心脏钠通道编码基因SCN5A是Brugada综合征（BrS）最主要的致病基因，尤其是位于“孔区”的SCN5A突变，能显著增加BrS患者的心血管事件风险。我们前期在BrS患者中发现了一个SCN5A“孔区”新突变T1708N，可导致峰钠电流密度减小以及细胞膜表面的钠通道蛋白数量减少，更有趣的是，减少的蛋白以高糖基化状态为主。我们据此提出假说：突变T1708N通过抑制内质网对钠通道蛋白的糖基化，阻碍钠通道蛋白的正常转运，进而导致峰钠电流密度减少，最终引起BrS。本项目拟利用病人来源的诱导多能干细胞心肌细胞（iPSC-CM）和基因敲入动物，应用全细胞膜片钳及分子、细胞生物学手段，从分子-细胞-动物整体层面揭示突变T1708N引发BrS表型的潜在分子机制，并探讨相应的药物干预策略。本研究从一个SCN5A“孔区”新突变入手，深入探讨BrS发生发展的新机制，有望为BrS的危险分层和对因治疗提供新的思路。

SCN5A is the most important susceptibility gene associated with Brugada Syndrome (BrS) ，especially mutations in the pore region would significantly increase risks of cardiovascular events in BrS patients. We discovered a novel mutation in the pore region named T1708N. The SCN5A-T1708N mutation could decrease peak sodium current density significantly compared to wide-type as well as the surface Nav1.5 protein. Interestingly, the decreased protein is mainly fully-glycosylated. We hypothesize that The SCN5A-T1708N mutation could inhibit glycosylation in ER and impair the trafficking of Nav1.5. As a result, the peak sodium current density was decreased. We plan to apply induced pluripotent stem cell derived cardiomyocyte and knock-in mice, combine patch clamp, molecular and cellular techniques in an effort to explore the mechanism how the SCN5A-T1708N mutation affects the BrS as well as potential pharmacological interventions, contributing to risk stratification and etiological treatment of Brugada Syndrome.