遗传性共济失调( Hereditary ataxia, HA)是一组具有高度的临床和遗传异质性的神经系 统遗传病与退行性疾病,前期工作中,我们在国内较早地开展了对HA家系的收集和DNA样本的 采集,建立了标准的基因诊断平台,并运用全基因外显子组测序、纯合子定位、生物信息学分 析及遗传学分析的方法遴选到一个近亲结婚的常染色体隐性遗传共济失调家系候选新致病基因 (暂命名:WX)。WX基因在中枢神经系统中高表达,与DNA复制、转录及修复有关。本项目, 在前期工作基础上，拟采用单核苷酸多态连锁分析、全基因外显子组测序、全基因组拷贝数变异和纯合子定位等先进技术和策略定位、克隆遗传性共济失调新的致病基因;并运用分子生物 学、分子遗传学等技术方法,构建新的HA候选致病基因如WX基因细胞模型、基因工程小鼠模型，研究遗传性共济失调致病基因的分子发病机制。

Hereditary ataxias (HA) are a group of neurodegenerative disorders that are characterized by complex clinically and genetic heterogeneity. On the prophase works, we have collected clinical data and DNA samples from hundreds of families of HA diseases. We also established the platform of gene diagnosis and identified a novel autosomal recessive cerebellar ataxia candidate gene (WX) in a two-generation Consanguineous ARCA family through exome sequencing, homozygosity mapping and copy number variation (CNV) analysis, bio information and genetic analysis. WX is highly expressed in the central nervous system and may participate in the replication, transcription and repair of DNA. In this project, based on our previous large collection of HA resources and successful experience in causative cloning, we are planning to locate and clone HA causative gene by using advanced technologies and strategies such as SNP linkage analysis, exome sequencing, homozygosity mapping and copy number variation analysis. In addition, cell model, Knock in/Knock out mice model carrying the novel candidate gene of HA, such as WX, will be generated. This work may help us to understand the physiological function of WX and provide new clues of pathogenesis of HA.