Mutation of HERC2 causes developmental delay with Angelman-like features
Mutation of HERC2 causes developmental delay with Angelman-like features
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DOI：
10.1136/jmedgenet-2012-101367
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发表时间：
2013-02-01
影响因子：
4
通讯作者：
Crosby, Andrew H.
中科院分区：
文献类型：
--
作者：
Harlalka, Gaurav V.;Baple, Emma L.;Crosby, Andrew H.
背景泛素连接酶E6AP（UBE 3A）活性的失调被公认为是导致Angelman综合征（AS）的发展的原因。HERC2基因编码的泛素连接酶HERC2被认为是E6AP的关键调节因子。方法与结果采用同源性作图和连锁分析相结合的方法，我们研究了一种常染色体隐性遗传的神经发育障碍，该疾病与AS有一定的表型相似性，发现于旧秩序阿米什人中。我们的分子研究确定了与疾病表型相关的HERC2突变。我们建立的编码突变HERC2蛋白具有减少的半衰期相比，其野生型对应物，这是与HERC2的水平在受影响的individual.Conclusions显着减少，我们的数据牵连的模型中，HERC2功能的中断与E6AP活性减少导致神经发育迟缓，这表明了以前未认识到的作用HERC2在AS的发病机制。
Background Deregulation of the activity of the ubiquitin ligase E6AP (UBE3A) is well recognised to contribute to the development of Angelman syndrome (AS). The ubiquitin ligase HERC2, encoded by the HERC2 gene is thought to be a key regulator of E6AP.Methods and results Using a combination of autozygosity mapping and linkage analysis, we studied an autosomal-recessive neurodevelopmental disorder with some phenotypic similarities to AS, found among the Old Order Amish. Our molecular investigation identified a mutation in HERC2 associated with the disease phenotype. We establish that the encoded mutant HERC2 protein has a reduced half-life compared with its wild-type counterpart, which is associated with a significant reduction in HERC2 levels in affected individuals.Conclusions Our data implicate a model in which disruption of HERC2 function relates to a reduction in E6AP activity resulting in neurodevelopmental delay, suggesting a previously unrecognised role of HERC2 in the pathogenesis of AS.