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基因座上发现了一种新的单核苷酸多态(SNP)，它改变了蛋白质保守区域中一个进化上保守的氨基酸。我们假设，这种跟踪受影响家庭自闭症诊断的SNP会改变发育中的神经元的蛋白质功能，从而导致疾病。我们已经开发了一个模型系统来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相关的细胞类型。该系统使用了在我的实验室中产生的一种新的条件基因敲除小鼠系，以及研究海马神经元(HCN)在培养中成熟的既定方法。我们的具体目标是回答以下问题：1.Dact1基因的缺失对前脑神经元有发育影响吗？2.自闭症变异型Dact1蛋白与野生型Dact1蛋白是否具有不同的生化性质？3.野生型和自闭症变异型Dact1蛋白在神经发育过程中是否表现出功能差异？这是对国家精神卫生研究所的一项探索性拨款，用于支持一名年轻的研究人员的实验室，他是一名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个机会来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。希望这将导致该实验室的一个主要研究领域，这将对自闭症领域的进展做出重要贡献。与公共健康相关：在美国，每150名儿童中就有1人患有自闭症，是一种行为障碍，对个人、他们的家庭和我们的社会具有高度负面影响。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。这个项目调查在一个自闭症家庭中发现的一种基因突变，以及这种突变是如何从生物学上导致疾病的。

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.