家族性肌萎缩侧索硬化症(FALS)一新致病基因的发现及其发病分子机制研究

项目名称： 家族性肌萎缩侧索硬化症(FALS)一新致病基因的发现及其发病分子机制研究

项目编号： No.81471155

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘勇

作者单位： 中国人民解放军军事科学院军事医学研究院

项目金额： 70万元

中文摘要： 肌萎缩侧索硬化症 (ALS)是一种进行性致死性神经系统变性疾病，选择性侵犯脑与脊髓的运动神经元。ALS可分为散发性ALS（SALS）和家族性ALS（FALS），其确切致病原因及发病机制不明。目前已经报道有20个基因的突变与FALS致病相关，但这些基因的突变形式并不能在所有FALS患者中检测到，表明还有未知的致病基因有待发现。我们前期对中国山东省一FALS家系3个患者DNA样品进行全基因组外显子测序，鉴定出新突变基因AMSH(c.889A>G)。Sanger 测序证实此FALS家系其它患者和500例SALS患者也存在该基因的突变形式，提示AMSH可能为ALS新的致病基因，其突变基因编码蛋白AMSH（N122D）可能与ALS发病相关。本项目旨在细胞水平和转基因动物水平进一步验证AMSH（N122D）与ALS的相关性，并以AMSH已知功能为线索，阐明AMSH（N122D）导致ALS发病的分子机制

中文关键词： 运动神经元病；神经退行性疾病；基因突变；发病机制；神经病学

英文摘要： Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neurodegenerative disease, which selectively affects motor neurons in the brain and spinal cord. ALS is traditionally classified into two categories: familial ALS (FALS) and sporadic ALS (SALS) and its etiology and pathogenesis are still unknown. So far 20 FALS-causative genes have been found, however, the FALS-linked mutation of those genes is not always detected in all FALS cases, which suggests that some unidentified ALS-causative genes still exist. In our previous research we used whole-exome sequencing on DNA samples from three affected individuals from a family with ALS in China's Shandong province and identified a novel variant AMSH(c.889>G) in each individual. Such variant of AMSH was also detected in additional affected individuals from this family and 500 SALS cases by Sanger sequencing. All of those results suggested that AMSH may be a novel ALS-causative gene and its mutant protein AMSH（N122D）may be linked to the occurrence of ALS.In this study,we will further confirm the linkage of AMSH（N122D）to the etiopathology of ALS on the levels of cells and transgenic animals.Based on the well-characterized functions of AMSH,the molecular pathogenesis of AMSH（N122D）-caused ALS will be elucidated.

英文关键词： Motor neuron disease;Neurodegenerative disease;Gene mutation;Pathogenesis;Neurology