Phenotypic Characterization of Novel Models of Dup15q Syndrome

项目摘要 母源性15q11.2-q13（Dup 15 q）的重复或三倍体是最常见的染色体异常之一。 与自闭症谱系障碍（ASD）相关的常见遗传变异，在1-3%中检测到 案件。在Dup 15 q中常见的突出特征包括智力残疾（ID）， 癫痫、发育迟缓、张力减退、言语障碍和轻微畸形特征。 定位于15q11.2-q13区域的泛素E3 A连接酶基因（UBE 3A）已被发现。 涉及多种神经发育障碍，包括ASD，Angelman综合征（AS）， Prader-Willi综合征（PWS）和ID。基于这些信息，我们假设， UBE 3A具有有害的结果。由于UBE 3A是专门印在神经元，我们将 使用新的小鼠模型来测试神经元中UBE 3A升高是主要的 表型的贡献者。众所周知，UBE 3A的三种差异剪接同种型 存在，促使我们追求次要的科学问题，其中同种型发挥最大作用 在Dup 15 q中的关键作用。迄今为止，没有体内研究评估表型贡献 与三种Ube 3a同种型中的每一种相关。初步数据表明， 前脑，Ube 3a同种型2的神经元选择性过表达足以引起行为 和解剖表型。在这里，我们提出了一个多方面的合作项目，以确定 异构体特异性Ube 3a的行为、神经解剖和表观遗传机制 过度表达这项建议将直接解决有关我们的最重要的问题， 一个主要的科学前提是UBE 3A的过度表达是主要的致病机制 导致Dup 15 q损伤我们还将讨论我们的次要前提，即不同的 神经元中的Ube 3a亚型引起不同的行为、病理和表观遗传异常。 我们将描绘表型，并确定在每一行的异构体特异性Ube 3a的病理- 过度表达小鼠分子，细胞， 组织病理学和行为表型将揭示神经基质的关键信息， Dup 15 q表型。这些研究将回答关于 UBE 3A过表达的致病性机制。

Project Summary Maternally derived duplications or triplications of 15q11.2-q13 (Dup15q) are one of the most common genetic variations associated with autism spectrum disorder (ASD), detected in 1-3% of cases. Prominent features commonly found in Dup15q include intellectual disability (ID), epilepsy, developmental delay, hypotonia, speech impairments, and minor dysmorphic features. The ubiquitin E3A ligase gene (UBE3A), which maps to the 15q11.2-q13 region, has been implicated in multiple neurodevelopmental disorders, including ASD, Angelman Syndrome (AS), Prader-Willi Syndrome (PWS) and ID. Based on this information, we postulate that dysregulated UBE3A has deleterious outcomes. Because UBE3A is imprinted specifically in neurons, we will use novel mouse models to test the hypothesis that elevated UBE3A in neurons is the major contributor to phenotypes. It is well known that three differentially spliced isoforms of UBE3A exist, propelling us to pursue the secondary scientific question of which isoform plays the most critical role in Dup15q. No in vivo studies, to date, have evaluated the phenotypic contributions associated with each of the three Ube3a isoforms. Preliminary data illustrate our discovery that forebrain, neuronal selective overexpression of Ube3a isoform 2 is sufficient to cause behavioral and anatomical phenotypes. Here, we propose a multifaceted, collaborative project to identify behavior, neuroanatomical and epigenetic mechanisms of isoform-specific Ube3a overexpression. This proposal will directly address the most important questions regarding our main scientific premise that overexpression of UBE3A is the principal pathogenic mechanism causing Dup15q impairments. We will also address our secondary premise, that different Ube3a isoforms in neurons cause differential behavioral, pathological and epigenetic anomalies. We will delineate phenotypes and identify pathologies in each line of isoform-specific Ube3a- overexpressing mice. Significant correlations and corroborations between molecular, cellular, histopathological and behavioral phenotypes will reveal key information on neural substrates of Dup15q phenotypes. These studies will answer the most important questions regarding the pathogenic nature of mechanisms underlying UBE3A overexpression.