Phenotypic Characterization of Novel Models of Dup15q Syndrome

Dup15q 综合征新模型的表型特征

• 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
• 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

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.

项目概要 15q11.2-q13 (Dup15q) 的母源重复或三倍是最常见的重复之一。 与自闭症谱系障碍 (ASD) 相关的常见遗传变异，检测率为 1-3% 案例数。 Dup15q 中常见的突出特征包括智力障碍 (ID)、 癫痫、发育迟缓、肌张力低下、言语障碍和轻微畸形特征。 泛素 E3A 连接酶基因 (UBE3A) 定位于 15q11.2-q13 区域，已被 与多种神经发育障碍有关，包括自闭症谱系障碍 (ASD)、天使综合症 (AS)、 普瑞德威利综合症 (PWS) 和 ID。根据这些信息，我们假设失调 UBE3A 具有有害的结果。因为 UBE3A 专门印记在神经元中，所以我们将 使用新型小鼠模型来检验神经元中 UBE3A 升高是主要因素的假设 表型的贡献者。众所周知，UBE3A 的三种差异剪接亚型 存在，推动我们去追求次要的科学问题，其中同工型发挥最大作用 Dup15q 中的关键作用。迄今为止，还没有体内研究评估了表型贡献 与三种 Ube3a 同种型中的每一种相关。初步数据表明我们的发现 前脑、神经元选择性过度表达 Ube3a 亚型 2 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来确定 亚型特异性 Ube3a 的行为、神经解剖学和表观遗传机制 过度表达。该提案将直接解决有关我们的最重要问题 UBE3A 过度表达是主要致病机制的主要科学前提 导致 Dup15q 损伤。我们还将解决我们的次要前提，即不同的 神经元中的 Ube3a 亚型会导致不同的行为、病理和表观遗传异常。 我们将描绘表型并识别各亚型特异性 Ube3a- 系的病理学 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 Dup15q 表型。这些研究将回答有关 UBE3A 过度表达机制的致病性质。