Investigating UBE3A as a driver gene in Duplication 15q syndrome

项目摘要 染色体15 q11-q13位点的母体重复（Dup 15 q综合征）是导致 自闭症谱系障碍UBE 3A包含在这个基因位点中;令人信服的证据表明它是 Dup 15 q综合征病理生理学的主要驱动因素。因此，UBE 3A水平的正常化可能 有效地治疗综合症，但这一直很难测试。为了验证这个想法，我们 产生了条件性Ube 3a过表达小鼠，其具有主要细胞遗传学的结构有效性。 Dup 15 q综合征的潜在异常：间质性15号染色体重复（Ube 3a的1个额外拷贝） 和等双着丝粒染色体15（2个额外拷贝的Ube 3a）。因此，我们的模型对于确定 UBE 3A蛋白水平的增加在多大程度上是必要的，并足以驱动Dup 15 q相关 病理生理学对于这些小鼠，我们也能够在不同的基因水平上使Ube 3a表达正常化。 年龄，使我们能够确定正常化提供实质性治疗益处的窗口。到 推进Dup 15 q综合征的知情干预策略，我们将使用我们的新小鼠模型（1） 建立UBE 3A过表达的行为和生理后果，（2）确定何时 UBE 3A的正常化挽救了病理生理学，以及（3）优化适当敲低的方法， UBE 3A和Ube 3a过表达小鼠中的正确病理生理学。

PROJECT SUMMARY Maternal duplication of the chromosome 15q11-q13 locus (Dup15q syndrome) is a major genetic cause of autism spectrum disorder. UBE3A is contained within this genetic locus; compelling evidence suggests it is the main driver of Dup15q syndrome pathophysiology. Accordingly, the normalization of UBE3A levels might effectively treat the syndrome, but this has been difficult to test. To allow us to test this idea, we have generated conditional Ube3a-overexpression mice that have construct validity for the principal cytogenetic abnormalities underlying Dup15q syndrome: interstitial chromosome 15 duplication (1 extra copy of Ube3a) and isodicentric chromosome 15 (2 extra copies of Ube3a). Thus, our models will be valuable for determining the extent to which increases in UBE3A protein levels are necessary and sufficient to drive Dup15q-relevant pathophysiology. With these mice, we are also able to genetically normalize Ube3a expression at different ages, allowing us to identify the window during which normalization provides substantial therapeutic benefit. To advance an informed intervention strategy for Dup15q syndrome, we will use our new mouse models to (1) establish the behavioral and physiological consequences of UBE3A overexpression, (2) determine when normalization of UBE3A rescues pathophysiology, and (3) optimize an approach to appropriately knock down UBE3A and correct pathophysiology in Ube3a-overexpression mice.