Autism-specific mutation in DACT1: Impact on brain development in a mouse model

DACT1 中自闭症特异性突变：对小鼠模型大脑发育的影响

• 批准号: 7638397
• 负责人: Benjamin N.R. Cheyette
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-08 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7638397
• 关键词: Address; Affect; Affinity; Amino Acids; Animal Model; Area; Autistic Disorder; Basic Science; Behavior; Behavior Disorders; Binding; Biochemical; Biological; Biological Models; Brain; Child; Complex; Development; Diagnosis; Dimerization; Disease; Electrophysiology (science); Engineering; Family; Funding; Gene Mutation; Generations; Genetic Predisposition to Disease; Goals; Grant; Hippocampus (Brain); Human; In Vitro; Individual; Inhibitory Synapse; Intention; Knock-in Mouse; Knockout Mice; Laboratories; Lead; Link; Methods; Morphology; Mutation; National Institute of Mental Health; Neurites; Neurons; Pathogenesis; Phenotype; Physiology; Positioning Attribute; Post-Translational Protein Processing; Property; Prosencephalon; Proteins; Psychiatrist; Psychiatry; Reading; Research; Research Personnel; Role; Scientist; Signal Transduction; Single Nucleotide Polymorphism; Slice; Societies; System; Tertiary Protein Structure; Training; United States; Variant; Vertebral column; autism spectrum disorder; base; career; cell type; design; genetic pedigree; improved; mouse model; neurodevelopment; novel; postnatal; protein function; public health priorities; public health relevance; research study; success; synaptogenesis

DESCRIPTION (provided by applicant): We have identified a novel single nucleotide polymorphism (SNP) in the DACT1 locus that alters an evolutionarily conserved amino acid in a conserved domain of the protein. We hypothesize that this SNP, which tracks with the diagnosis of autism in an affected family, alters protein function in developing neurons to cause the disease. We have developed a model system in which to study functions of the corresponding protein in early postnatal forebrain neurons, a cell type that is likely to be relevant to autism pathogenesis. This system uses a novel conditional knock-out mouse line generated in my laboratory together with established methods for studying the maturation of hippocampal neurons (HCNs) in culture. Our specific aims are to answer the following questions: 1. Does loss of Dact1 have developmental consequences in forebrain neurons? 2. Does the autism-variant Dact1 protein have different biochemical properties than the wild type Dact1 protein? 3. Do the wild type and autism-variant Dact1 proteins display functional differences during neural development? This is an exploratory grant to the National Institute of Mental Health to support the laboratory of a young investigator who is a psychiatrist trained as a basic scientist. Our goal is to rapidly exploit this opportunity to investigate functions of a wild type and an autism-linked variant Dact1 protein during neural development. It is hoped that this will lead to a major area of research in this laboratory that will contribute importantly to progress in the autism field. PUBLIC HEALTH RELEVANCE: Autism afflicts as many as 1 in 150 children in the United States and is a behavioral disorder with a high negative impact on individuals, their families, and our society. Understanding its biological basis in order to improve diagnosis and treatment are high priorities for public health. This project investigates a gene mutation discovered in a family with autism and how this leads biologically to the disease.

描述（由申请人提供）：我们在 DACT1 基因座中鉴定出一种新的单核苷酸多态性 (SNP)，它改变了蛋白质保守结构域中进​​化上保守的氨基酸。我们假设这个 SNP 会追踪受影响家庭的自闭症诊断，改变发育神经元中的蛋白质功能，从而导致该疾病。我们开发了一个模型系统，用于研究出生后早期前脑神经元中相应蛋白质的功能，这种细胞类型可能与自闭症发病机制相关。该系统使用我实验室生成的新型条件敲除小鼠系以及用于研究培养物中海马神经元 (HCN) 成熟的既定方法。我们的具体目标是回答以下问题： 1. Dact1 的缺失是否会对前脑神经元的发育产生影响？ 2. 自闭症变异体 Dact1 蛋白与野生型 Dact1 蛋白具有不同的生化特性吗？ 3. 野生型和自闭症变异体 Dact1 蛋白在神经发育过程中是否表现出功能差异？这是向国家心理健康研究所提供的一笔探索性赠款，用于支持一位年轻研究员的实验室，这位年轻研究员是一位接受过基础科学家培训的精神病学家。我们的目标是快速利用这个机会来研究野生型和与自闭症相关的变体 Dact1 蛋白在神经发育过程中的功能。希望这将成为该实验室的一个主要研究领域，为自闭症领域的进展做出重要贡献。公共卫生相关性：在美国，每 150 名儿童中就有 1 人患有自闭症，它是一种行为障碍，对个人、家庭和社会产生严重负面影响。了解其生物学基础以改善诊断和治疗是公共卫生的当务之急。该项目调查了在一个患有自闭症的家庭中发现的基因突变以及该基因突变如何在生物学上导致该疾病。