MOLECULAR & CYTOGENETIC ANALYSIS--UBE3A/E6-AP IN ANGELMAN SYNDROME

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Angelman syndrome (AS), a genetic disorder characterized by severe mental retardation, seizures, easily provoked smiling and laughter, abnormal gait, and sleep disorder, is caused in about 70% of cases by de novo maternal deletions of 15q11q13, in 2-3% of cases by paternal uniparental disomy (UPD) of chromosome 15, and in 2-3% of cases by "imprinting mutations". The remaining 20-25% of cases show no abnormality by standard diagnostic tests, including FISH (fluorescence in situ hybridization) or methylation analysis. Within this group of NDUI (nondeletion/non-UPD/non-imprinting mutation) AS cases are a number of familial AS cases. The investigators have found point mutations of the UBE3A/E6-AP gene in NDUI AS individuals that are predicted to lead to complete loss of function of the UBE3A gene product, which is a ubiquitin-protein ligase. The detection of UBE3A mutations in AS indicates a possible abnormality in ubiquitin-mediated protein degradation during brain development in this disorder. Detection of additional mutations will contribute to improved understanding of structure-function relationships in UBE3A/E6- AP and will permit more accurate genetic counseling in this group of AS patients. Specific goals: 1) Identify additional UBE3A mutations in other NDUI AS patients using SSCP analysis of coding and regulatory regions 2) Correlate phenotypes with molecular alterations of UBE3A 3) Test mutant forms of the UBE3A protein for ubiquitination of p53 in an in vitro assay