Research Information System
Journal of Cellular Physiology, vol.237, no.10, pp.3900-3911, 2022 (SCI-Expanded)
Tachycardia is characterized by high beating rates that can lead to life-threatening fibrillations. Mutations in several ion-channel genes were implicated with tachycardia; however, the complex genetic contributors and their modes of action are still unclear. Here, we investigated the influence of an SCN5A gene variant on tachycardia phenotype by deriving patient-specific iPSCs and cardiomyocytes (iPSC-CM). Two tachycardia patients were genetically analyzed and revealed to inherit a heterozygous p.F1465L variant in the SCN5A gene. Gene expression and immunocytochemical analysis in iPSC-CMs generated from patients did not show any significant changes in mRNA levels of SCN5A or gross NaV1.5 cellular mislocalization, compared to healthy-derived iPSC-CMs. Electrophysiological and contraction imaging analysis in patient iPSC-CMs revealed intermittent fibrillation-like states, occasional arrhythmic events, and sustained high-paced contractions that could be selectively reduced by flecainide treatment. The patch-clamp analysis demonstrated a negative shift in the voltage-dependent activation at the patient-derived iPSC-CMs compared to the healthy control line, suggestive of a gain-of-function activity associated with the SCN5A+/p.F1465L variant. Our patient-derived iPSC-CM model recapitulated the clinically relevant characteristics of tachycardia associated with a novel pathogenic SCN5A+/p.F1465L variant leading to altered Na+ channel kinetics as the likely mechanism underlying high excitability and tachycardia phenotype.