Characterization of Autism Susceptibility Genes on Chromosome 15q11-13

染色体 15q11-13 上自闭症易感基因的特征

• 批准号: 7912550
• 负责人: Stephen Edward Paucha Smith
• 金额: $ 4.76万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-05 至 2013-03-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912550
• 关键词: 15q; Anxiety; Autistic Disorder; Behavior; Behavioral; Brain; Child; Chromosome abnormality; Chromosomes; Copy Number Polymorphism; Defect; Disease; Electrophysiology (science); Face; Functional disorder; Genes; Genetic Models; Goals; High Prevalence; Infant; Inherited; Knockout Mice; Lead; Mediating; Mental Retardation; Mental disorders; Metabolic; Modeling; Molecular; Mothers; Mus; Mutate; Neurons; Pathway interactions; Phenotype; Proteins; Role; Seizures; Social Behavior; Social Interaction; Speech; Stereotyping; Structure; Susceptibility Gene; Symptoms; Syndrome; Thalamic structure; Ubiquitin; Ubiquitination; autism spectrum disorder; base; disorder risk; early childhood; imprint; infancy; mouse model; neuropsychiatry; novel; overexpression; public health relevance; ubiquitin-protein ligase; uptake; vocalization

DESCRIPTION (provided by applicant): Maternal duplication of chromosome 15q11-13 is the most common copy number variation causing autism spectrum disorder (ASD), present in 1-3% of all ASD cases. Importantly, paternal duplication does not cause ASD, suggesting that the causative gene(s) are imprinted. Of 40 genes in the chromosomal region, only UBE3A is expressed exclusively from the maternal chromosome in the brain. UBE3A, Angleman's syndrome (AS) gene, is an E3 ubiquitin ligase mutated to cause mental retardation, impaired speech, overly-social behavior, excess laughing, seizures and stereotyped facial features. Given the gene's role in causing this severe mental disorder, and the recent evidence implicating ubiquitin pathways in ASD pathophysiology, we hypothesize that Ube3a mediates ASD risk in 15q11-13 duplication. In order to study UBE3A function in brain, we obtained UBE3A maternal-deificent (knockout) mice, and generated novel mice harboring two extra copies of UBE3A, modeling isodicentric 15q disorder which shows a high prevalence of ASD. Importantly, we have shown that this idic15 mouse model displays a marked increase of brain protein ubiquitination. Based on the observed opposing symptoms of AS (15q11-13 deletion) and ASD (15q11-13 duplication), such as hyper- tonia vs hypo-tonia in infancy and hyper-social behavior vs. hypo-social behavior in early childhood, respectively, we predict that mice lacking Ube3a and overexpressing Ube3a will show opposing phenotypes which will highlight the normal function of UBE3A. The objectives of the current proposal are the following: 1) to demonstrate that UBE3A contributes to the ASD observed in children inheriting extra copies of 15q11-13 from their mother, and 2) to elucidate the cellular basis of these disorders and UBE3A function in neuronal circuit function. Towards this goal, we will first characterize behaviors directly relevant to ASD (social interaction, infant vocalization) and to neuropsychiatric disease (e.g., anxiety) in our novel overexpressing mice. Second, thalamic neurons express high levels of Ube3a, display reduced metabolic activity (FDG uptake) in ASD, and could underlie behavioral defects. Therefore, we will perform a comprehensive electrophysiology-based characterization of thalamic circuitry structure and function in both UBE3A overexpressing and deficent mice. Overall, we predict excess UBE3A will be sufficent to replicate many of the features of 15q11-13 ASD, defining a new genetic model of ASD. PUBLIC HEALTH RELEVANCE: The most common chromosomal abnormality that causes autism is duplication of chromosome 15q11- 13, which results in a child having too many copies of several genes. We will insert extra copies of a gene likely to be important in 15q duplication into mice, characterize the behavior of the mice, and investigate, on a molecular level, how these genes might lead to abnormal behaviors related to autism.

描述（由申请人提供）： 母亲染色体15 q11 - 1 - 3的重复是导致自闭症谱系障碍（ASD）的最常见的拷贝数变异，存在于所有ASD病例的1-3%中。重要的是，父系复制不会导致ASD，这表明致病基因是印记的。在染色体区域的40个基因中，只有UBE 3A在大脑中仅从母体染色体表达。UBE 3A，Angleman综合征（AS）基因，是一种E3泛素连接酶突变，可导致智力低下，言语障碍，过度社会行为，过度大笑，癫痫发作和刻板的面部特征。考虑到该基因在导致这种严重精神障碍中的作用，以及最近的证据表明泛蛋白途径与ASD病理生理学有关，我们假设Ube 3a介导15 q11 -13重复中的ASD风险。为了研究UBE 3A在脑中的功能，我们获得了UBE 3A母源缺陷（敲除）小鼠，并产生了携带两个额外拷贝的UBE 3A的新型小鼠，建立了显示ASD高患病率的等双着丝粒15 q紊乱的模型。重要的是，我们已经证明，这种idic 15小鼠模型显示出脑蛋白遍在化的显着增加。基于观察到的AS（15 q11 -13缺失）和ASD（15 q11 -13重复）的相反症状，例如婴儿期的张力亢进与张力减退，以及幼儿期的过度社会行为与低社会行为，我们预测缺乏Ube 3a和过表达Ube 3a的小鼠将显示相反的表型，这将突出UBE 3A的正常功能。本研究的目的如下：1）证明UBE 3A与从母亲遗传额外15 q11 -13拷贝的儿童中观察到的ASD有关，2）阐明这些疾病的细胞基础和UBE 3A在神经元回路功能中的作用。为了实现这一目标，我们将首先描述与ASD（社会互动，婴儿发声）和神经精神疾病（例如，焦虑）。第二，丘脑神经元表达高水平的Ube 3a，在ASD中显示降低的代谢活性（FDG摄取），并且可能是行为缺陷的基础。因此，我们将在UBE 3A过表达和缺陷小鼠中对丘脑电路结构和功能进行全面的基于电生理学的表征。总的来说，我们预测过量的UBE 3A将足以复制15 q11 -13 ASD的许多特征，从而定义一种新的ASD遗传模型。 公共卫生相关性： 导致自闭症的最常见的染色体异常是染色体15 q11 - 13的重复，这导致儿童具有过多的几个基因的拷贝。我们将在小鼠中插入一个可能在15 q重复中很重要的基因的额外拷贝，描述小鼠的行为，并在分子水平上研究这些基因如何导致与自闭症相关的异常行为。