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: 8145607
• 负责人: Stephen Edward Paucha Smith
• 金额: $ 4.02万
• 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 2011-12-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8145607
• 关键词: 15q; Age; Alleles; Anxiety; Autistic Disorder; Axon; Behavior; Behavioral; Biological Assay; Brain; Child; Chromosome abnormality; Chromosomes; Copy Number Polymorphism; Defect; Development; Disease; Disease model; Electroencephalogram; Electrophysiology (science); Event; Excitatory Postsynaptic Potentials; Excitatory Synapse; Face; Frequencies; Functional disorder; Gene Dosage; Genes; Genetic Models; Glutamate Receptor; Goals; High Prevalence; Image; Individual; Infant; Inherited; Inhibitory Synapse; Injection of therapeutic agent; Knock-out; Knockout Mice; Lead; Learning; Length; Measures; Mediating; Membrane Potentials; Mental Retardation; Mental disorders; Metabolic; Modeling; Molecular; Mothers; Motor; Mus; Muscle Hypertonia; Muscle hypotonia; Mutate; Neurobiology; Neurons; Newborn Infant; Output; Pathway interactions; Patients; Pattern; Phenotype; Property; Proteins; Reflex action; Relative (related person); Risk; Role; Seizures; Sensory; Shapes; Sleep; Sleep disturbances; Social Behavior; Social Interaction; Speech; Staining method; Stains; Stereotyping; Stimulus; Structure; Sudden Death; Susceptibility Gene; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Syndrome; Testing; Thalamic structure; Transgenic Organisms; Ubiquitin; Ubiquitination; Vertebral column; autism spectrum disorder; base; behavior test; biocytin; conditioned fear; density; disorder risk; early childhood; electrical property; imprint; in vivo; infancy; morris water maze; mouse model; neuropsychiatry; novel; overexpression; postnatal; prepulse inhibition; public health relevance; pup; research study; response; retinogeniculate; ubiquitin-protein ligase; uptake; vocalization; voltage clamp

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）： 母体染色体 15q11-13 重复是导致自闭症谱系障碍 (ASD) 的最常见拷贝数变异，占所有 ASD 病例的 1-3%。重要的是，父系重复不会导致自闭症谱系障碍，这表明致病基因是有印记的。在染色体区域的 40 个基因中，只有 UBE​​3A 完全由大脑中的母体染色体表达。 UBE3A，即安格曼综合症 (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、过度社交行为、过度大笑、癫痫发作和面部特征刻板。鉴于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素通路在 ASD 病理生理学中的作用，我们假设 Ube3a 在 15q11-13 重复中介导 ASD 风险。为了研究UBE3A在大脑中的功能，我们获得了UBE3A母体缺陷（基因敲除）小鼠，并产生了携带两个额外UBE3A拷贝的新型小鼠，模拟了等双着丝粒15q疾病，该疾病显示自闭症谱系障碍的高患病率。重要的是，我们已经证明这个 idic15 小鼠模型显示出大脑蛋白质泛素化的显着增加。根据观察到的 AS（15q11-13 缺失）和 ASD（15q11-13 重复）相反的症状，例如婴儿期肌张力亢进与肌张力低下以及儿童早期的过度社交行为与低社交行为，我们预测缺乏 Ube3a 和过度表达 Ube3a 的小鼠将表现出相反的表型，这将突出 UBE3A 的正常功能。当前提案的目标如下：1) 证明 UBE3A 有助于从母亲那里遗传额外的 15q11-13 拷贝的儿童中观察到的自闭症谱系障碍 (ASD)；2) 阐明这些疾病的细胞基础以及 UBE3A 在神经元回路功能中的作用。为了实现这一目标，我们将首先描述我们的新型过度表达小鼠中与 ASD（社交互动、婴儿发声）和神经精神疾病（例如焦虑）直接相关的行为。其次，丘脑神经元表达高水平的 Ube3a，在 ASD 中表现出代谢活动（FDG 摄取）降低，并且可能是行为缺陷的基础。因此，我们将对 UBE3A 过度表达和缺陷小鼠的丘脑电路结构和功能进行全面的基于电生理学的表征。总体而言，我们预测过量的 UBE3A 将足以复制 15q11-13 ASD 的许多特征，从而定义 ASD 的新遗传模型。 公共卫生相关性： 导致自闭症的最常见染色体异常是染色体 15q11-13 的重复，这会导致孩子的多个基因拷贝过多。我们将在小鼠体内插入一个可能对 15q 复制很重要的基因的额外拷贝，表征小鼠的行为，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。