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

• 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
• 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

 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.