左室致密化不全心肌病（LVNC）是一种常见的遗传性心肌疾病，其分子遗传机制尚未完全明确。为阐明我国汉族人群LVNC发病的遗传学基础，我们前期采用靶向测序技术在100例LVNC先证者中对72个心肌病相关基因进行了检测，发现一个DSP基因突变c.1_2insC在患者中显著富集，家系分析发现该突变与疾病共分离，且携带者均出现室性心律失常，提示该突变可能导致心律失常型LVNC。本项目以此作为切入点，1）继续完善现有先证者的家系分析，寻求DSP基因突变致病的证据；2）构建心肌特异性突变敲入小鼠模型并进行表型鉴定，进一步明确DSP是否为LVNC的新致病基因；3）通过免疫共沉淀联合质谱分析、细胞免疫荧光染色、转录组测序探究突变对蛋白相互作用、下游信号通路的影响，并通过上调及敲低实验明确关键调控分子，揭示c.1_2insC突变致病的分子机制。以期进一步完善LVNC致病基因谱，加深对发病机制的理解。

Left ventricular noncompaction cardiomyopathy (LVNC) is a common form of inherited myocardial disease. The genetic basis of LVNC remains unclear. In order to clarify the genetic background of LVNC among Chinese Han population, a total of 72 cardiomyopathy-associated genes have been comprehensively screened in 100 LVNC patients by targeted sequencing. We found that a mutation in DSP (c.1_2insC) was significantly enriched in patients compared with the general population. Pedigree analysis showed that this mutation co-separated with the disease. The current project aimed 1) to complete the pedigree analysis of additional carriers to provide further evidence for the pathogenicity of the mutation; 2) to develop a cardiac-specific knock-in mouse model for phenotype identification to verify DSP as a disease gene of LVNC; 3) to investigate the impact of the mutation on protein interaction and signaling pathway by using co-immunoprecipitation, mass spectrometry，immunofluorescent staining and transcriptional sequencing, and the key regulatory molecule by using overexpression and knockdown technique at cellular level. We hope that the project can extend our understanding of the genetic basis and molecular mechanism of LVNC.