A novel mutation in KCNH2 yields loss-of-function of hERG potassium channel in long QT syndrome 2.

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 channels, hERG channels have markedly decreased total and surface expressions. W410R mutation dramatically reduces hERG channel currents (I) and shifts its steady-state activation curve to depolarization. Moreover, hERG channels make dominant-negative effects on hERG channels. Significantly, we find hERG channel blocker E-4031 could partially rescue the function of hERG channels by increasing the membrane expression. By using in silico model, we reveal that hERG 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 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.