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

描述（由申请人提供）：我们在DACT1位点发现了一个新的单核苷酸多态性（SNP），它改变了蛋白质保守区域的一个进化上保守的氨基酸。我们假设，这种SNP，在一个受影响的家庭中追踪自闭症的诊断，改变了发育神经元中的蛋白质功能，从而导致疾病。我们已经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，这是一种可能与自闭症发病有关的细胞类型。该系统使用了我实验室生成的一种新型条件敲除小鼠系，以及在培养中研究海马神经元（HCNs）成熟的既定方法。我们的具体目标是回答以下问题：1。Dact1缺失对前脑神经元发育有影响吗？2. 自闭症变异的Dact1蛋白是否与野生型Dact1蛋白具有不同的生化特性？3. 野生型和自闭症变体Dact1蛋白在神经发育过程中表现出功能差异吗？这是一笔拨给国家心理健康研究所的探索性拨款，用于支持一名年轻研究员的实验室，他是一名接受过基础科学家培训的精神病学家。我们的目标是迅速利用这一机会，研究野生型和自闭症相关变异Dact1蛋白在神经发育过程中的功能。我们希望这将引领这个实验室的一个重要研究领域，为自闭症领域的进步做出重要贡献。公共卫生相关性：在美国，每150名儿童中就有1名患有自闭症，这是一种对个人、家庭和社会产生高度负面影响的行为障碍。了解其生物学基础以改进诊断和治疗是公共卫生的高度优先事项。这个项目调查了在一个自闭症家庭中发现的基因突变，以及这是如何从生物学上导致这种疾病的。

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.