核修饰基因YARS2与线粒体tRNASer(UCN) 7511T>C突变互作致聋机制的研究

耳聋是临床上最常见的疾病之一，超过50%的患者是由遗传因素造成的。线粒体DNA突变是母系遗传性耳聋的重要原因之一，核修饰基因可能参与线粒体DNA突变相关表型的表达。前期工作中，我们鉴定了核修饰基因YARS2 G191V突变可能作为修饰因子调控tRNASer(UCN) 7511T>C突变相关耳聋表型表达。本项目拟在此基础上，以源自tRNASer(UCN) 7511T>C突变中国耳聋家系的永生淋巴细胞系为模型，研究核修饰基因YARS2对携带tRNASer(UCN) 7511T>C突变细胞线粒体功能的影响；通过YARS2基因过表达和敲减，构建核修饰基因与线粒体tRNASer(UCN) 7511T>C突变相互作用的细胞模型，进一步阐明线粒体tRNA基因与核基因互作致聋机制。本项目的完成将有助于诠释核基因与线粒体基因互作相关线粒体功能异常的分子致聋基础，为遗传性耳聋的干预和治疗提供新的理论基础。

Deafness is the most common sensory disorder, and more than 50% of cases of deafness are due to genetic factors. Mutations in the mitochondrial DNA are one of the important causes of maternally transmitted deafness. Our previous data showed that nuclear modifier gene YARS2 may modulate the phenotypic manifestation of tRNASer(UCN) 7511T>C mutation. However, the pathogenesis of deafness caused by mitochondrial tRNA mutations is poorly understood. The aim of this study is to further understand the molecular pathogenesis of deafness associated with mitochondrial tRNA mutations. First, we will analyze the effects of YARS2 G191V mutation on mitochondrial dysfunction associated with tRNASer(UCN) 7511T>C mutation based on the lymphocytes lines derived from the deafness individuals with 7511T>C mutation and controls in a large Chinese deafness pedigree. Secondly, the cell models of knock-down or overexpress of YARS2 with 7511T>C mutation will be constructed to assess the interaction between the nuclear and mitochondrial genome associated with maternally transmitted deafness. Thus, the success of this project will help to define the role of nuclear modifier genes in the molecular pathogenesis of deafness caused by mitochondrial dysfunction, and provide valuable information for development of intervention for inherited deafness.