Functional analysis of ANKLE2 in microcephaly using a genetic model system

使用遗传模型系统对小头畸形中 ANKLE2 进行功能分析

基本信息

批准号：
8908259
负责人：
NICHOLE L LINK
金额：
$ 5.8万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8908259
关键词：
Alleles Apical Basal Cell Biological Assay Biological Models Brain Caenorhabditis elegans Cell Cycle Cell Cycle Regulation Cell Line Cell Maintenance Cell Polarity Cell division Cells Clustered Regularly Interspaced Short Palindromic Repeats Cognitive Data Databases Defect Disease Drosophila genus Embryonic Development Event Exhibits Genes Genetic Genetic Models Genetic Screening Genomics Goals Head Homologous Gene Human Lead Learning Life Link Maintenance Mendelian disorder Microcephaly Mitosis Mutation Nerve Degeneration Nervous system structure Neuraxis Neurodevelopmental Disorder Neurologic Neurons Nuclear Envelope Patients Peripheral Nervous System Phenotype Phosphorylation Phosphotransferases Protein phosphatase Proteins Regulation Role Sampling Stem cells Structure Surveys System Translating atypical protein kinase C barrier-to-autointegration factor base brain volume cell type cellular imaging exome exome sequencing fly human disease insight men mutant nerve stem cell nervous system development neuroblast neurodevelopment neuron loss novel prevent public health relevance rare variant research study tool

项目摘要

DESCRIPTION (provided by applicant): Causative mutations of Mendelian disease can be identified using exome sequencing of patient samples, but the presence of rare variants can prevent loci identification. To circumvent these difficulties, mutations from a Drosophila forward genetic screen that identified genes involved in neurodegeneration or neurodevelopment were used to screen a human exome database for loci that cause rare Mendelian disorders. This screen identified mutations in a gene called ANKLE2 that caused severe microcephaly as well as significant cognitive and neurological defects. Mutations in the Drosophila counterpart also lead to neuronal loss and smaller brains. ANKLE2 has been implicated to function in nuclear envelope formation during mitosis in C. elegans. However, it is unclear whether this function is conserved or how the loss of this gene causes microcephaly phenotypes in flies and men. The goal of this project is to understand how ANKLE2 and its interacting partners cause microcephaly using a genetic model system and to determine how this protein contributes to the development of the nervous system. Using Drosophila as a model system, the function of ANKLE2 in the nervous system will be determined.

描述（由适用提供）：可以使用患者样品的外显子组测序来鉴定孟德尔疾病的病因突变，但是稀有变体的存在可以防止局部鉴定。为了避免这些困难，使用果蝇向前遗传筛选的突变，该突变使用鉴定出参与神经退行性的基因或神经发育的基因来筛选引起罕见孟德尔疾病的基因座人类外显子组数据库。该屏幕确定了一个称为Ankle2的基因中的突变，该突变引起了严重的小头畸形以及明显的认知和神经系统缺陷。果蝇对应物中的突变也导致神经元丧失和较小的大脑。秀丽隐杆线虫中有丝分裂期间，ANKLE2已暗示在核膜形成中起作用。但是，尚不清楚该功能是保守的还是该基因的丧失如何导致苍蝇和男性中的小头畸形表型。该项目的目的是了解ankle2及其相互作用的伴侣如何使用遗传模型系统引起小头畸形，并确定该蛋白质如何促进神经系统的发展。将使用果蝇作为模型系统，将确定Ankle2在神经系统中的功能。