左室心肌致密化不全(left ventricular noncompaction, LVNC)是一种遗传性心肌病，胎儿以及新生期均可发病。患儿心源性猝死率较高。申请者前期发现TBX5 c835C>T为新的潜在LVNC致病突变。TBX5在心肌小梁的正常发育中发挥重要作用，但TBX5突变在LVNC中的致病机制不清。前期证明TBX5和YAP1形成蛋白复合体，TBX5能直接结合Hey2基因启动子。而TBX5 c835C>T 突变蛋白促进心肌细胞增殖，失去与YAP1的结合能力，激活心肌细胞Hey2及其上游Notch1的表达。推测：TBX5 c835C>T 突变蛋白干扰与YAP1结合，失去对Notch1下游靶基因Hey2的转录抑制，致心肌细胞过度增殖，继而引发LVNC表型。本研究拟证实该科学假说，研究成果为深入理解LVNC患者异常心脏表型的发生机制以及探寻治疗LVNC的潜在靶点提供一定理论依据。

Left ventricular noncompaction (LVNC) is a inherited cardiomyopathy, with a high rate of sudden cardiac death in children. In the previous study，TBX5 c835C>T was found to be a new potential LVNC pathogenic mutation. TBX5 plays an important role in the normal development of left ventricular trabecula, but the molecular mechanism of TBX5 c835C>T in LVNC is unclear. It has been proved that TBX5 and YAP1 form protein complex and TBX5 can directly bind Hey2 gene promoter. TBX5 c835C>T protein promoted the proliferation of cardiomyocytes, loses the binding ability with YAP1, and activated the expression of Hey2 and its upstream Notch 1 signaling pathway in cardiomyocytes. It is speculated that TBX5 c835 C>T mutant protein interferes with YAP1 binding and loses the transcriptional inhibition of Hey2 which is the downstream target gene of Notch 1, and this leads to the over proliferation of cardiomyocytes, and then leads to LVNC phenotype. The purpose of this study is to confirm the scientific hypothesis. The research results would provide a theoretical basis for further understanding the mechanism of abnormal cardiac phenotype in LVNC patients and exploring the potential therapeutic target of LVNC.