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

安杰曼综合征(AS)是一种遗传性疾病，其特征是严重 智力低下，癫痫发作，很容易引起微笑和笑声， 步态异常和睡眠障碍大约70%的病例是由 母亲15q11q13的新缺失，在2%-3%的病例中由父亲决定 15号染色体的单亲二体(UPD)，在2%-3%的病例中 “印记突变”。其余20%-25%的病例显示没有 标准诊断测试异常，包括FISH(荧光 原位杂交)或甲基化分析。在这组人中 NDUI(非删除/非更新/非印记突变)，因为病例是一个数字 家族性AS病例。调查人员发现了基因的点突变 NDUI中的UBE3A/E6-AP基因作为预测的先导个体 完全丧失UBE3A基因产物的功能，这是一种 泛素-蛋白质连接酶。 在AS中检测到UBE3A突变表明可能存在异常 在脑发育过程中泛素介导的蛋白质降解 这种紊乱。检测更多的突变将有助于 提高了对UBE3A/E6-的结构-功能关系的理解 美联社并将允许在这一组AS中进行更准确的遗传咨询 病人。 具体目标： 1)在其他NDUI患者中发现其他UBE3A突变 编码区和调控区的SSCP分析 2)表型与UBE3A分子改变的相关性 3)检测突变形式的UBE3A蛋白对P53泛素化的影响 一种体外试验

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