Significant advances in our understanding of the molecular mechanisms that cause congenital long QT syndrome (LQTS) have been made. A wide variety of experimental approaches, including heterologous expression of mutant ion channel proteins and the use of inducible pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from LQTS patients offer insights into etiology and new therapeutic strategies. This review briefly discusses the major molecular mechanisms underlying LQTS type 2 (LQT2), which is caused by loss-of-function (LOF) mutations in the KCNH2 gene (also known as the human ether-à-go-go-related gene or hERG). Almost half of suspected LQT2-causing mutations are missense mutations, and functional studies suggest that about 90% of these mutations disrupt the intracellular transport, or trafficking, of the KCNH2-encoded Kv11.1 channel protein to the cell surface membrane. In this review, we discuss emerging strategies that improve the trafficking and functional expression of trafficking-deficient LQT2 Kv11.1 channel proteins to the cell surface membrane and how new insights into the structure of the Kv11.1 channel protein will lead to computational approaches that identify which KCNH2 missense variants confer a high-risk for LQT2.

中文翻译：

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2 型长 QT 综合征：纠正 2 类 KCNH2 (hERG) 突变和识别新患者的新兴策略。


我们对导致先天性长 QT 综合征 (LQTS) 的分子机制的理解取得了重大进展。各种各样的实验方法，包括突变离子通道蛋白的异源表达和使用来自 LQTS 患者的诱导型多能干细胞衍生的心肌细胞 (iPSC-CM)，为病因学和新的治疗策略提供了见解。这篇综述简要讨论了 2 型 LQTS (LQT2) 的主要分子机制，这是由KCNH2基因（也称为人类 ether-à-go-go 相关基因或脑电图）。几乎一半疑似引起 LQT2 的突变是错义突变，功能研究表明，约 90% 的突变会破坏KCNH2编码的 Kv11.1 通道蛋白向细胞表面膜的细胞内运输或运输。在这篇综述中，我们讨论了改善运输缺陷的 LQT2 Kv11.1 通道蛋白向细胞表面膜的运输和功能表达的新兴策略，以及对 Kv11.1 通道蛋白结构的新见解将如何导致计算方法确定哪些KCNH2错义变异赋予 LQT2 高风险。