Pro-arrhythmic effects of gain-of-function potassium channel mutations in the short QT syndrome

Abstract

The congenital short QT syndrome (SQTS) is a rare condition characterized by abbreviated rate-corrected QT (QTc) intervals on the electrocardiogram and by increased susceptibility to both atrial and ventricular arrhythmias and sudden death. Although mutations to multiple genes have been implicated in the SQTS, evidence of causality is particularly strong for the first three (SQT1-3) variants: these result from gain-of-function mutations in genes that encode K⁺ channel subunits responsible, respectively, for the I_Kr, I_Ks and I_K1 cardiac potassium currents. This article reviews evidence for the impact of SQT1-3 missense potassium channel gene mutations on the electrophysiological properties of I_Kr, I_Ks and I_K1 and of the links between these changes and arrhythmia susceptibility. Data from experimental and simulation studies and future directions for research in this field are considered. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

Keywords: KCNJ2; KCNQ1; SQTS; arrhythmia; hERG; short QT syndrome.

Figure 1.

Potassium ion channels affected in SQTS variants 1–3. Panels (a–d) show simulated profiles of the three key repolarizing currents affected in SQT1, SQT2 and SQT3. (a) Shows a ventricular AP (elicited at stimulation rate of 1 Hz) from the ten Tusscher and Panfilov ventricular cell model [40]. Panel (b) shows corresponding time-course of I_Kr, (c) shows corresponding time-course of I_Ks, (d) shows corresponding time-course of I_K1. (e–g) illustrate the locations of K⁺ channel SQTS mutants within the channel structures (identified by gene name). Mutants are highlighted on a single channel subunit (green). The KCNH2 structure in (e) is from PDB:5VA2 ([41]; the C terminal cytoplasmic domain containing R1135 is not present in the structure). For KCNQ1, all SQTS mutants to date locate to the membrane domain and only this is shown in (f)—a second subunit (yellow) illustrates the manner in which subunits are assembled (as tetramers) in the membrane (all channels shown assemble as tetramers). The KCNQ1 structure is from PDB:6V00 [42]; and in (g) the KCNJ2 derived Kir2.1 protein is an AlphaFold structure [43] with disordered cytoplasmic loops removed. (Online version in colour.)

Figure 2.

Summary of proarrhythmic effects of the N588K hERG mutation. Schematic diagram summarizing main proarrhythmic mechanisms of N588K hERG mutation in SQT1, identified from experiments on recombinant channels and computer simulations. Upper panels show shifted current voltage relation (left panel) and augmented current and altered current profile during ventricular AP (right panel). In simulations of human ventricular APs, the changes to I_Kr lead to abbreviated AP duration (APD) in epicardium (EPI), midmyocardium (MCELL) and endocardium (ENDO) and to augmented transmural dispersion of repolarization (TDR) [55,74]. At the tissue level, the QT interval becomes abbreviated and T wave amplitude increased. These changes increased susceptibility of ventricular tissue to ventricular tachycardia (VT)/fibrillation (VF) (bottom panels). Figure is reproduced from [17], under a CC BY Creative Commons 4.0 licence (https://creativecommons.org/licenses/by/4.0/legalcode). (Online version in colour.)

Figure 3.

Summary of proarrhythmic effects of the V307L KCNQ1 mutation. Panel (a) shows changes to I_Ks under conventional voltage clamp (upper panel) and AP voltage clamp (lower panel), showing gain-of-function consequences of the V307L KCNQ1 mutation. Panel (b) shows simulated changes to ventricular AP durations in epicardium (EPI), midmyocardium (MCELL) and endocardium (ENDO); upper panel shows control APs and lower panels show abbreviated APs when effects of V307L mutation on I_Ks are incorporated. Panel (c) shows simulated pseudo-ECG, demonstrating QT interval abbreviation owing to V307L-KCNQ1. Panel (d) shows consequences at whole ventricle levels of the V307L mutation (spiral wave re-entry at two-dimensional level, scroll wave re-entry at three-dimensional level), with the tissue able to sustain high-frequency excitation. The figure is based on and modified from [92], under a CC BY Creative Commons 4.0 licence (https://creativecommons.org/licenses/by/4.0/legalcode)/. (Online version in colour.)