Mutations in hERG (human ether-à-go-go-related gene) potassium channel are closely associated with long QT syndromes. By direct Sanger sequencing, we identified a novel KCNH2 mutation W410R in the patient with long QT syndrome 2 (LQT2). However, the electrophysiological functions of this mutation remain unknown. In comparison to hERG^WT channels, hERG^W410R channels have markedly decreased total and surface expressions. W410R mutation dramatically reduces hERG channel currents (I_Kr) and shifts its steady-state activation curve to depolarization. Moreover, hERG^W410R channels make dominant-negative effects on hERG^WT channels. Significantly, we find hERG channel blocker E-4031 could partially rescue the function of hERG^W410R channels by increasing the membrane expression. By using in silico model, we reveal that hERG^W410R channels obviously elongate the repolarization of human ventricular myocyte action potentials. Collectively, W410R mutation decreases the currents of hERG channel, because of diminished membrane expression of mutant channels, that subsequently leads to elongated repolarization of cardiomyocyte, which might induce the pathogenesis of LQT2. Furthermore, E-4031 could partially rescue the decreased activity of hERG^W410R channels. Thus, our work identifies a novel loss-of-function mutation in KCNH2 gene, which might provide a rational basis for the management of LQT2.

hERG（人类ether-à-go-go相关基因）钾通道的突变与长QT综合征密切相关。通过直接 Sanger 测序，我们在长 QT 综合征 2 (LQT2) 患者中发现了一个新的KCNH2突变 W410R。然而，这种突变的电生理功能仍然未知。与 hERG ^WT通道相比，hERG ^W410R通道的总表达和表面表达显着降低。W410R 突变显着降低了 hERG 通道电流 ( I _Kr ) 并将其稳态激活曲线转移到去极化。此外，hERG ^W410R通道对 hERG ^WT产生显性负效应渠道。值得注意的是，我们发现 hERG 通道阻滞剂 E-4031 可以通过增加膜表达来部分挽救 hERG ^W410R通道的功能。通过使用计算机模型，我们发现 hERG ^W410R通道明显延长了人心室肌细胞动作电位的复极化。总的来说，W410R 突变降低了 hERG 通道的电流，因为突变通道的膜表达减少，随后导致心肌细胞复极延长，这可能诱导 LQT2 的发病机制。此外，E-4031 可以部分挽救 hERG ^W410R通道活性降低。因此，我们的工作确定了KCNH2 中一种新的功能丧失突变 基因，这可能为 LQT2 的管理提供合理的基础。