原发性震颤新致病基因/易感基因克隆及功能机制研究

原发性震颤（essential tremor，ET）是最常见的运动障碍疾病之一，存在明显的临床异质性和遗传异质性，严重影响患者的工作能力与生活质量。ET的病因及发病机制不明，与环境因素、老化因素、遗传因素及其共同作用相关，其中遗传因素是ET发病机制的重要因素。ET致病基因/易感基因等遗传因素的研究将为ET的发病机制提供重要理论基础，将为ET的诊断与治疗提供新的思路与方法。前期工作中我们建立了中国帕金森病及运动障碍疾病多中心数据库及协作网，启动了首个中国原发性震颤注册登记队列研究，对核心家族性ET家系进行连锁分析，定位了染色体区间，筛选了相关候选基因，构建了C-ET1-KO小鼠模型；同时，发现了NOTCH2NLC 5’端GGC异常重复扩增与ET相关。本项目拟在前期工作的基础上，克隆与鉴定ET新致病基因/易感基因，在细胞模型、果蝇模型及基因工程小鼠模型中探讨ET新致病基因/易感基因的分子机制。

Essential tremor (ET) is one of the most common movement disorders, with high clinical and genetic heterogeneities, which seriously affects the working ability and quality of life of patients. The etiology and pathogenesis of ET are unknown, which are related to environmental factor, aging factor, genetic factor and their combined effects, among which genetic factor is an important factor in the pathogenesis of ET. Genetic studies, especially researches on pathogenic/susceptibility genes will provide an important theoretical basis for the pathogenesis of ET and provide new ideas and methods for the diagnosis and treatment of ET. In the preliminary work, we established “Parkinson’s disease Multicenter database and Collaborative network in China”, firstly launched “The Chinese Essential Tremor Registry”. We performed linkage analysis on core familial ET families, located the candidate chromosome regions, screened the relevant candidate genes, and constructed the C-ET1-knock out mouse model. In addition, we found that abnormal GGC repeat expansion in the 5’ region of NOTCH2NLC gene is associated with ET. Furthermore, we will clone and identify new pathogenic/susceptibility genes of ET, and explore the molecular mechanisms of new pathogenic/susceptibility genes of ET in cell model, drosophila model and genetically engineered mouse model.