肥厚型心肌病（HCM）是青少年心源性猝死的最常见原因。线粒体基因突变是HCM 重要致病因素，机理尚不明确。我们前期工作发现一个HCM 家系，共四代，有且仅有全体母系成员确诊患病，有且仅有全体母系成员携带线粒体16S rRNA 2336T>C突变；该位点高度保守，该突变破坏16S rRNA功能区Ⅲ2336U-A2438碱基配对；病人细胞的线粒体功能障碍。表明：线粒体16S rRNA 2336T>C 突变可能是母系遗传性HCM 相关的新的重要致病原因之一（Journal of Medical Genetics, 2014,51:176-184）。本项目在上述工作基础上，筛查鉴定m.2336T>C突变在中国HCM人群的发生频率，建立患者淋巴细胞系和转线粒体细胞系，阐明该突变对线粒体结构功能、Ca2+信号及细胞生理等的影响，揭示HCM的遗传和分子机制。

Hypertrophic cardiomyopathy (HCM) is the commonest cause of sudden cardiac death in individuals especially for teenagers and athletes. Mutations in mitochondrial DNA have been found to be one of the most important causes of HCM, but the pathogenesis mechanism remains poorly understood. Recently we found a 4-generation Han Chinese pedigree with the maternally transmmited HCM. In this pedigree, only all the four maternal members suffered from HCM, and a novel 16S rRNA 2336T>C mutation only occurred in the four maternal members. The 2336T>C mutation, highly evolutionarily conserved, disturbs 2336U-A2438 base pair in 16S rRNA Domain III, and might affect the steady state level of 16S rRNA. Functional assay indicated that there exited mitochondrial dysfunction and abnormal energy metabolism in patient cells, suggesting that the novel mitochondrial 2336T>C mutation is probably the important pathogenesis cause for maternally transmitted HCM (Journal of Medical Genetics, 2014,51:176-184). In this project, we will identify the frequency of m.2336T>C mutations in Chinese HCM population. Furthermore, through constructing immortalized lymphocyte cell lines and transmitochondrial cell lines, we can study the effects of 2336T>C mutation on the mitochondrial structures and functions, Ca2+ signal transduction and cellular physiology, which will reveal the genetic and molecular mechanisms of hypertrophic cardiomyopathy.