Functional analysis of ANKLE2 in microcephaly using a genetic model system

 描述（由申请人提供）：可以使用患者样本的外显子组测序来鉴定孟德尔疾病的致病突变，但罕见变体的存在可能会妨碍基因座鉴定。为了规避这些困难，从果蝇正向遗传筛选中鉴定出参与神经变性或神经发育的基因的突变被用于筛选人类外显子组数据库中导致罕见孟德尔疾病的基因座。这项筛查发现了一种名为ANKLE2的基因突变，这种突变导致严重的小头畸形以及显著的认知和神经缺陷。果蝇中的突变也会导致神经元丢失和大脑变小。ANKLE 2在C.优雅然而，目前还不清楚这种功能是否是保守的，或者这种基因的缺失如何导致苍蝇和人类的小头畸形表型。该项目的目标是了解ANKLE2及其相互作用的伙伴如何使用遗传模型系统引起小头畸形，并确定这种蛋白质如何促进神经系统的发育。使用果蝇作为模型系统，将确定ANKLE 2在神经系统中的功能。

 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.