A leaky voltage sensor domain of cardiac sodium channels causes arrhythmias associated with dilated cardiomyopathy

Scientific Reports
Adrien MoreauMohamed Chahine

Abstract

Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers and impairs cardiac contractility. The SCN5A gene encodes Nav1.5, the predominant cardiac sodium channel alpha subunit. SCN5A mutations have been identified in patients with arrhythmic disorders associated with DCM. The characterization of Nav1.5 mutations located in the voltage sensor domain (VSD) and associated with DCM revealed divergent biophysical defects that do not fully explain the pathologies observed in these patients. The purpose of this study was to characterize the pathological consequences of a gating pore in the heart arising from the Nav1.5/R219H mutation in a patient with complex cardiac arrhythmias and DCM. We report its properties using cardiomyocytes derived from patient-specific human induced pluripotent stem cells. We showed that this mutation generates a proton leak (called gating pore current). We also described disrupted ionic homeostasis, altered cellular morphology, electrical properties, and contractile function, most probably linked to the proton leak. We thus propose a novel link between SCN5A mutation and the complex pathogenesis of cardiac arrhythmias and DCM. Furthermore, we suggest that leaky c...Continue Reading

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Citations

Jan 10, 2019·The Journal of Physiology·Lorenzo R Sewanan, Stuart G Campbell
Oct 6, 2020·BioMed Research International·Kai HuangXiaotian Sun
Sep 7, 2019·International Journal of Molecular Sciences·Andreas BrodehlHendrik Milting
Sep 22, 2019·International Journal of Molecular Sciences·Cosmin I CiotuMichael J M Fischer
Sep 12, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Laura SoléMichael M Tamkun
Nov 23, 2021·Frontiers in Pharmacology·Vyacheslav S KorkoshBoris S Zhorov

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Methods Mentioned

BETA
fluorescence activated cell sorting
Flow cytometry
FACS
atomic force microscopy
biopsies
AFM

Software Mentioned

AutoTT
MATLAB
GraphPad
GraphPad prism
ImageJ
Clampfit
Flowing
VMD
Diva

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