ArticleEuropace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology2026
C-terminal long-QT type 1 R562S-Kv7.1 variant, the first variant in helix C impairing β-adrenergic response of the slow delayed rectifier K+ channel.
Article in Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
aimsKv7.1 variants, associated with long QT syndrome type 1 (LQT1) and altering the function of the slow delayed rectifier K+ (IKs) channel, may result in arrhythmias, especially during exercise. This study focused on complex analysis of the R562S-Kv7.1 variant located in helix C of the Kv7.1 C terminus, which was identified in four putatively unrelated families in the Czech Republic. METHODS AND
resultsThe clinical and genetic investigation was followed by functional analysis (whole-cell patch clamp, confocal microscopy, computational simulations) and structural modelling. The genetic analysis suggested that R562S-Kv7.1 might be a founder LQT1 variant in Central Europe. R562S carriers showed a significantly prolonged corrected QT (QTc) interval at rest and a significantly higher QTc prolongation after exercise vs. healthy relatives. The functional analysis of R562S channels demonstrated their preserved membrane localization, a significant decrease in IKs with a rightward shift of the voltage dependence of activation, and, importantly, a lack of responsiveness to β-adrenergic stimulation. The latter seems to be related to a modified interaction of the modulatory KCNE1 subunit with Kv7.1. The pro-arrhythmic potential of R562S dysfunction, mediated by delayed afterdepolarizations during β-adrenergic stimulation, could be effectively prevented by mild (5%) inhibition of L-type Ca2+ current (ICa).
conclusionR562S-Kv7.1 is the first variant in helix C causing an impaired response of IKs channel to β-adrenergic stimulation, likely due to altered interactions between channel subunits, namely Kv7.1 and KCNE1. Mild ICa inhibition was suggested as a new treatment option.
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