Phenotypic Characterization of Novel Models of Dup15q Syndrome

Dup15q 综合征新模型的表型特征

基本信息

批准号：
9310098
负责人：
Jill Lynn Silverman
金额：
$ 34.34万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-15 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310098
关键词：
Address Affect Alleles Amygdaloid structure Anatomy Angelman Syndrome Anxiety Autistic Disorder Autopsy Behavior Behavioral Brain Brain region Cell model Chromatin Cognitive Copy Number Polymorphism Cytoplasm DNA DNA Methylation Data Developmental Delay Disorders Epigenetic Process Epilepsy Etiology Exhibits Genes Genetic Genetic Transcription Genetic Variation Genomic Imprinting Hippocampus (Brain)Human Impairment Inheritance Patterns Intellectual functioning disability Learning Ligase Link Maps Minor Modeling Molecular Motor Seizures Mus Muscle hypotonia Mutant Strains Mice Mutation Nature Neurobiology Neurodevelopmental Disorder Neurons Nuclear Outcome Pathogenicity Pathologic Pathology Phenotype Play Prader-Willi Syndrome Prosencephalon Protein Isoforms RNA Splicing Role Speech Structure Synapses Syndrome Testing Transgenic Mice UBE3A gene Ubiquitin autism spectrum disorder base behavioral impairment behavioral outcome epigenomics functional outcomes genome-wide imprint in vivo mouse model mutant neuronal cell body neuropathology novel overexpression relating to nervous system

项目摘要

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.

项目摘要 15q11.2-Q13（DUP15Q）的母体得出的重复或三分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。 DUP15Q中常见的突出特征包括智力残疾（ID），癫痫，发育延迟，肌张力低下，语音障碍和较小的畸形特征。构图到15q11.2-Q13区域的泛素E3A连接酶基因（UBE3A）已是与多种神经发育障碍有关，包括ASD，Angelman综合征（AS）， Prader-Willi综合征（PWS）和ID。基于这些信息，我们假设该信息失调 UBE3A具有有害的结果。因为ube3a专门印在神经元中，我们将使用新颖的鼠标模型来测试假设神经元中的UBE3A升高是主要的表型的贡献者。众所周知，ube3a的三个差剪接的同工型存在，促使我们追求哪种同工型的次要科学问题在DUP15Q中的关键作用。迄今为止，尚无体内研究评估表型的贡献与三个UBE3A同工型中的每一个相关联。初步数据说明了我们发现的发现前脑，UBE3A同工型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协作项目，以识别同工型特异性UBE3A的行为，神经解剖学和表观遗传机制过表达。该建议将直接解决有关我们的最重要的问题 UBE3A过度表达的主要科学前提是主要致病机制导致DUP15Q损伤。我们还将解决我们的次要前提神经元中的UBE3A同工型引起差异行为，病理和表观遗传异常。我们将描述表型并确定同工型特异性UBE3A-的每一系中的病理过表达的小鼠。分子，细胞，组织病理学和行为表型将揭示有关神经底物的关键信息 DUP15Q表型。这些研究将回答有关 UBE3A过表达的机制的致病性质。