Abstract
Angelman syndrome (AS), characterized by mental retardation, seizures, frequent smiling and laughter, and abnormal gait, is one of the best examples of human disease in which genetic imprinting plays a role1. In about 70% of cases, AS is caused by de novo maternal deletions at 15q11–q13 (ref. 2). Approximately 2% of AS cases are caused by paternal uniparental disomy (UPD) of chromosome 15 (ref. 3) and 2–3% are caused by ‘imprinting mutations’ 4. In the remaining 25% of AS cases, no deletion, uniparental disomy (UPD), or methylation abnormality is detectable, and these cases, unlike deletions or UPD, can be familial5–7. These cases are likely to result from mutations in a gene that is expressed either exclusively or preferentially from the maternal chromosome 15. We have found that a 15q inversion inherited by an AS child from her normal mother disrupts the 5′ end of the UBE3A (E6-AP) gene, the product of which functions in protein ubiquitination16. We have looked for novel UBE3A mutations in nondeletion/non-UPD/non-imprinting mutation (NDUI) AS patients and have found one patient who is heterozygous for a 5-bp de novo tandem duplication. We have also found in two brothers a heterozygous mutation, an A to G transition that creates a new 3′ splice junction 7 bp upstream from the normal splice junction. Both mutations are predicted to cause a frameshift and premature termination of translation. Our results demonstrate that UBE3A mutations are one cause of AS and indicate a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disease.
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References
Williams, C.A. et al. Angelman syndrome. Curr. Probl. Pediatr. 25, 216–231 (1995).
Knoll, J.H.M. et al. 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).
Malcolm, S. et al. Uniparental paternal disomy in Angelman's syndrome. Lancet 337, 694–697 (1991).
Buiting, K. et al. Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nature Genet. 9, 395–400 (1995).
Wagstaff, J. et al. Maternal but not paternal transmission of 15q11-13-linked nondeletion Angelman syndrome leads to phenotypic expression. Nature Genet. 1, 291–294 (1992).
Clayton-Smith, J. . et al. Further evidence for dominant inheritance at the chromosome 15q11-13 locus in familial Angelman syndrome. Am. J. Med. Genet. 44, 256–260 (1992).
Meijers-Heijboer, E.J. . J. et al. Linkage analysis with chromosome 15q11-13 markers shows genomic imprinting in familial Angelman syndrome. J. Med. Genet. 29, 853–857 (1992).
Reed, M.L. & Leff, S.E. Maternal imprinting of human SNRPN, 6, 163–167 (1994).
Sutcliffe, J.S. . S. et al. Deletions of a differentially methylated CpG island at the SNRPN 8, 52–58 (1994).
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).
Ning, Y. et al. Identification of a novel paternally expressed transcript adjacent to snRPN in the Prader-Willi syndrome critical region. Genome Res. 6, 735–741 (1996).
Burke, L.W. et al. Familial cryptic translocation resulting in Angelman syndrome: implications for imprinting or location of the Angelman gene? Am. J. Hum. Genet. 58, 777–784 (1996).
Greger, V., Reis, A. & Lalande, M. The critical region for Angelman syndrome lies between D15S122 and D15S113. Am. J. Med. Genet. 53, 396–398 (1994).
Woodage, T. et al. 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).
Nakao, M. et al. Imprinting analysis of three genes in the Prader-Willi/Angelman region: SNRPN, E6-associated protein, and PAR-2 (D15S225E). Hum. Molec. Genet. 3, 309–315 (1994).
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. Mol.Cell. Biol. 13, 775–784 (1993).
Huibregtse, J.M., Scheffner, M., Beaudenon, S. & Howley, P.M. A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase. Proc. Natl Acad. Sci. USA. 92, 2563–2567 (1995).
Cooper, D.N. & Krawczak, M. Mechanisms of insertional mutagenesis in human genes causing genetic disease. Hum. Genet. 87, 409–415 (1991).
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).
Wagstaff, J., Shugart, Y.Y. & Lalande, M. Linkage analysis in familial Angelman syndrome. Am. J. Hum. Genet. 53, 105–112 (1993).
DeChiara, T.M., Robertson, E.J. & Efstratiadis, A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell 64, 849–859 (1991).
Giddings, S.J., Harman, K.W., Flood, J.F. & Carnaghi, L. R. Allele specific inactivation of insulin 1 and 2, in the mouse yolk sac, indicates imprinting. Nature Genet. 6, 310–313 (1994).
Ekstrom, T.J., Cui, H., Li, X. & Ohlsson, R. Promoter-specific IGF2 imprinting status and its plasticity during human liver development. Development 121, 309–316 (1995).
Deltour, L., Montagutelli, X., Guenet, J.-L., Jami, J. & Paldi, A. Tissue- and developmental stage-specific imprinting of the mouse proinsulin gene. Ins2. Dev. Biol. 168, 686–688 (1995).
Kalscheuer, V.M., Mariman, E.C., Schepens, M.T., Rehder, H. & Ropers, H.-H. The insulin-like growth factor type-2 receptor gene is imprinted in the mouse but not in humans. Nature Genet. 5, 74–78 (1993).
Pearsall, R.S. . S. et al. Absence of imprinting in U2AFBPL, a human homologue of the imprinted mouse gene U2afbp-rs. Biochem. Biophys. Res. Comm. 222, 171–177 (1996).
Riesewijk, A.M., Schepens, M.T., Mariman, E.M., Ropers, H.-H. & Kalscheuer, V.M., MAS proto-oncogene is not imprinted. Genomics 35, 380–382 (1996).
Vu, T.H. & Hoffman, A.R. Promoter-specific imprinting of the human insulin-like growth factor-ll gene. Nature 371, 714–717 (1994).
Chung, W.-Y., Yuan, L., Feng, L., Hensle, T. & Tycko, B. Chromosome 11p15.5 regional imprinting: comparative analysis of KIP2 and H19 in human tissues and Wilms' tumors. Hum. Molec. Genet. 5, 1101–1108 (1996).
Scheffner, M., Nuber, U. & Huibregtse, J.M. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. 373, 81–83 (1995).
Muralidhar, M.G. & Thomas, J.B., The Drosophila bendless gene encodes a neural protein related to ubiquitin-conjugating enzymes. Neuron 11, 253–266 (1993).
Palombella, V.J., Rando, O.J., Goldberg, A.L. & Maniatis, T. The ubiquitin-proteasome pathway is required for processing the NF-KB1 precursor protein and the activation of NF-KB. Cell 78, 773–785 (1994).
Church, D.M., Stotler, C.J., Rutter, J.L., Murrell, J.R., Trofatter, J.A. & Isolation of genes from complex sources of mammalian genomic DNA using exon amplification. Nature Genet. 6, 98–105 (1994).
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Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet 15, 70–73 (1997). https://doi.org/10.1038/ng0197-70
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DOI: https://doi.org/10.1038/ng0197-70
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