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Studying Brugada syndrome with an SCN1B variants in human-induced pluripotent stem cell-derived cardiomyocytes

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Item Type:Article
Title:Studying Brugada syndrome with an SCN1B variants in human-induced pluripotent stem cell-derived cardiomyocytes
Creators Name:El-Battrawy, I. and Müller, J. and Zhao, Z. and Cyganek, L. and Zhong, R. and Zhang, F. and Kleinsorge, M. and Lan, H. and Li, X. and Xu, Q. and Huang, M. and Liao, Z. and Moscu-Gregor, A. and Albers, S. and Dinkel, H. and Lang, S. and Diecke, S. and Zimmermann, W.H. and Utikal, J. and Wieland, T. and Borggrefe, M. and Zhou, X. and Akin, I.
Abstract:BACKGROUND: Among rare channelopathies BrS patients are at high risk of sudden cardiac death (SCD). SCN5A mutations are found in a quarter of patients. Other rare gene mutations including SCN1B have been implicated to BrS. Studying the human cellular phenotype of BrS associated with rare gene mutation remains lacking. OBJECTIVES: We sought to study the cellular phenotype of BrS with the SCN1B gene variants using human-induced pluripotent stem cell (hiPSCs)–derived cardiomyocytes (hiPSC-CMs). METHODS AND RESULTS: A BrS patient suffering from recurrent syncope harboring a two variants (c.629T > C and c.637C > A) in SCN1B, which encodes the function-modifying sodium channel beta1 subunit, and three independent healthy subjects were recruited and their skin biopsies were used to generate hiPSCs, which were differentiated into cardiomyocytes (hiPSC-CMs) for studying the cellular electrophysiology. A significantly reduced peak and late sodium channel current (I(Na)) and a shift of activation curve to more positive potential as well as a shift of inactivation curve to more negative potential were detected in hiPSC-CMs of the BrS patient, indicating that the SCN1B variants impact the function of sodium channels in cardiomyocytes. The reduced I(Na) led to a reduction of amplitude (APA) and upstroke velocity (V(max)) of action potentials. Ajmaline, a sodium channel blocker, showed a stronger effect on APA and Vmax in BrS cells as compared to cells from healthy donors. Furthermore, carbachol was able to increase arrhythmia events and the beating frequency in BrS. CONCLUSION: Our hiPSC-CMs from a BrS-patient with two variants in SCN1B recapitulated some key phenotypic features of BrS and can provide a platform for studies on BrS with SCN1B variants.
Keywords:Brugada, Sudden Cardiac Death, Channelopathy, Genetic, Sodium Channel
Source:Frontiers in Cell and Developmental Biology
Publisher:Frontiers Research Foundation (Switzerland)
Page Range:261
Date:1 November 2019
Official Publication:https://doi.org/10.3389/fcell.2019.00261
PubMed:View item in PubMed

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