hERG基因突变与大环内酯类抗生素诱发的aLQTS的遗传易感性及分子机制

Recently, several reports and our study identified macrolide antibiotics (MAs) to increase the risk for acquired long QT syndrome (aLQTS), a major cause of sudden cardiac death in hospital settings. Accumulating evidence indicates that subclinical congenital long QT syndrome due to genetic mutation might be an important risk factor for drug-induced aLQTS, but its role in the genetic susceptibility to MAs-induced aLQTS remains unclear. In the pilot study, we proved hERG mutation (R1134H) could increase the inhibition of azithromycin on hERG channel. We hypothesized that hERG mutation might increase the susceptibility to hERG channel inhibition by MAs, thus predisposing affected individuals to aLQTS. In the present study, based on clinical data and biological samples collected from patients survived from MAs–induced aLQTS, with DNA sequencing, molecular biotechnology and whole-cell patch-clamp techniques, we aim to further explore the gene structure of hERG, the function and phenotype of hERG channel and hERG channel function of cardiomyocytes derived from patient specific induced pluripotent stem cells (iPSCs) , in order to elucidate the underlying molecular mechanism of hERG mutation in the genetic susceptibility to MAs-induced aLQTS. Consequently, the present study could provide early warning for MAs-induced aLQTS and help guide individual clinical treatment decisions.

最近国外及我们的研究显示大环内酯类抗生素（MAs）增加获得性长QT综合征（aLQTS）风险，为院内心脏性猝死的重要原因。大量证据表明，基因突变所致亚临床遗传性长QT综合征是药物诱发aLQTS的重要危险因素，但MAs致aLQTS的遗传易感性机制尚不明确。我们预实验发现hERG基因突变（R1134H）可增强阿奇霉素对hERG通道的抑制作用。由此，我们假说hERG基因突变增加MAs抑制hERG通道的易感性，使MAs诱发aLQTS的风险增加。本研究基于MAs诱发aLQTS个体临床资料和生物样本，利用基因测序、分子生物技术及全细胞膜片钳技术等，从心脏hERG基因结构、hERG通道功能表型和病人特异性诱导多能干细胞（iPSCs）来源心肌细胞的hERG通道功能特性等层面探寻hERG基因突变与MAs诱发aLQTS的遗传易感性的分子机制，将为临床MAs诱发aLQTS风险提供预警手段及个体化用药提供理论依据。

大环内酯类抗生素（MAs）增加获得性长QT综合征（aLQTS）风险，为院内心脏性猝死的重要原因。虽然目前对于长QT综合征的遗传机制已经明确，但是MAs相关性aLQTS的遗传易感性机制尚不清楚。本课题旨在发现MAs相关性aLQTS的致病基因和基因突变，并进一步揭示其遗传学及电生理致病机制。课题组成员在本国家自然科学基金的指导和资助下，按照国家基金委管理条例和项目计划，严格实施并顺利完成课题研究内容。本研究在7例MAs相关性aLQTs患者中检测到hERG基因发生5种突变：R1134H（c.3404G>A）；I1025N（c.3074T>A）；T151I（c.455C>T）；R163C（c.490C>T）及W926G（c.2799T>G）。进一步研究发现，R1134H显著降低hERG通道稳态电流及尾电流幅度，但不改变hERG通道动力学特征（包括激活、失活、复活及去活过程），R1134H基因突变还可导致hERG通道蛋白迁移障碍R1134H基因突变与阿奇霉素对hERG通道的抑制具有协同作用。对I1025N研究发现其亦显著降低hERG通道稳态电流及尾电流幅度，但不改变hERG通道激活及失活过程。研究成果为MAs相关性aLQTS的遗传学背景提供了实验室依据，为将来提高aLQTS突变检测效率，对临床使用MAs的患者发生aLQTS风险提供预警手段，并为临床个体化用药提供理论依据。