Prader-Willi综合征蛋白Necdin调节心脏功能的分子机制研究

Prader-Willi综合征（PWS）是由于第15号染色体长臂15q11-q13区域异常所导致的罕见性神经发育疾病，发病率约为1/15000。PWS以肌张力低、生长发育迟缓、智能障碍、肥胖等为主要临床特征。同时，PWS患者大多存在心脏功能紊乱问题，例如心脏收缩舒张功能异常，射血分数较常人低等，然而其具体机制还不明确。在前期工作中，我们发现PWS相关基因Necdin缺失可以导致小鼠心肌病表型。为了进一步研究Necdin导致心肌病的分子机制，我们利用酵母双杂交文库筛选的方法发现Necdin可以与MYL12a相互作用。MYL12a在心脏组织中具有较高的表达，同时全基因组关联分析显示MYL12a与心血管疾病高度相关。这提示我们，Necdin有可能通过MYL12a参与了心脏功能的调控。本项目的完成将促进PWS的诊治，提高病人的生存率及生存质量，而且将有助于发现心脏功能调控的新机制。

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder caused by abnormality of 15q11-q13 in region of chromosome 15, with a prevalence of 1/15000. Individuals with this disorder is characterized by a range of psychological and physiological abnormalities including hypotonia, growth retardation, mental retardation and obesity. PWS patients usually accompany with cardiac dysfunction, such as abnormal systolic and diastolic function, low ejection fraction. However, the mechanism underlying dysfunctions of heart are still elusive. In previous studies, we found that the deletion of Necdin, a PWS related gene, can lead to cardiomyopathy phenotype in mice. In order to further study the molecular mechanism of Necdin causing cardiomyopathy, we used yeast two-hybrid library screening method to find that Necdin can interact with MYL12a. MYL12a is highly expressed in heart tissues, and genome-wide association analysis shows that MYL12a is highly correlated with cardiovascular diseases. This suggests that Necdin may be involved in the regulation of cardiac function through MYL12a. The completion of this project will promote the diagnosis and treatment of PWS, improve the survival rate and quality of life of patients, and help to identify new mechanisms of cardiac function regulation.