-13. (Abstract) J. Med. Genet. 25: 274, 1988. PubMed ID : 3367356 89. Pujana, M. A.; Nadal, M.; Guitart, M.; Armengol, L.; Gratacos, M.; Estivill, X. : Human chromosome 15q11-q14 regions of rearrangements contain clusters of LCR15 duplicons. Europ. J. Hum. Genet. 10: 26-35, 2002. PubMed ID : 11896453 90. Purvis-Smith, S. G.; Saville, T.; Manass, S.; Yip, M.-Y.; Lam-Po-Tang, P. R. L.; Duffy, B.; Johnston, H.; Leigh, D.; McDonald, B. : Uniparental disomy 15 resulting from 'correction' of an initial trisomy 15. (Letter) Am. J. Hum. Genet. 50: 1348-1350, 1992. PubMed ID : 1598916 91. Reis, A.; Kunze, J.; Ladanyi, L.; Enders, H.; Klein-Vogler, U.; Niemann, G. : Exclusion of the GABA(A)-receptor beta-3 subunit gene as the Angelman's syndrome gene. (Letter) Lancet 341: 122-123, 1993. PubMed ID : 8093396 92. Reish, O.; King, R. A. : Angelman syndrome at an older age. (Letter) Am. J. Med. Genet. 57: 510-511, 1995. PubMed ID : 7677166 93. Robb, S. A.; Pohl, K. R. E.; Baraitser, M.; Wilson, J.; Brett, E. M. : The 'happy puppet' syndrome of Angelman: review of the clinical features. Arch. Dis. Child. 64: 83-86, 1989. PubMed ID : 2466440 94. Robinson, W. P.; Bernasconi, F.; Mutirangura, A.; Ledbetter, D. H.; Langlois, S.; Malcolm, S.; Morris, M. A.; Schinzel, A. A. : Nondisjunction of chromosome 15: origin and recombination. Am. J. Hum. Genet. 53: 740-751, 1993. PubMed ID : 8352279 95. Saitoh, S.; Harada, N.; Jinno, Y.; Hashimoto, K.; Imaizumi, K.; Kuroki, Y.; Fukushima, Y.; Sugimoto, T.; Renedo, M.; Wagstaff, J.; Lalande, M.; Mutirangura, A.; Kuwano, A.; Ledbetter, D. H.; Niikawa, N. : Molecular and clinical study of 61 Angelman syndrome patients. Am. J. Med. Genet. 52: 158-163, 1994. PubMed ID : 7802001 96. Sandanam, T.; Beange, H.; Robson, L.; Woolnough, H.; Buchholz, T.; Smith A. : Manifestations in institutionalised adults with Angelman syndrome due to deletion. Am. J. Med. Genet. 70: 415-420, 1997. PubMed ID : 9182785 97. Scheffer, I.; Brett, E. M.; Wilson, J.; Baraitser, M. : Angelman's syndrome. (Letter) J. Med. Genet. 27: 275-277, 1990. PubMed ID : 2325111 98. Smith, A.; Wiles, C.; Haan, E.; McGill, J.; Wallace, G.; Dixon, J.; Selby, R.; Colley, A.; Marks, R.; Trent, R. J. : Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion. J. Med. Genet. 33: 107-112, 1996. PubMed ID : 8929945 99. Smith, J. C.; Webb, T.; Pembrey, M. E.; Nichols, M.; Malcolm, S. : Maternal origin of deletion 15q11-13 in 25/25 cases of Angelman syndrome. Hum. Genet. 88: 376-378, 1992. PubMed ID : 1740313 100. Spence, J. E.; Perciaccante, R. G.; Greig, G. M.; Willard, H. F.; Ledbetter, D. H.; Hejtmancik, J. F.; Pollack, M. S.; O'Brien, W. E.; Beaudet, A. L. : Uniparental disomy as a mechanism for human genetic disease. Am. J. Hum. Genet. 42: 217-226, 1988. PubMed ID : 2893543 101. Stalker, H. J.; Williams, C. A. : Genetic counseling in Angelman syndrome: the challenges of multiple causes. Am. J. Med. Genet. 77: 54-59, 1998. PubMed ID : 9557895 102. Tekin, M.; Jackson-Cook, C.; Buller, A.; Ferreira-Gonzalez, A.; Pandya, A.; Garrett, C. T.; Bodurtha, J. : Fluorescence in situ hybridization detectable mosaicism for Angelman syndrome with biparental methylation. Am. J. Med. Genet. 95: 145-149, 2000. PubMed ID : 11078565 103. Tonk, V.; Wyandt, H. E.; Michand, L.; Milunsky, A. : Deletion of 15q12 in Angelman syndrome: report of 3 new cases. Clin. Genet. 42: 229-233, 1992. PubMed ID : 1486699 104. Trent, R. J.; Sheffield, L. J.; Deng, Z.-M.; Kim, W. S.; Nassif, N. T.; Ryce, C.; Woods, C. G.; Michaelis, R. C.; Tarleton, J.; Smith, A. : The elusive Angelman syndrome critical region. J. Med. Genet. 34: 714-718, 1997. PubMed ID : 9321755 105. Varela, M. C.; Kok, F.; Otto, P. A.; Koiffmann, C. P. : Phenotypic variability in Angelman syndrome: comparison among different deletion classes and between deletion and UPD subjects. Europ. J. Hum. Genet. 12: 987-992, 2004. PubMed ID : 15470370 106. Viani, F.; Romeo, A.; Viri, M.; Mastrangelo, M.; Lalatta, F.; Selicorni, A.; Gobbi, G.; Lanzi, G.; Bettio, D.; Briscioli, V.; Di Segni, M.; Parini, R.; Terzoli, G. : Seizure and EEG patterns in Angelman's syndrome. J. Child Neurol. 10: 467-471, 1995. PubMed ID : 8576558 107. Wagstaff, J.; Knoll, J. H. M.; Glatt, K. A.; Shugart, Y. Y.; Sommer, A.; Lalande, M. : Maternal but not paternal transmission of 15q11-13-linked nondeletion Angelman syndrome leads to phenotypic expression. Nature Genet. 1: 291-294, 1992. PubMed ID : 1338769 108. Wagstaff, J.; Shugart, Y. Y.; Lalande, M. : Linkage analysis in familial Angelman syndrome. Am. J. Hum. Genet. 53: 105-112, 1993. PubMed ID : 8317476 109. Wang, J.-C. C.; Passage, M. B.; Yen, P. H.; Shapiro, L. J.; Mohandas, T. K. : Uniparental heterodisomy for chromosome 14 in a phenotypically abnormal familial balanced 13/14 Robertsonian translocation carrier. Am. J. Hum. Genet. 48: 1069-1074, 1991. PubMed ID : 2035528 110. Watson, P.; Black, G.; Ramsden, S.; Barrow, M.; Super, M.; Kerr, B.; Clayton-Smith, J. : Angelman syndrome phenotype associated with mutations in MECP2, a gene encoding a methyl CpG binding protein. J. Med. Genet. 38: 224-228, 2001. PubMed ID : 11283202 111. Willems, P. J.; Dijkstra, I.; Brouwer, O. F.; Smit, G. P. A. : Recurrence risk in the Angelman ('happy puppet') syndrome. Am. J. Med. Genet. 27: 773-780, 1987. PubMed ID : 3321989 112. Williams, C. A.; Donlon, T. A.; Gray, B. A.; Stone, J. W.; Hendrickson, J. E.; Cantu, E. S. : Incidence of 15q deletions in the Angelman syndrome: a survey of 14 affected persons. (Abstract) Am. J. Hum. Genet. 43: A75, 1988. 113. Williams, C. A.; Frias, J. L. : The Angelman ('happy puppet') syndrome. Am. J. Med. Genet. 11: 453-460, 1982. PubMed ID : 7091188 114. Williams, C. A.; Hendrickson, J. E.; Cantu, E. S.; Donlon, T. A. : Angelman syndrome in a daughter with del(15)(q11q13) associated with brachycephaly, hearing loss, enlarged foramen magnum, and ataxia in the mother. Am. J. Med. Genet. 32: 333-338, 1989. PubMed ID : 2729353 115. Williams, C. A.; Lossie, A.; Driscoll, D.; R. C. Philips Unit : Angelman syndrome: mimicking conditions and phenotypes. Am. J. Med. Genet. 101: 59-64, 2001. PubMed ID : 11343340 116. Williams, C. A.; Zori, R. T.; Stone, J. W.; Gray, B. A.; Cantu, E. S.; Ostrer, H. : Maternal origin of 15q11-13 deletions in Angelman syndrome suggests a role for genomic imprinting. Am. J. Med. Genet. 35: 350-353, 1990. PubMed ID : 2309781 ### CONTRIBUTORS George E. Tiller - updated : 2/21/2005 Marla J. F. O'Neill - updated : 1/6/2005 Natalie E. Krasikov - updated : 11/3/2004 Deborah L. Stone - updated : 6/16/2003 Victor A. McKusick - updated : 1/22/2003 Michael J. Wright - updated : 10/22/2002 Victor A. McKusick - updated : 9/19/2002 Victor A. McKusick - updated : 7/22/2002 Michael J. Wright - updated : 7/1/2002 Victor A. McKusick - updated : 5/22/2002 Victor A. McKusick - updated : 6/15/2001 Victor A. McKusick - updated : 5/16/2001 Sonja A. Rasmussen - updated : 12/12/2000 Victor A. McKusick - updated : 9/12/2000 Victor A. McKusick - updated : 6/7/2000 Victor A. McKusick - updated : 2/16/2000 Victor A. McKusick - updated : 2/3/2000 Victor A. McKusick - updated : 11/8/1999 Wilson H. Y. Lo - updated : 9/2/1999 Victor A. McKusick - updated : 2/18/1999 Victor A. McKusick - updated : 1/25/1999 Orest Hurko - updated : 11/9/1998 Victor A. McKusick - updated : 7/20/1998 Victor A. McKusick - updated : 5/27/1998 Victor A. McKusick - updated : 4/21/1998 Michael J. Wright - updated : 2/11/1998 Victor A. McKusick - updated : 8/25/1997 Victor A. McKusick - updated : 8/20/1997 Victor A. McKusick - updated : 7/17/1997 Victor A. McKusick - updated : 3/14/1997 Iosif W. Lurie - updated : 7/21/1996 Orest Hurko - updated : 4/3/1996 ### CREATION DATE Victor A. McKusick : 10/9/1992 ### EDIT HISTORY wwang : 3/2/2005 terry : 2/21/2005 carol : 1/24/2005 carol : 1/7/2005 terry : 1/6/2005 carol : 11/3/2004 carol : 6/16/2003 tkritzer : 1/24/2003 terry : 1/22/2003 tkritzer : 10/29/2002 tkritzer : 10/24/2002 terry : 10/22/2002 tkritzer : 9/24/2002 tkritzer : 9/19/2002 tkritzer : 9/19/2002 tkritzer : 7/29/2002 tkritzer : 7/29/2002 terry : 7/22/2002 alopez : 7/2/2002 terry : 7/1/2002 cwells : 6/4/2002 cwells : 6/4/2002 terry : 5/22/2002 carol : 11/5/2001 cwells : 6/27/2001 mcapotos : 6/27/2001 mcapotos : 6/21/2001 terry : 6/15/2001 mcapotos : 5/23/2001 mcapotos : 5/22/2001 terry : 5/16/2001 mgross : 4/11/2001 mcapotos : 12/12/2000 carol : 9/14/2000 terry : 9/12/2000 carol : 6/9/2000 terry : 6/7/2000 mgross : 3/14/2000 terry : 2/16/2000 mgross : 2/3/2000 alopez : 11/12/1999 terry : 11/8/1999 mgross : 10/21/1999 carol : 9/8/1999 carol : 9/2/1999 terry : 4/30/1999 carol : 2/22/1999 terry : 2/18/1999 carol : 1/25/1999 carol : 11/25/1998 terry : 11/9/1998 carol : 7/22/1998 terry : 7/20/1998 terry : 6/18/1998 terry : 5/27/1998 carol : 5/9/1998 terry : 4/21/1998 alopez : 2/18/1998 terry : 2/11/1998 mark : 1/19/1998 terry : 11/14/1997 jenny : 8/28/1997 terry : 8/25/1997 jenny : 8/22/1997 terry : 8/20/1997 alopez : 7/30/1997 alopez : 7/30/1997 terry : 7/25/1997 terry : 7/17/1997 mark : 7/16/1997 jenny : 7/9/1997 terry : 3/14/1997 joanna : 2/13/1997 jenny : 1/14/1997 terry : 1/8/1997 carol : 7/22/1996 carol : 7/22/1996 carol : 7/21/1996 terry : 4/29/1996 mark : 4/27/1996 terry : 4/22/1996 terry : 4/15/1996 mark : 4/3/1996 terry : 3/23/1996 mark : 2/22/1996 terry : 2/20/1996 mark : 8/18/1995 carol : 10/18/1994 davew : 8/17/1994 terry : 7/18/1994 pfoster : 3/24/1994 mimadm : 3/11/1994 Copyright © 1966-2005 Johns Hopkins University
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| DNA METHYLTRANSFERASE 3-LIKE PROTEIN; DNMT3L
#### Alternative titles; symbols DNA CYTOSINE-5-METHYLTRANSFERASE 3-LIKE PROTEIN ### TABLE OF CONTENTS #### TEXT CLONING GENE STRUCTURE MAPPING ANIMAL MODEL REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 21q22.3 ### TEXT DNA cytosine-5-methyltransferase-3 proteins are involved in de novo methylation of CpG islands. Mutations in the DNMT3B gene (602900) cause the ICF immunodeficiency syndrome (242860). DNA methyltransferases and regulatory factors are likely to be involved in the establishment of maternal imprints in growing diplotene oocytes and paternal imprints in perinatal prospermatogonia. Imprinting is essential for viable development. #### CLONING By database analysis, PCR with specific primers based on predicted and trapped exon sequences, and screening of testis, fetal liver, placenta, and thymus mRNA and cDNA libraries, Aapola et al. (2000) isolated a cDNA encoding DNMT3L. Sequence analysis predicted that the 387-amino acid protein contains a cysteine-rich region with a novel ADD (for ATRX (300032), DNMT3, and DNMT3L) C2-C2 zinc finger motif near an imperfect PHD zinc finger with C4-C4. RT-PCR analysis detected highest expression of DNMT3L in testis, followed by ovary, thymus, and fetal thymus. Northern blot analysis failed to detected expression of DNMT3L. #### GENE STRUCTURE By genomic sequence analysis, Aapola et al. (2000) determined that the DNMT3L gene contains 12 exons and spans 16 kb. The translation initiation codon is in exon 2. The authors detected a splice variant lacking exon 8. #### MAPPING By genomic DNA sequence analysis, Aapola et al. (2000) localized the DNMT3L gene to chromosome 21q22.3, 24 kb centromeric to the AIRE gene (240300) and 5.4 kb telomeric to the KIAA0653 gene (B7H2; 605717). #### ANIMAL MODEL By disrupting homologous recombination in mouse embryonic stem cells, Bourc'his et al. (2001) generated viable but sterile mice with mutated Dnmt3l (termed Dnmt3lG) in which male testes had severe hypogonadism and a Sertoli cell-only phenotype. The heterozygous offspring of females with Dnmt3lG failed to develop past 9.5 days postcoitum due to embryonic rather than uterine defects. Bisulfite genomic sequence analysis of the differentially methylated region (DMR) of imprinted and maternally repressed genes such as Snrpn (182279) detected undermethylation of oocytes from Dnmt3lG homozygous females, showing that Dnmt3l is required for the establishment of maternal methylation imprints. Heterozygous embryos from Dnmt3lG homozygotes displayed biallelic expression of genes that are normally expressed only from the allele of paternal origin. Bourc'his et al. (2001) concluded that DNMT3L is required specifically for the establishment of genomic imprints but is dispensable for their propagation, and it is essential for the de novo methylation of single-copy DNA sequences. The authors proposed that DNMT3L is likely to function as a regulator of methylation at imprinted loci rather than a DNA cytosine methyltransferase because of a lack of catalytic motifs in its sequence. Bourc'his and Bestor (2004) demonstrated that in mice, Dnmt3l is expressed in testes during a brief perinatal period in the nondividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation. Deletion of the Dnmt3l gene prevented the de novo methylation of both long terminal repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes. Loss of Dnmt3l from early germ cells also caused meiotic failure in spermatocytes, which do not express Dnmt3l. Whereas dispersed repeated sequences were demethylated in mutant germ cells, tandem repeats in pericentric regions were methylated normally. Bourc'his and Bestor (2004) concluded that the DNMT3L protein might have a function in the de novo methylation of dispersed repeated sequences in a premeiotic genome scanning process that occurs in male germ cells at about the time of birth. Webster et al. (2005) found that, in addition to hypomethylation in early stages of spermatogenesis, Dnmt3l -/- spermatocytes showed abnormalities during later stages of development. Chromatin compaction was impaired in meiotic cells, as evidenced by differences in the accessibility of histone epitopes. Homologous chromosomes failed to align and form synaptonemal complexes, leading to spermatogenetic arrest and loss of spermatocytes through apoptosis and sloughing. Webster et al. (2005) concluded that many of the specialized changes in chromatin morphology during meiosis require DNMT3L, either directly or indirectly. ### REFERENCES 1. Aapola, U.; Shibuya, K.; Scott, H. S.; Ollila, J.; Vihinen, M.; Heino, M.; Shintani, A.; Kawasaki, K.; Minoshima, S.; Krohn, K.; Antonarakis, S. E.; Shimizu, N.; Kudoh, J.; Peterson, P. : Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cysteine-5-methyltransferase 3 gene family. Genomics 65: 293-298, 2000. PubMed ID : 10857753 2. Bourc'his, D.; Bestor, T. H. : Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431: :96-98, 2004. PubMed ID : 15318244 3. Bourc'his, D.; Xu, G.-L.; Lin, C.-S.; Bollman, B.; Bestor, T. H. : Dnmt3L and the establishment of maternal genomic imprints. Science 294: 2536-2539, 2001. PubMed ID : 11719692 4. Webster, K. E.; O'Bryan, M. K.; Fletcher, S.; Crewther, P. E.; Aapola, U.; Craig, J.; Harrison, D. K.; Aung, H.; Phutikanit, N.; Lyle, R.; Meachem, S. J.; Antonarakis, S. E.; de Kretser, D. M.; Hedger, M. P.; Peterson, P.; Carroll, B. J.; Scott, H. S. : Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis. Proc. Nat. Acad. Sci. 102: 4068-4073, 2005. PubMed ID : 15753313 ### CONTRIBUTORS Patricia A. Hartz - updated : 4/18/2005 Ada Hamosh - updated : 11/11/2004 ### CREATION DATE Paul J. Converse : 1/2/2002 ### EDIT HISTORY mgross : 4/19/2005 terry : 4/18/2005 tkritzer : 11/11/2004 mgross : 1/2/2002 Copyright © 1966-2005 Johns Hopkins University
7: | *605436 | Links
| PRADER-WILLI CRITICAL REGION 1; PWCR1
#### Alternative titles; symbols HBII-85 ### TABLE OF CONTENTS #### TEXT REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q11.2 ### TEXT De los Santos et al. (2000) identified and characterized a novel imprinted gene, which they designated PWCR1, within the Prader-Willi critical region on 15q11.2. They mapped the mouse ortholog, Pwcr1, to the conserved syntenic region on mouse chromosome 7. Expressed only from the paternal allele, both genes require the imprinting-center regulatory element for expression and are transcribed from the same strand. Both genes are intronless and do not appear to encode a protein product. High human/mouse sequence similarity (87% identity) is limited to a 99-bp region, called the HMCR (human-mouse conserved region). The HMCR sequence has features of a C/D box small nuclear RNA (snoRNA) and is represented in an abundant small transcript in both species. Located in nucleoli, snoRNAs serve as methylation guidance RNAs in the modification of ribosomal RNA and other small nuclear RNAs. In addition to the nonpolyadenylated small RNAs, larger polyadenylated PWCR1 transcripts were found in most human tissues, whereas expression of any Pwcr1 RNAs was limited to mouse brain. Genomic sequence analysis showed the presence of multiple copies of PWCR1 and Pwcr1 that were organized within local tandem-repeat clusters. On a multispecies Southern blot, hybridization to an HMCR probe encoding the putative snoRNA was limited to mammals. De los Santos et al. (2000) reviewed genes identified in the 15q11-q13 region that are expressed only from the paternally derived allele. Balanced translocations affecting the paternal copy of 15q11-q13 are a rare cause of Prader-Willi syndrome (PWS) or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation, t(X;15)(q28;q12), in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene (182279) and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85, as well as IPW (601491) and PAR1 (600161), were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype. Runte et al. (2001) reported that a processed antisense transcript of UBE3A (601623) starts at the imprinting center. The SNURF-SNRPN sense/UBE3A antisense transcription unit spans more than 460 kb and contains at least 148 exons, including the previously identified IPW exons. It serves as the host for the previously identified HBII-13, HBII-85, and HBII-52 snoRNAs, as well as for 4 additional snoRNAs (HBII-436, HBII-437, HBII-438A, and HBII-438B). Almost all of those snoRNAs are encoded within introns of this large transcript. Northern blot analysis revealed that most if not all of the snoRNAs are expressed by processing from these introns. The authors proposed that a lack of these snoRNAs may be causally involved in Prader-Willi syndrome. ### REFERENCES 1. de los Santos, T.; Schweizer, J.; Rees, C. A.; Francke, U. : Small evolutionarily conserved RNA, resembling C/D box small nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which is highly expressed in brain. Am. J. Hum. Genet. 67: 1067-1082, 2000. PubMed ID : 11007541 2. Runte, M.; Huttenhofer, A.; Gross, S.; Kiefmann, M.; Horsthemke, B.; Buiting, K. : The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Molec. Genet. 10: 2687-2700, 2001. PubMed ID : 11726556 3. Wirth, J.; Back, E.; Huttenhofer, A.; Nothwang, H.-G.; Lich, C.; Gross, S.; Menzel, C,; Schinzel, A.; Kioschis, P.; Tommerup, N.; Ropers, H.-H.; Horsthemke, B.; Buiting, K. : A translocation breakpoint cluster disrupts the newly defined 3-prime end of the SNURF-SNRPN transcription unit on chromosome 15. Hum. Molec. Genet. 10: 201-210, 2001. PubMed ID : 11159938 ### CONTRIBUTORS George E. Tiller - updated : 9/13/2002 George E. Tiller - updated : 4/17/2001 ### CREATION DATE Victor A. McKusick : 11/29/2000 ### EDIT HISTORY cwells : 9/13/2002 cwells : 4/26/2001 cwells : 4/20/2001 cwells : 4/17/2001 carol : 4/9/2001 carol : 11/29/2000 Copyright © 1966-2005 Johns Hopkins University
8: | *602631 | Links
| SOLUTE CARRIER FAMILY 22 (ORGANIC CATION TRANSPORTER), MEMBER 1-LIKE; SLC22A1L
#### Alternative titles; symbols BECKWITH-WIEDEMANN SYNDROME CHROMOSOME REGION 1, CANDIDATE A; BWSCR1A BECKWITH-WIEDEMANN REGION 1A; BWR1A IMPRINTED POLYSPECIFIC MEMBRANE TRANSPORTER 1; IMPT1 ORGANIC-CATION TRANSPORTER-LIKE 2; ORCTL2 TUMOR-SUPPRESSING SUBCHROMOSOMAL TRANSFERABLE FRAGMENT CANDIDATE GENE 5; TSSC5 BECKWITH-WIEDEMANN SYNDROME CRITICAL REGION, INCLUDED ### TABLE OF CONTENTS #### TEXT ALLELIC VARIANTS View List REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 11p15.5 ### TEXT Chromosome region 11p15.5 harbors a number of genes involved in neoplasms and in the genetic disease Beckwith-Wiedemann syndrome (BWS; 130650). By genomic analysis of a 170-kb region at 11p15.5 between loci D11S601 and D11S679, Schwienbacher et al. (1998) identified 6 transcriptional units. Three genes, NAP2 (601651), CDKN1C (600856), and KVLQT1 (607542), had been well characterized, whereas the other 3 genes were novel. The 3 additional genes were symbolized BWR1A, BWR1B (SLC22A1LS; 603240), and BWR1C (TSSC3; 602131), with BWR designating 'Beckwith-Wiedemann region.' Full-length cDNAs corresponding to these 3 genes were cloned and nucleotide sequences were determined. Schwienbacher et al. (1998) cloned the full-length BWR1A cDNA from a human fetal liver cDNA library. The open reading frame encodes a protein of 424 amino acids. The BWR1A gene consists of 11 exons spanning a genomic area of 23 kb. BWR1A cDNA probes recognized a 1.7-kb transcript with highest expression in liver, heart, and kidney. Schwienbacher et al. (1998) carried out a mutation analysis of the BWR1A coding region in tumor cell lines and BWS samples, with identification of genetic alterations in the BWR1A gene in 2 cases (602631.0001, 602631.0002). A megabase-scale region on 11p15.5 in humans and the corresponding area of distal chromosome 7 in mice contain at least 6 imprinted genes: IGF2 (147470), H19 (103280), ASCL2 (601886), p57(KIP2) (CDKN1C), KVLQT1, IPL (BWR1C), and in the mouse Ins2. A subset of these genes regulate fetal and/or placental growth, and the H19, IGF2, and p57(KIP2) genes show dysregulated expression and, in the case of H19, pathologic biallelic hypermethylation in human embryonal tumors. Dao et al. (1998) described the identification, structural characterization, and allelic expression analysis of mouse and human versions of a novel imprinted gene, IMPT1 (imprinted multimembrane-spanning polyspecific transporter-like gene-1) (GenBank AF028738), located in the 11p15.5 region between IPL and p57(KIP2). The gene encodes a predicted protein with multiple membrane-spanning segments that belongs to the polyspecific transporter/multidrug resistance gene family. The fact that Impt1 is relatively repressed on the mouse paternal allele, together with data from other imprinted genes, allowed a statistical conclusion that the primary effect of the human chromosome 11p15.5/mouse distal chromosome 7 imprinting is domainwide relative repression of genes on the paternal homolog. Dosage regulation of the metabolite transporter gene(s) by imprinting may regulate placental and fetal growth. Cooper et al. (1998) identified the organic-cation transporter-like-2 (ORCTL2) (GenBank AF037064) and ORCTL2-antisense (ORCTL2S, or SLC22A1LS) genes by sequencing overlapping PAC clones from the BWS region in 11p15.5 and identifying matching ESTs. The ORCTL2 and ORCTL2S genes overlap in their 5-prime regions in divergent orientations, with the first exon of ORCTL2S sharing 31 bp with the second exon of ORCTL2. Northern blot analysis indicated that the ORCTL2 and ORCTL2S genes are predominantly expressed in fetal and adult liver and kidney. The authors isolated full-length human and mouse ORCTL2 cDNAs; these are approximately 75% identical through the open reading frames. They mapped the mouse Orctl2 gene to chromosome 7 by hybridization to PAC clones. The ORCTL2 gene exhibits 'leaky' imprinting in both human fetal kidney and fetal liver, whereas the Orctl2 gene is specifically and completely expressed from the maternal allele in mouse fetal liver. Cooper et al. (1998) did not detect disease-associated mutations in the ORCTL2 genes of 62 Wilms tumor (WT; see 194071) patients or 10 BWS patients. Morisaki et al. (1998) isolated the human and mouse ITM, or SLC22A1L, genomic sequences and corresponding full-length cDNAs. They suggested that translation begins at the second methionine codon in the open reading frame, which would result in a 408-amino acid human ITM protein. Exon 1 of the mouse Itm gene is alternatively spliced. Morisaki et al. (1998) found that the mouse Itm gene is preferentially expressed from the maternal allele in fetal, newborn, and most adult tissues, but is biallelically expressed in adult kidney and liver, where its expression is highest. Polyspecific organic-cation transporters located at the apical and basolateral surfaces of renal epithelial cells mediate kinetically distinct excretion of several endogenous and exogenous compounds. Reece et al. (1998) investigated the transport properties of ORCTL2 and showed that it confers resistance to chloroquine and quinidine when overexpressed in bacteria. Immunohistochemistry analyses on human renal sections indicated that ORCTL2 is localized on the apical membrane surface of the proximal tubules. The authors suggested that ORCTL2 may play a role in the transport of chloroquine- and quinidine-related compounds in the kidney. Recombinant ORCTL2 expressed in mammalian cells had an apparent molecular mass of approximately 40 kD by Western blot analysis. Lee et al. (1998) isolated an SLC22A1L cDNA, which they called TSSC5, located within a subchromosomal transferable fragment from 11p15.5. TSSC5 was found to encode a predicted protein of 424 amino acids, and sequence analysis suggested that it is a membrane protein with 10 transmembrane segments. The TSSC5 gene is located between 2 imprinted genes, p57(KIP2) and TSSC3. Northern blot analysis detected a 1.6-kb transcript in multiple adult tissues and in fetal liver and kidney, consistent with a potential role in embryonal tumors. Lee et al. (1998) found that TSSC5 is imprinted with preferential expression from the maternal chromosome. They identified an arg309-to-gln mutation in the TSSC5 gene in a Wilms tumor, the matched normal kidney, and in the patient's mother. It was unclear whether this was a rare polymorphism or a tumor-predisposing mutation, because the mutant allele was of maternal origin and preferentially expressed in the patient's tissue. A second mutation, ser233 to phe (602631.0003), was identified in a lung cancer (211980). This substitution was absent from the matched normal tissue and thus represented a somatic mutation. Lee et al. (1998) also found loss of heterozygosity in the lung cancer, suggesting that TSSC5 may be a conventional tumor suppressor gene in the adult human lung and an imprinted tumor suppressor gene in the fetal kidney. Onyango et al. (2002) found that 3 imprinted genes, TSSC5, H19, and SNRPN (182279), show monoallelic expression in in vitro differentiated human cells derived from embryonic germ cells, and that a fourth gene, IGF2, shows partially relaxed imprinting at a ratio from 4:1 to 5:1, comparable to that found in normal somatic cells. In addition, they found normal methylation of an imprinting control region (ICR) that regulates H19 and IGF2 imprinting, suggesting that imprinting may not be a significant epigenetic barrier to human embryonic germ cell transplantation. Onyango et al. (2002) constructed an in vitro mouse model of genomic imprinting by generating germ cells from 8.5-day embryos of an interspecific cross, in which undifferentiated cells showed biallelic expression and acquired preferential parental allele expression after differentiation. They suggested that the model should allow experimental manipulation of epigenetic modifications of cultured embryonic germ cells that may not be possible in human stem cell studies. Commenting on this work, Sapienza (2002) pointed out that embryonic stem cells may not be the best source of therapeutic material for transplantation therapy. ### ALLELIC VARIANTS (selected examples) #### .0001 BREAST CANCER [SLC22A1L, 111-BP INS] In the breast cancer (114480) cell line BT549, Schwienbacher et al. (1998) identified an insertion that introduced a stop codon in the BWR1A gene. The insertion consisted of 111 nucleotides between nucleotides 1295 and 1296 of the cDNA sequence. These nucleotides represented the junction between exon 8 and exon 9 of the BWR1A gene. Therefore, this inserted segment behaved like a new exon. Indeed, the newly added 111-nucleotide segment was found within intron 8, at 331 nucleotides from the 3-prime end of exon 8. The presence of the canonical splicing sites at the boundaries of the genomic sequence confirmed that the segment had been inserted in the normal BWR1A transcript by an mRNA splicing event. Though it did not introduce a frameshift, it did introduce an in-frame stop codon after 18 nucleotides, removing the last 136 amino acids at the normal polypeptide sequence. This result indicated that the mRNA was aberrant and not a product of alternative splicing. #### .0002 RHABDOMYOSARCOMA [SLC22A1L, 688G-A ] In the rhabdomyosarcoma (268210) cell line TE125.5, Schwienbacher et al. (1998) found a G-to-A transition at nucleotide 688 that introduced an arginine in place of a cysteine in the product of the BWR1A gene. The change was present in a homozygous state, suggesting that loss of the normal allele occurred during the tumorigenic conversion. #### .0003 LUNG CANCER, SOMATIC [SLC22A1L, SER233PHE ] In a lung cancer (211980), Lee et al. (1998) identified an apparent somatic mutation, a C-to-T transition at nucleotide 892 of the SLC22A1L gene, resulting in a ser233-to-phe substitution. They also found loss of heterozygosity in the lung cancer, suggesting that SLC22A1L may be a conventional tumor suppressor gene in the adult human lung and an imprinted tumor suppressor gene in the fetal kidney. ### REFERENCES 1. Cooper, P. R.; Smilinich, N. J.; Day, C. D.; Nowak, N. J.; Reid, L. H.; Pearsall, R. S.; Reece, M.; Prawitt, D.; Landers, J.; Housman, D. E.; Winterpacht, A.; Zabel, B. U.; Pelletier, J.; Weissman, B. E.; Shows, T. B.; Higgins, M. J. : Divergently transcribed overlapping genes expressed in liver and kidney and located in the 11p15.5 imprinted domain. Genomics 49: 38-51, 1998. PubMed ID : 9570947 2. Dao, D.; Frank, D.; Qian, N.; O'Keefe, D.; Vosatka, R. J.; Walsh, C. P.; Tycko, B. : IMPT1, an imprinted gene similar to polyspecific transporter and multi-drug resistance genes. Hum. Molec. Genet. 7: 597-608, 1998. PubMed ID : 9499412 3. Lee, M. P.; Reeves, C.; Schmitt, A.; Su, K.; Connors, T. D.; Hu, R.-J.; Brandenburg, S.; Lee, M. J.; Miller, G.; Feinberg, A. P. : Somatic mutation of TSSC5, a novel imprinted gene from human chromosome 11p15.5. Cancer Res. 58: 4155-4159, 1998. PubMed ID : 9751628 4. Morisaki, H.; Hatada, I.; Morisaki, T.; Mukai, T. : A novel gene, ITM, located between p57(KIP2) and IPL, is imprinted in mice. DNA Res. 5: 235-240, 1998. PubMed ID : 9802569 5. Onyango, P.; Jiang, S.; Uejima, H.; Shamblott, M. J.; Gearhart, J. D.; Cui, H.; Feinberg, A. P. : Monoallelic expression and methylation of imprinted genes in human and mouse embryonic germ cell lineages. Proc. Nat. Acad. Sci. 99: 10599-10604, 2002. PubMed ID : 12114541 6. Reece, M.; Prawitt, D.; Landers, J.; Kast, C.; Gros, P.; Housman, D.; Zabel, B. U.; Pelletier, J. : Functional characterization of ORCTL2--an organic cation transporter expressed in the renal proximal tubules. FEBS Lett. 433: 245-250, 1998. PubMed ID : 9744804 7. Sapienza, C. : Imprinted gene expression, transplantation medicine, and the 'other' human embryonic stem cell. Proc. Nat. Acad. Sci. 99: 10243-10245, 2002. PubMed ID : 12149520 8. Schwienbacher, C.; Sabbioni, S.; Campi, M.; Veronese, A.; Bernardi, G.; Menegatti, A.; Hatada, I.; Mukai, T.; Ohashi, H.; Barbanti-Brodano, G.; Croce, C. M.; Negrini, M. : Transcriptional map of 170-kb region at chromosome 11p15.5: identification and mutational analysis of the BWR1A gene reveals the presence of mutations in tumor samples. Proc. Nat. Acad. Sci. 95: 3873-3878, 1998. PubMed ID : 9520460 ### CONTRIBUTORS Victor A. McKusick - updated : 9/26/2002 Victor A. McKusick - updated : 2/1/2000 Patti M. Sherman - updated : 2/1/1999 ### CREATION DATE Victor A. McKusick : 5/18/1998 ### EDIT HISTORY mgross : 10/28/2004 carol : 3/11/2003 ckniffin : 2/5/2003 carol : 9/30/2002 tkritzer : 9/26/2002 tkritzer : 9/26/2002 carol : 3/8/2002 terry : 3/8/2002 alopez : 2/25/2000 alopez : 2/24/2000 psherman : 2/3/2000 psherman : 2/3/2000 psherman : 2/3/2000 mgross : 2/2/2000 terry : 2/1/2000 psherman : 9/9/1999 psherman : 9/8/1999 alopez : 8/11/1999 alopez : 7/22/1999 carol : 2/5/1999 psherman : 2/1/1999 psherman : 1/27/1999 alopez : 10/30/1998 alopez : 6/18/1998 terry : 6/4/1998 alopez : 5/22/1998 alopez : 5/18/1998 Copyright © 1966-2005 Johns Hopkins University
9: | *602117 | GeneTests, Links
| NECDIN; NDN
### TABLE OF CONTENTS #### CLONING GENE STRUCTURE MAPPING ANIMAL MODEL REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q11-q13 ### TEXT #### CLONING Reasoning that additional imprinted genes may lie within the Prader-Willi syndrome (PWS; 176270) deletion interval 15q11-q13, MacDonald and Wevrick (1997) searched for transcribed sequences in the region between the 2 imprinted genes ZNF127 (MKRN3; 603856) and SNRPN (182279). An EST showed 99% sequence identity to the 3-prime end of a GenBank sequence (U35139), defined as 'a human necdin-related protein mRNA.' Mouse necdin (Ndn) was originally identified by Maruyama et al. (1991) as a protein encoded by a neural differentiation-specific mRNA, derived from embryonal carcinoma cells. The necdin protein was localized to the nuclei of postmitotic neurons and was expressed in almost all postmitotic neurons in the CNS from the beginning of neural differentiation and into adult life. MacDonald and Wevrick (1997) demonstrated that expression of the Ndn mouse gene and the NDN human gene is limited to the paternal allele, with highest levels of expression in brain and placenta. They suggested that loss of necdin gene expression may contribute to the disorder of brain development in individuals with PWS. Jay et al. (1997) likewise cloned a human cDNA with close similarities to the mouse necdin gene. NDN displayed several characteristics of an imprinted locus, including allelic DNA methylation and an asynchronous DNA replication. Jay et al. (1997) found a complete lack of NDN expression in PWS brain and fibroblasts, indicating that the gene is expressed exclusively from the paternal allele in these tissues and suggesting a possible role of this gene in PWS. Necdin is a growth suppressor expressed in virtually all postmitotic neurons in the brain. Nakada et al. (1998) isolated and characterized the human NDN gene and its promoter region. They found that NDN encodes a protein of 321 amino acids, 4 residues shorter than the mouse protein. Watrin et al. (1997) demonstrated paternal-specific expression of the Ndn gene in mouse CNS and showed that paternal alleles display a differential methylation profile in the coding region. #### GENE STRUCTURE MacDonald and Wevrick (1997) determined that the mouse Ndn gene contains a single exon. Consistent with the observation that imprinted genes have few and small introns (Hurst et al., 1996), human NDN is contained within a single exon, like its mouse ortholog. Nakada et al. (1998) identified CpG islands in a region of NDN extending from the proximal 5-prime flanking sequence to the protein-coding region. The 5-prime flanking sequence, which lacks canonical TATA and CAAT boxes, possessed a promoter activity in postmitotic neurons derived from murine embryonal carcinoma P19 cells. Methylation in vitro of HhaI CpG sites in the promoter region reduced transcriptional activity. These results suggested that the necdin gene is silenced through methylation of the CpG island encompassing its promoter region. #### MAPPING MacDonald and Wevrick (1997) concluded that the NDN gene is a single locus in proximal 15q, as determined by radiation hybrid mapping, localization of the appropriate PCR-amplified fragments to overlapping YACs, and absence in other YACs from the PWS deletion region. The mouse Ndn gene was mapped to chromosome 7 in a region of conserved synteny with human 15q11-q13 by MacDonald and Wevrick (1997) using genetic mapping in an interspecific backcross panel. Jay et al. (1997) mapped the NDN gene to 15q11-q13 by fluorescence in situ hybridization (FISH), and confirmed the location by PCR analysis of DNA extracted from a panel of hamster/human somatic cell hybrids. Both approaches suggested that the NDN gene maps to 15q11-q13 but that a homologous gene or pseudogene maps to 12q21. Jay et al. (1997) also mapped NDN by hybridization to a YAC contig covering the PWS critical region. They suggested that NDN is located approximately 100 kb distal to ZNF127 and 1 to 1.5 Mb proximal to SNRPN. By fluorescence in situ hybridization, Nakada et al. (1998) localized the NDN gene to chromosome 15q11.2-q12. Watrin et al. (1997) established the localization of the mouse necdin gene in the region of mouse chromosome 7 showing conserved synteny to the human PWS region. By FISH, they demonstrated an asynchronous pattern of replication at the Ndn locus. #### ANIMAL MODEL Tsai et al. (1999) prepared a null mutation in the mouse by deleting the coding region for Ndn, and transmitted the deletion to the germline. Mice with paternal deficiency and homozygous mice were viable. Northern blot analysis showed absence of Ndn expression in brain and liver of mice heterozygous for paternal deficiency. Mice of all genotypes were recovered at the predicted mendelian ratios at weaning following matings between heterozygotes. Mice of all genotypes, including homozygotes, were fertile and did not develop obesity up to 10 months of age. Behavioral studies had not yet been done; thus, any potential relationship to the mental retardation of PWS remained unknown. To determine the possible contribution of Ndn to the Prader-Willi syndrome phenotype, Gerard et al. (1999) generated Ndn mutant mice. Heterozygous mice inheriting the mutated maternal allele were indistinguishable from their wildtype littermates. On the other hand, mice carrying a paternally inherited Ndn deletion allele demonstrated early postnatal lethality. Gerard et al. (1999) claimed this was the first example of a single gene being responsible for phenotypes associated with PWS. Nicholls (1999) commented on the work of Gerard et al. (1999), which he called 'the latest episode of a seat-gripping saga.' He noted the discrepancy between the findings of Tsai et al. (1999) and those of Gerard et al. (1999). He further discussed other 'suspicious characters,' i.e., other genes that may be implicated in PWS, and suggested that several genes in the PWS region may affect the failure-to-thrive phenotype. He suggested that this aspect of the PWS story resembles the plot of 'Murder on the Orient Express' by Agatha Christie. The famed train transported a number of suspects, all of whom were eventually found to have had a part in the crime. Muscatelli et al. (2000) produced mice deficient for necdin and suggested that postnatal lethality associated with loss of the paternal gene may vary depending on the strain. Viable necdin mutants showed a reduction in both oxytocin (167050)-producing and luteinizing hormone-releasing hormone (LHRH; 152760)-producing neurons in the hypothalamus; increased skin scraping activity; and improved spatial learning and memory. The authors proposed that underexpression of necdin is responsible for at least a subset of the multiple clinical manifestations of PWS. ### REFERENCES 1. Gerard, M.; Hernandez, L.; Wevrick, R.; Stewart, C. L. : Disruption of the mouse necdin gene results in early post-natal lethality. Nature Genet. 23: 199-202, 1999. PubMed ID : 10508517 2. Hurst, L. D.; McVean, G.; Moore, T. : Imprinted genes have few and small introns. (Letter) Nature Genet. 12: 234-237, 1996. PubMed ID : 8589711 3. Jay, P.; Rougeulle, C.; Massacrier, A.; Moncla, A.; Mattei, M.-G.; Malzac, P.; Roeckel, N.; Taviaux, S.; Lefranc, J.-L. B.; Cau, P.; Berta, P.; Lalande, M.; Muscatelli, F. : The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nature Genet. 17: 357-360, 1997. PubMed ID : 9354807 4. MacDonald, H. R.; Wevrick, R. : The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum. Molec. Genet. 6: 1873-1878, 1997. PubMed ID : 9302265 5. Maruyama, K.; Usami, M.; Aizawa, T.; Yoshikawa, K. : A novel brain-specific mRNA encoding nuclear protein (necdin) expressed in neurally differentiated embryonal carcinoma cells. Biochem. Biophys. Res. Commun. 178: 291-296, 1991. PubMed ID : 2069569 6. Muscatelli, F.; Abrous, D. N.; Massacrier, A.; Boccaccio, I.; Le Moal, M.; Cau, P.; Cremer, H. : Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome. Hum. Molec. Genet. 9: 3101-3110, 2000. PubMed ID : 11115855 7. Nakada, Y.; Taniura, H.; Uetsuki, T.; Inazawa, J.; Yoshikawa, K. : The human chromosomal gene for necdin, a neuronal growth suppressor, in the Prader-Willi syndrome deletion region. Gene 213: 65-72, 1998. PubMed ID : 9630521 8. Nicholls, R. D. : Incriminating gene suspects, Prader-Willi style. Nature Genet. 23: 132-134, 1999. PubMed ID : 10508501 9. Tsai, T.-F.; Armstrong, D.; Beaudet, A. L. : Necdin-deficient mice do not show lethality or the obesity and infertility of Prader-Willi syndrome. (Letter) Nature Genet. 22: 15-16, 1999. PubMed ID : 10319852 10. Watrin, F.; Roeckel, N.; Lacroix, L.; Mignon, C.; Mattei, M.-G.; Disteche, C.; Muscatelli, F. : The mouse necdin gene is expressed from the paternal allele only and lies in the 7C region of the mouse chromosome 7, a region of conserved synteny to the human Prader-Willi syndrome region. Europ. J. Hum. Genet. 5: 324-332, 1997. PubMed ID : 9412790 ### CONTRIBUTORS George E. Tiller - updated : 3/5/2001 Victor A. McKusick - updated : 9/28/1999 Victor A. McKusick - updated : 4/27/1999 Victor A. McKusick - updated : 8/26/1998 Victor A. McKusick - updated : 12/19/1997 ### CREATION DATE Victor A. McKusick : 11/12/1997 ### EDIT HISTORY mgross : 5/12/2005 terry : 2/2/2005 carol : 11/5/2001 cwells : 3/6/2001 cwells : 3/5/2001 cwells : 3/5/2001 mgross : 10/21/1999 alopez : 9/30/1999 terry : 9/28/1999 alopez : 4/29/1999 terry : 4/27/1999 carol : 8/27/1998 terry : 8/26/1998 mark : 1/10/1998 terry : 12/19/1997 dholmes : 11/18/1997 jenny : 11/12/1997 Copyright © 1966-2005 Johns Hopkins University
10: | *600161 | Links
| PRADER-WILLI/ANGELMAN REGION 1
#### Alternative titles; symbols PAR1 D15S227E ### TABLE OF CONTENTS #### TEXT REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q11-q13 ### TEXT To determine the molecular basis of Prader-Willi syndrome (PWS; 176270) and Angelman syndrome (AS; 105830), Sutcliffe et al. (1994) isolated new transcripts from 15q11-q13. They found that 2 novel transcripts located within 300 kb telomeric to the small nuclear ribonucleoprotein-associated polypeptide N gene (SNRPN; 182279) were paternally expressed in cultured cells, along with SNRPN, thereby defining a large imprinted transcriptional domain. In 2 sibs with PWS and a third sporadic case, small deletions removed a differentially methylated CpG island containing a newly described 5-prime exon, designated alpha, of SNRPN, and caused loss of expression of the 3 imprinted transcripts and altered methylation over hundreds of kilobases. (Sequences previously designated as exon 1 of SNRPN had been found, in fact, to lie approximately 12 kb telomeric of exon alpha, the true first exon of the gene.) The smallest PWS deletion was familial and was asymptomatic when transmitted through the mother. Sutcliffe et al. (1994) interpreted their data as indicating the presence of a paternal imprinting control region near exon alpha. Balanced translocations affecting the paternal copy of 15q11-q13 are a rare cause of Prader-Willi syndrome (PWS) or PWS-like features. Wirth et al. (2001) reported a de novo balanced reciprocal translocation, t(X;15)(q28;q12), in a female patient with atypical PWS. The translocation breakpoints in this patient and 2 previously reported patients mapped 70 to 80 kb distal to the SNURF-SNRPN gene and defined a breakpoint cluster region. The breakpoints disrupted one of several previously unknown 3-prime exons of this gene. RT-PCR experiments demonstrated that sequences distal to the breakpoint, including the C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85 (605436), as well as IPW (601491) and PAR1, were not expressed in the patient. The authors suggested that lack of expression of these sequences may contribute to the PWS phenotype. Runte et al. (2001) reported that a processed antisense transcript of UBE3A (601623) starts at the imprinting center. The SNURF-SNRPN sense/UBE3A antisense transcription unit spans more than 460 kb and contains at least 148 exons, including the previously identified IPW exons. It serves as the host for the previously identified HBII-13, HBII-85, and HBII-52 snoRNAs, as well as for 4 additional snoRNAs (HBII-436, HBII-437, HBII-438A, and HBII-438B). Almost all of those snoRNAs are encoded within introns of this large transcript. Northern blot analysis revealed that most if not all of the snoRNAs are expressed by processing from these introns. The authors proposed that a lack of these snoRNAs may be causally involved in Prader-Willi syndrome. ### REFERENCES 1. Runte, M.; Huttenhofer, A.; Gross, S.; Kiefmann, M.; Horsthemke, B.; Buiting, K. : The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A. Hum. Molec. Genet. 10: 2687-2700, 2001. PubMed ID : 11726556 2. Sutcliffe, J. S.; Nakao, M.; Christian, S.; Orstavik, K. H.; Tommerup, N.; Ledbetter, D. H.; Beaudet, A. L. : Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region. Nature Genet. 8: 52-58, 1994. PubMed ID : 7987392 3. Wirth, J.; Back, E.; Huttenhofer, A.; Nothwang, H.-G.; Lich, C.; Gross, S.; Menzel, C,; Schinzel, A.; Kioschis, P.; Tommerup, N.; Ropers, H.-H.; Horsthemke, B.; Buiting, K. : A translocation breakpoint cluster disrupts the newly defined 3-prime end of the SNURF-SNRPN transcription unit on chromosome 15. Hum. Molec. Genet. 10: 201-210, 2001. PubMed ID : 11159938 ### CONTRIBUTORS George E. Tiller - updated : 9/13/2002 George E. Tiller - updated : 4/17/2001 ### CREATION DATE Victor A. McKusick : 10/25/1994 ### EDIT HISTORY alopez : 2/4/2003 cwells : 9/13/2002 cwells : 4/26/2001 cwells : 4/20/2001 cwells : 4/17/2001 cwells : 4/17/2001 dkim : 7/7/1998 terry : 10/26/1994 terry : 10/25/1994 Copyright © 1966-2005 Johns Hopkins University
11: | %231090 | GeneTests, Links
| HYDATIDIFORM MOLE
#### Alternative titles; symbols HYDM GESTATIONAL TROPHOBLASTIC DISEASE ### TABLE OF CONTENTS #### TEXT REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Clinical Synopsis Gene map locus 19q13.3-q13.4 ### TEXT In India, Ambani et al. (1980) observed gestational trophoblastic disease in multiple pregnancies of sisters in 3 unrelated kindreds. In 1 family a first cousin of 2 'affected' sisters also had a mole pregnancy and the 3 husbands of the 'affected' females had a common ancestral couple, i.e., were related as second cousins, although not related to their wives. Kajii and Ohama (1977) presented evidence for solely paternal genome in hydatidiform moles. On the basis of genetic origin, hydatidiform mole can be divided into 3 types. Approximately 25% of hydatidiform moles ascertained clinically are partial moles. They are triploid, the additional set of chromosomes generally being paternally derived. They do not seem to be associated with the development of choriocarcinoma. A second type of mole that can be classified pathologically is the complete mole. These moles are genetically diploid but are unusual in that all chromosomes are paternally derived, although the cytoplasm has been shown to be maternally derived as in normal conceptions. Complete hydatidiform moles may have 1 of 2 different origins. Most, about 90%, are homozygous, arising from duplication of a haploid sperm. More rarely, complete mole arises by dispermy, the fertilization of an anucleate egg by 2 sperm, and are therefore heterozygous. In 1 choriocarcinoma following pregnancy with hydatidiform mole, Fisher et al. (1988) demonstrated homozygosity. The incidence of hydatidiform mole varies among ethnic groups and reaches 1 in every 250 pregnancies in eastern Asia. The frequency in the U.S. is approximately 1 in every 1,500 pregnancies (Lindor et al., 1992). Moglabey et al. (1999) found reports of 7 familial cases. Helwani et al. (1999) provided a partial pedigree of a Lebanese family with recurrent hydatidiform moles involving 3 sibships, the offspring of consanguineous parents. They pointed out that the same family had been reported by Vejerslev et al. (1991), Sunde et al. (1993), and Seoud et al. (1995). Using microsatellite markers amplified by PCR, they performed a genetic study on 8 independent molar tissues occurring in 2 sisters. Karyotype and genotype data demonstrated a diploid and biparental constitution in 7 of the analyzed moles, suggesting a common mechanism underlying the etiology of the various molar pregnancies in this family. The data suggested that complete and partial hydatidiform moles are not always separate entities and that women with familial recurrent hydatidiform moles are homozygous for an autosomal recessive mutation. In this pedigree, not only were the parents of the molar pregnancies consanguineous, but the women were in each case the product of a consanguineous mating. One of their patients had had at least 8 molar pregnancies and several abortions but no viable children. Women with recurrent hydatidiform moles usually fail to have normal pregnancies. Helwani et al. (1999) suggested that the defective gene may be required in the fertilized/unfertilized ovum or in the maternal reproductive tract. They noted that the initial development of the mammalian zygote is under the control of maternally inherited proteins and mRNA produced and stored in the oocyte during oogenesis. Moreover, the progression of the fertilized ovum through cleavage, blastocyst formation, and implantation is dependent on the successful interaction between the preimplantation embryo and the maternal reproductive tract. Therefore, a defective maternal gene at any of these levels might deregulate the imprinting process in diploid zygotes and lead to abnormal embryonic development and to a phenotype similar to that observed in androgenetic diploid and diandric triploid conceptuses. To map the hydatidiform mole locus, Moglabey et al. (1999) performed a genomewide scan on the Lebanese family reported by Helwani et al. (1999) and on a previously reported German family. They demonstrated that a defective maternal gene is responsible for recurrent hydatidiform moles. This gene mapped to 19q13.3-q13.4 in a 15.2-cM interval flanked by D19S924 and D19S890. They claimed that this was the first genetic mapping of a maternal locus involved in early embryogenesis in mammals. In a family in southern Italy, Sensi et al. (2000) confirmed that recurrent familial hydatidiform moles are diploid and biparental and arise from independent conceptions. A narrowing of the gene interval on 19q13.3-q13.4 was suggested by haplotype analysis in 2 sisters. The 2 sisters were related in each case to their husbands and all 4 were related to each other. One sister experienced 8 reproductive failures, including 6 complete moles. One pregnancy was attempted by ovum donation, but STS analysis and HLA molecular typing of the molar conceptus established that it was originated by the fertilization of a maternal ovum. This mole was persistent and treated with methotrexate. The proband's sister reported the recurrence of 3 molar pregnancies. Judson et al. (2002) studied the sixth molar pregnancy of the index case in a biparental complete hydatidiform mole family with complex consanguinity, originating from the Mirpur region of Pakistan. The authors demonstrated biparental origin of the complete hydatidiform mole DNA using markers on 6 autosomes. They reported an inherited global imprinting defect, a recessive maternal-effect mutation disrupting the specification of imprint at multiple noncontiguous loci, with the result that genes normally carrying a maternal methylation imprint assume a paternal epigenetic pattern on the maternal allele. The resulting conception is phenotypically indistinguishable from an androgenetic complete hydatidiform mole, in which abnormal extraembryonic tissue proliferates while development of the embryo is absent or nearly so. In the family studied by Judson et al. (2002), lack of homozygosity for the Dnmt3l gene (606588), which prevents specification of maternal imprints in the mouse germline, ruled out involvement of that locus. In addition, this family was not homozygous for the previously described 19q locus, making its involvement unlikely. However, autozygosity mapping should allow identification of the locus in this family. In a series of patients with biparental complete HYDM, Fisher et al. (2002) observed dramatic underexpression of p57(KIP2) (CDKN1C; 600856) identical to the pattern seen in complete HYDM of androgenetic origin. The series included 2 sisters, both of whom had biparental complete HYDM. Genotyping of this family identified a 15-cM region of homozygosity for 19q13.3-q13.4 similar to that found in 3 other families with recurrent biparental complete HYDM. Fisher et al. (2002) concluded that biparental complete HYDM, like HYDM of androgenetic origin, may result from abnormal expression of imprinted genes (such as CDKN1C), and that a locus on 19q13.3-q13.4 may regulate expression of imprinted genes on other chromosomes. El-Maarri et al. (2003) reported the methylation status of 4 imprinted genes in 2 biparental complete HYDMs from 2 sisters, a 16-year-old normal offspring, and 2 sporadic biparental complete HYDMs from unrelated patients. Using 2 bisulfite-based methods, the authors demonstrated a general trend of abnormal hypomethylation at the paternally expressed genes PEG3 (601483) and SNRPN (182279), and hypermethylation at the maternally expressed genes NESP55 (see 139320) and H19 (103280), in 2 to 4 biparental complete HYDMs. Using single-nucleotide polymorphisms, the authors provided evidence that SNRPN, NESP55, and H19 were abnormally methylated on the maternal alleles in biparental complete HYDMs. They showed, in biparental complete HYDM from the 2 sisters, that the abnormally methylated H19 allele was inherited from a maternal grandparent. These data suggested that the abnormal methylation in biparental complete HYDM may not be due to an error in erasing the parental imprinting marks, but rather in the reestablishment of the new maternal marks during oogenesis or their postzygotic maintenance. The defective 19q13.4 locus may have led to the development of variable degrees of faulty paternal marks on the maternal chromosomes. ### REFERENCES 1. Ambani, L. M.; Vaidya, R. A.; Rao, C. S.; Daftary, S. D.; Motashaw, N. D. : Familial occurrence of trophoblastic disease--report of recurrent molar pregnancies in sisters in three families. Clin. Genet. 18: 27-29, 1980. PubMed ID : 6251988 2. El-Maarri, O.; Seoud, M.; Coullin, P.; Herbiniaux, U.; Oldenburg, J.; Rouleau, G.; Slim, R. : Maternal alleles acquiring paternal methylation patterns in biparental complete hydatidiform moles. Hum. Molec. Genet. 12: 1405-1413, 2003. PubMed ID : 12783848 3. Fisher, R. A.; Hodges, M. D.; Rees, H. C.; Sebire, N. J.; Seckl, M. J.; Newlands, E. S.; Genest, D. R.; Castrillon, D. H. : The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles. Hum. Molec. Genet. 11: 3267-3272, 2002. PubMed ID : 12471053 4. Fisher, R. A.; Lawler, S. D.; Povey, S.; Bagshawe, K. D. : Genetically homozygous choriocarcinoma following pregnancy with hydatidiform mole. Brit. J. Cancer 58: 788-792, 1988. PubMed ID : 2906253 5. Helwani, M. N.; Seoud, M.; Zahed, L.; Zaatari, G.; Khalil, A.; Slim, R. : A familial case of recurrent hydatidiform molar pregnancies with biparental genomic contribution. Hum. Genet. 105: 112-115, 1999. PubMed ID : 10480363 6. Judson, H.; Hayward, B. E.; Sheridan, E.; Bonthron, D. T. : A global disorder of imprinting in the human female germ line. Nature 416: 539-542, 2002. PubMed ID : 11932746 7. Kajii, T.; Ohama, K. : Androgenetic origin of hydatidiform mole. Nature 268: 633-634, 1977. PubMed ID : 561314 8. Lindor, N. M.; Ney, J. A.; Gaffey, T. A.; Jenkins, R. B.; Thibodeau, S. N.; Dewald, G. W. : A genetic review of complete and partial hydatidiform moles and nonmolar triploidy. Mayo Clin. Proc. 67: 791-799, 1992. PubMed ID : 1434919 9. Moglabey, Y. B.; Kircheisen, R.; Seoud, M.; El Mogharbel, N.; Van den Veyver, I.; Slim, R. : Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum. Molec. Genet. 8: 667-671, 1999. PubMed ID : 10072436 10. Sensi, A.; Gualandi, F.; Pittalis, M. C.; Calabrese, O.; Falciano, F.; Maestri, I.; Bovicelli, L.; Calzolari, E. : Mole maker phenotype: possible narrowing of the candidate region. Europ. J. Hum. Genet. 8: 641-644, 2000. PubMed ID : 10951527 11. Seoud, M.; Khalil, A.; Frangieh, A.; Zahed, L.; Azar, G.; Nuwayri-Salti, N. : Recurrent molar pregnancies in a family with extensive intermarriage: report of a family and review of the literature. Obstet. Gynec. 86: 692-695, 1995. PubMed ID : 7675417 12. Sunde, L.; Vejerslev, L. O.; Jensen, M. P.; Pedersen, S.; Hertz, J. M.; Bolund, L. : Genetic analysis of repeated, biparental, diploid, hydatidiform moles. Cancer Genet. Cytogenet. 66: 16-22, 1993. PubMed ID : 8096796 13. Vejerslev, L.; Sunde, L.; Hansen, B. F.; Larsen, J. K.; Christensen, I. J.; Larsen, G. : Hydatidiform mole and fetus with normal karyotype: support of a separate entity. Obstet. Gynec. 77: 868-874, 1991. PubMed ID : 2030859 ### CONTRIBUTORS George E. Tiller - updated : 3/21/2005 George E. Tiller - updated : 9/13/2004 Ada Hamosh - updated : 4/9/2002 Victor A. McKusick - updated : 11/2/2000 Victor A. McKusick - updated : 9/13/1999 Victor A. McKusick - updated : 8/23/1999 Victor A. McKusick - updated : 4/6/1999 ### CREATION DATE Victor A. McKusick : 6/3/1986 ### EDIT HISTORY alopez : 3/21/2005 alopez : 10/27/2004 tkritzer : 9/20/2004 tkritzer : 9/13/2004 alopez : 3/17/2004 alopez : 4/11/2002 terry : 4/9/2002 mcapotos : 11/13/2000 terry : 11/2/2000 jlewis : 9/13/1999 terry : 8/23/1999 carol : 4/6/1999 mimadm : 2/19/1994 carol : 5/21/1993 supermim : 3/16/1992 supermim : 3/20/1990 ddp : 10/26/1989 root : 3/23/1989 Copyright © 1966-2005 Johns Hopkins University
12: | *137192 | Links
| GAMMA-AMINOBUTYRIC ACID RECEPTOR, BETA-3; GABRB3
#### Alternative titles; symbols GABA-A RECEPTOR, BETA-3 POLYPEPTIDE ### TABLE OF CONTENTS #### TEXT ALLELIC VARIANTS View List REFERENCES CONTRIBUTORS CREATION DATE EDIT HISTORY Gene map locus 15q11.2-q12 ### TEXT GABA is the major inhibitory neurotransmitter in the mammalian brain where it acts at GABA-A receptors, which are ligand-gated chloride channels. Chloride conductance of these channels can be modulated by agents such as benzodiazepines that bind to the GABA-A receptor. At least 13 distinct subunits of GABA-A receptors have been identified. Glatt et al. (1997) stated that functional GABA-A receptors appear to be composed of 5 homologous, variable subunits arranged to form a central channel that conducts chloride ions through the cell membrane. Each subunit consists of a long, variable extracellular region, 4 transmembrane domains, and a variable cytoplasmic region between the third and fourth transmembrane domains. The subunits have been divided into 5 classes on the basis of amino acid sequence homology, with 70 to 80% identity within a class, and 30 to 50% identity between classes. Zinc ions regulate GABA-A receptors by inhibiting receptor function via an allosteric mechanism that is critically dependent on the receptor subunit composition. Hosie et al. (2003) used molecular modeling to identify 3 discrete sites that mediate zinc inhibition: one is located within the ion channel and comprises subunit beta-3 his267 and glu270, and the other 2 are on the external N-terminal face of the receptor and require the coordination of subunit alpha-1 (137160) glu137 and his141 and beta-3 glu 182. The characteristically low zinc sensitivity of GABA-A receptors containing the gamma-2 subunit (137164) results from disruption of 2 of the 3 sites after subunit assembly. Glatt et al. (1997) reported that the GABRB3 gene is composed of 9 exons spanning 250 kb. There are 2 alternative first exons encoding signal peptides. Wagstaff et al. (1991) showed that the gene encoding the beta-3 subunit of the GABA-A receptor (GABRB3) maps to the region of 15q involved in Angelman syndrome (AS; 105830) and Prader-Willi syndrome (PWS; 176270). Deletion of the gene was found in patients of both types with interstitial cytogenetic deletions. The gene was also deleted in an Angelman syndrome patient with an unbalanced 13;15 translocation but not in a PWS patient with an unbalanced 9;15 translocation. Wagstaff et al. (1991) suggested that this receptor gene may be involved in the pathogenesis of one or both of these syndromes. This is the first gene to be mapped to this region. Wagstaff et al. (1991) showed that the gene is located on mouse chromosome 7, very closely linked to 2 other genes that in the human have been mapped to the 15q11-q13 region. Saitoh et al. (1992) studied a highly informative family in which 3 sibs had Angelman syndrome and a deletion of one GABRB3 gene. The mother had the same deletion which she had inherited from her father. The finding supported the possibility that GABRB3 is the Angelman gene and indicated that the genes for AS and PWS are different since transmission of the deletion from the grandfather to the mother of the affected children did not result in PWS. Using the combined techniques of field-inversion gel electrophoresis (FIGE) and phage genomic library screening, Sinnett et al. (1993) constructed a high-resolution physical map covering nearly 1.0 Mb in the proximal region of 15q. The map showed that GABRB3 and GABRA5 (gamma-aminobutyric acid receptor alpha-5 subunit gene; 137142) are separated by less than 100 kb and are arranged in a head-to-head configuration. GABRB3 encompasses approximately 250 kb, while GABRA5 is contained within 70 kb. The difference in size is due largely to an intron of 150 kb within GABRB3. Chromosomal rearrangement breakpoints in 2 patients with Angelman syndrome were located within the large GABRB3 intron. Russek and Farb (1994) stated that the gene encoding the gamma-3 form of the GABA-A receptor (GABRG3; 600233) is located on 15q11-q13 in a cluster with GABRA5 and GABRB3. Knoll et al. (1994) studied DNA replication within chromosome 15q11-q13, a region subject to genomic imprinting, by fluorescence in situ hybridization. Asynchronous replication between homologs was observed in cells from normal persons and in Prader-Willi and Angelman syndrome patients with chromosome 15 deletions but not in PWS patients with maternal uniparental disomy. Opposite patterns of allele-specific replication timing between homologous loci were observed: paternal early/maternal late at the GABRB3 gene; maternal early/paternal late at the more distal GABRA5 locus. By means of microcell-mediated chromosome transfer, Meguro et al. (1997) constructed mouse A9 hybrids containing a single normal human chromosome 15. Cytogenetic and DNA-polymorphic analyses identified mouse A9 hybrids that contained either a paternal or a maternal human chromosome 15. They showed that paternal-specific expression of the known imprinted genes SNRPN (182279) and IPW (601491) was maintained in the A9 hybrids. By using this system, they demonstrated that 3 human GABA-A receptor subunit genes, GABRB3, GABRA5, and GABRG3, are expressed exclusively from the paternal allele and that UBE3A (601623) is biallelically expressed. Moreover, the 5-prime portion of the GABRB3 gene was found to be hypermethylated on the paternal allele. Scapoli et al. (2002) found significant linkage disequilibrium between GABRB3 and nonsyndromic cleft lip with or without cleft palate (CL/P; 119530). They noted that knockout of the Gabrb3 in mice causes clefting of the secondary palate only (Homanics et al., 1997). Tanabe et al. (2000) found no evidence that the GABRB3 gene is involved in clefting in Japanese cases. Holopainen et al. (2001) used positron emission tomography (PET) to study brain binding of (11C)flumazenil in 4 patients with Angelman syndrome. Patients 1, 2, and 3 had a maternal deletion of 15q11-q13 leading to a loss of the GABRB3 gene, whereas patient 4 had a mutation in the ubiquitin protein ligase (UBE3A) and the GABRB3 gene was spared. (11C)flumazenil binding potential in the frontal, parietal, hippocampal, and cerebellar regions was significantly lower in patients 1 to 3 than in patient 4. Holopainen et al. (2001) proposed that the deletion leads to a reduced number of GABRB3 receptors, which could partially explain the neurologic deficits of Angelman syndrome patients. Buxbaum et al. (2002) noted that cytogenetic abnormalities in the Prader-Willi/Angelman syndrome critical region have been described in individuals with autism. They performed an association analysis for a marker of GABRB3 called 155CA-2, using the transmission disequilibrium test (TDT) in a set of 80 autism families (59 multiplex and 21 trios). Four additional markers (69CA, 155CA-1, 85CA, and A55CA-1) located within 150 kb of 155CA-2 were also assayed. Both the multiallelic TDT (P less than 0.002) and the TDT (P less than 0.004) demonstrated association between autistic disorder and 155CA-2 in these families. Buxbaum et al. (2002) suggested that genetic variants within the GABA receptor gene complex in 15q11-q13 may play a role in autistic disorder. Buhr et al. (2002) screened 124 individuals for SNPs of the alpha-1 (GABRA1; 137160), beta-3, and gamma-2 (GABRG2; 137164) genes of the GABA(A) receptor in the regions corresponding to the ligand-binding domains on the protein level. In 1 patient with chronic insomnia, an arg192-to-his mutation (137192.0001) was found in the GABRB3 gene in heterozygous state. Functional studies suggested the possibility of decreased GABAergic inhibition contributing to insomnia, from which some members of the patient's family suffered. ### ALLELIC VARIANTS (selected examples) #### .0001 INSOMNIA [GABRB3, ARG192HIS] In a patient with insomnia who also had relatives who suffered from the condition, Buhr et al. (2002) found a G-to-A transition in exon 6 of the GABRB3 gene, which resulted in an arg192-to-his (R192H) change in the mature beta-3 subunit. Buhr et al. (2002) pointed out that the beta-3 subunit had been implicated in sleep processes independently, by the observation that mice lacking beta-3 lose the hypnotic response to oleamide (Laposky et al., 2001). ### REFERENCES 1. Buhr, A.; Bianchi, M. T.; Baur, R.; Courtet, P.; Pignay, V.; Boulenger, J. P.; Gallati, S.; Hinkle, D. J.; Macdonald, R. L.; Sigel, E. : Functional characterization of the new human GABA(A) receptor mutation beta-3(R192H). Hum. Genet. 111: 154-160, 2002. PubMed ID : 12189488 2. Buxbaum, J. D.; Silverman, J. M.; Smith, C. J.; Greenberg, D. A.; Kilifarski, M.; Reichert, J.; Cook, E. H., Jr.; Fang, Y.; Song, C.-Y.; Vitale, R. : Association between a GABRB3 polymorphism and autism. Molec. Psychiat. 7: 311-316, 2002. 3. Glatt, K.; Glatt, H.; Lalande, M. : Structure and organization of GABRB3 and GABRA5. Genomics 41: 63-69, 1997. PubMed ID : 9126483 4. Holopainen, I. E.; Metsahonkala, E.-L.; Kokkonen, H.; Parkkola, R. K.; Manner, T. E.; Nagren, K.; Korpi, E. R. : Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA-A receptor beta-3 subunit deletions. Ann. Neurol. 49: 110-113, 2001. PubMed ID : 11198279 5. Homanics, G. E.; DeLorey, T. M.; Firestone, L. L.; Quinlan, J. J.; Handforth, A.; Harrison, N. L.; Krasowski, M. D.; Rick, C. E. M.; Korpi, E. R.; Makela, R.; Brilliant, M. H.; Hagiwara, N.; Ferguson, C.; Snyder, K.; Olsen, R. W. : Mice devoid of gamma-aminobutyrate type A receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc. Nat. Acad. Sci. 94: 4143-4148, 1997. PubMed ID : 9108119 6. Hosie, A. M.; Dunne, E. L.; Harvey, R. J.; Smart, T. G. : Zinc-mediated inhibition of GABA-A receptors: discrete binding sites underlie subtype specificity. Nature Neurosci. 6: 362-369, 2003. PubMed ID : 12640458 7. Knoll, J. H. M.; Cheng, S.-D.; Lalande, M. : Allele specificity of DNA replication timing in the Angelman/Prader-Willi syndrome imprinted chromosomal region. Nature Genet. 6: 41-46, 1994. PubMed ID : 8136833 8. Laposky, A. D.; Homanics, G. E.; Baile, A.; Mendelson, W. B. : Deletion of the GABA(A) receptor beta 3 subunit eliminates the hypnotic actions of oleamide in mice. Neuroreport 12: 4143-4147, 2001. PubMed ID : 11742254 9. Meguro, M.; Mitsuya, K.; Sui, H.; Shigenami, K.; Kugoh, H.; Nakao, M.; Oshimura, M. : Evidence for uniparental, paternal expression of the human GABA-A receptor subunit genes, using microcell-mediated chromosome transfer. Hum. Molec. Genet. 6: 2127-2133, 1997. PubMed ID : 9328477 10. Russek, S. J.; Farb, D. H. : Mapping of the beta-2 subunit gene (GABRB2) to microdissected human chromosome 5q34-q35 defines a gene cluster for the most abundant GABA-A receptor isoform. Genomics 23: 528-533, 1994. PubMed ID : 7851879 11. Saitoh, S.; Kubota, T.; Ohta, T.; Jinno, Y.; Niikawa, N.; Sugimoto, T.; Wagstaff, J.; Lalande, M. : Familial Angelman syndrome caused by imprinted submicroscopic deletion encompassing GABA(A) receptor beta(3)-subunit gene. (Letter) Lancet 339: 366-367, 1992. PubMed ID : 1346439 12. Scapoli, L.; Martinelli, M.; Pezzetti, F.; Carinci, F.; Bodo, M.; Tognon, M.; Carinci, P. : Linkage disequilibrium between GABRB3 gene and nonsyndromic familial cleft lip with or without cleft palate. Hum. Genet. 110: 15-20, 2002. PubMed ID : 11810291 13. Sinnett, D.; Wagstaff, J.; Glatt, K.; Woolf, E.; Kirkness, E. J.; Lalande, M. : High-resolution mapping of the gamma-aminobutyric acid receptor subunit beta-3 and alpha-5 gene cluster on chromosome 15q11-q13, and localization of breakpoints in two Angelman syndrome patients. Am. J. Hum. Genet. 52: 1216-1229, 1993. PubMed ID : 8389098 14. Tanabe, A.; Taketani, S.; Endo-Ichikawa, Y.; Tokunaga, R.; Ogawa, Y.; Hiramoto, M. : Analysis of the candidate genes responsible for non-syndromic cleft lip and palate in Japanese people. Clin. Sci. 99: 105-111, 2000. PubMed ID : 10918043 15. Wagstaff, J.; Chaillet, J. R.; Lalande, M. : The GABA(A) receptor beta-3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7. Genomics 11: 1071-1078, 1991. PubMed ID : 1664410 16. Wagstaff, J.; Knoll, J. H. M.; Fleming, J.; Kirkness, E. F.; Martin-Gallardo, A.; Greenberg, F.; Graham, J. M., Jr.; Menninger, J.; Ward, D.; Venter, J. C.; Lalande, M. : Localization of the gene encoding the GABA(A) receptor beta-3 subunit to the Angelman/Prader-Willi region of human chromosome 15. Am. J. Hum. Genet. 49: 330-337, 1991. PubMed ID : 1714232 ### CONTRIBUTORS Cassandra L. Kniffin - updated : 3/18/2003 Victor A. McKusick - updated : 10/2/2002 John Logan Black, III - updated : 8/14/2002 Victor A. McKusick - updated : 7/2/2002 Victor A. McKusick - updated : 1/25/2002 Rebekah S. Rasooly - updated : 5/29/1998 Victor A. McKusick - updated : 11/20/1997 ### CREATION DATE Victor A. McKusick : 10/25/1991 ### EDIT HISTORY terry : 8/15/2003 alopez : 4/1/2003 carol : 3/18/2003 ckniffin : 3/18/2003 tkritzer : 10/4/2002 terry : 10/2/2002 carol : 8/14/2002 cwells : 7/16/2002 terry : 7/2/2002 terry : 3/11/2002 carol : 2/6/2002 carol : 2/6/2002 terry : 1/25/2002 alopez : 5/29/1998 terry : 11/24/1997 terry : 11/20/1997 mark : 4/10/1997 carol : 2/7/1994 carol : 6/16/1993 carol : 10/9/1992 carol : 9/8/1992 supermim : 3/16/1992 carol : 12/5/1991 Copyright © 1966-2005 Johns Hopkins University
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