Functional evaluation of the tachycardia patient-derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant

Şahoğlu Göktaş, SevilayKazcı, Yusuf EnesTuncay, ErkanTorun, TuğçeAkdeniz, CelalTuzcu, VolkanÇağavi, Esra2022-11-222022-11-222022Şahoğlu Göktaş, S., Kazcı, Y. E., Tuncay, E., Torun, T., Akdeniz, C., Tuzcu, V. ... Çağavi, E. (2022). Functional evaluation of the tachycardia patient-derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variant. Journal of Cellular Physiology, 237(10), 3900-3911. https://doi.org/10.1002/jcp.308430021-95411097-4652https://doi.org/10.1002/jcp.30843https://hdl.handle.net/20.500.12511/10009Tachycardia 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.eninfo:eu-repo/semantics/embargoedAccessCardiovascular DiseasesIn Vitro Disease ModelIPSCSCN5A VariantTachycardiaFunctional evaluation of the tachycardia patient-derived iPSC cardiomyocytes carrying a novel pathogenic SCN5A variantArticle237103900391110.1002/jcp.30843Q10008395640000012-s2.0-8513585597935959596Q1