Abstract
Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers from the same family. When comparing asymptomatic and symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium current density, and arrhythmicity on adrenaline exposure were similar, but a difference in Ca2+ transients was observed. The major differences were, however, observed at aggregate level with increased susceptibility to arrhythmias on exposure to adrenaline or potassium channel blockers on CM aggregates derived from the symptomatic individual. The effect of this mutation was modeled in-silico which indicated the reactivation of an inward calcium current as one of the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major phenotype characteristics observed in LQT2 mutation carriers and strong phenotype differences between LQT2 asymptomatic vs. symptomatic were revealed at CM-aggregate level.
Highlights
Genetic long QT syndrome (LQTS) is an autosomal dominant disorder with a prevalence of 1 in 2000 people in the Caucasian population and its prevalence has been estimated to be 1 in 250–500 in Finland [1,2,3]
To understand the variability in this disease phenotype, Human-induced pluripotent stem cells (hiPSCs)-CMs were generated from the dermal fibroblasts from these two mutation carriers and two healthy volunteers to determine if this genotype–phenotype difference could be observed invitro
In our in-vitro studies, we successfully reproduced the adrenaline-induced arrhythmia including irregular monomorphic tachycardiac-like arrhythmia, alternans (ALT), early after depolarization-like arrhythmias (EADs)-like arrhythmias, premature ectopic beats (PEBs), repolarization abnormality with monomorphic triggered activity, non-sustained ventricular tachycardia (NSVT) and non-sustained ventricular fibrillation (NSVF)-like arrhythmia (Figure 4F), more commonly in the hiPSC-CM aggregates from the symptomatic patient compared to the long QT syndrome type-2 (LQT2) asymptomatic and the healthy controls (Figure 4D,E). These findings suggested that the distinction in phenotype was more pronounced at the CM-aggregate level compared to the single-cell where both the LQT2 asymptomatic and symptomatic derived hiPSC-CMs were arrhythmic
Summary
Genetic long QT syndrome (LQTS) is an autosomal dominant disorder with a prevalence of 1 in 2000 people in the Caucasian population and its prevalence has been estimated to be 1 in 250–500 in Finland [1,2,3]. LQTS type (LQT2) is the second most common cause of LQTS with symptoms of syncope, seizures and sudden cardiac death due to ventricular arrhythmia [4,5,6,7,8]. LQT2 is a channelopathy with a mutation in the HERG gene on chromosome 7 [9,10]. HERG or KCNH2 codes for the α-subunits of one of the principle cardiac repolarizing potassium (K+ ) channel current i.e., the rapid component of delayed-rectifier repolarizing potassium current (IKr). A mutation here typically reduces IKr and increases the repolarization time which could lead to arrhythmias [4].
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