STUB1基因突变导致Gordon Holmes综合征的机制研究

Gordon Holmes综合征是遗传性共济失调类疾病的一种特殊亚型，临床表现为进行性共济失调合并性腺发育不全，其遗传方式为常染色体隐性遗传。尽管临床上对于此疾病的认识已有100年时间， 直到去年5月，其第一、二种致病基因RNF216和OTUD4才被鉴定克隆。我们在前期工作中发现：STUB1是Gordon Holmes综合征的第三种致病基因。本研究在前期工作基础上，拟进一步构建体外细胞模型、STUB1基因突变Knock-in小鼠模型、患者特异iPSC模型等三种新的Gordon Holmes综合征疾病模型，并采用免疫荧光、免疫印迹、免疫共沉淀、泛素化测定、高通量测序、锌指核酸酶靶基因定点修饰等技术其进一步深入探讨STUB1基因突变引起其编码蛋白泛素E3连接酶CHIP功能障碍导致Gordon Holmes综合征的分子病理机制，将为遗传性共济失调类疾病发生机制的相关研究提供新的方法与思路。

Gordon Holmes syndrome is a rare hereditary neurological disorder with manifestations of progressive ataxia and hypogonadism. It often accompanies an autosomal recessive inheritance model and is also considered to be a special subtype of hereditary ataxia. Although this disorder had been recognized more than 100 years, until May in last year, its first and second disease-causing gene RNF216 and OTUD4 had just been identified. In our previous work, we found that STUB1 is the third disease-causing gene of Gordon Holmes syndrome. In this study, based on the new finding, we plan to establish the in vitro cell model, Knock-in transgenic mice model and patient-specific iPSC model and use the technology of Immunofluorescence, Western-blot, Co-IP, in vivo and vitro ubiquitin assay, high-throughput sequencing, and Zinc-finger nucleases based targeted gene modifying to further investigate the pathogenesis mechanism of how deficiency of E3 ubiquitin ligase CHIP caused by STUB1 mutation leads to Gordon Holmes syndrome. This study will also provide new methods and ideas for the research of hereditary ataxia.