Review
The role of mutations in the SCN5A gene in cardiomyopathies

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Highlights

  • Genetic variance in SCN5A gene can be found in at least 10 different cardiac diseases including cardiomyopathies (CMP).

  • So far mutations in SCN5A gene were found in patients with DCM, ARVC, and atrial standstill but not in HCM patients.

  • Mutations causing CMP do not affect specific domain or share common biophysical properties.

  • Non-canonical functions of Nav1.5 channel can be involved into pathogenesis of cardiomyopathies.

  • Common feature of SCN5A-related CMP is numerous rhythm and conduction defects. Cardiac remodeling may be arrhythmia-induced.

Abstract

The SCN5A gene encodes the alpha-subunit of the Nav1.5 ion channel protein, which is responsible for the sodium inward current (INa). Since 1995 several hundred mutations in this gene have been found to be causative for inherited arrhythmias including Long QT syndrome, Brugada syndrome, cardiac conduction disease, sudden infant death syndrome, etc. As expected these syndromes are primarily electrical heart diseases leading to life-threatening arrhythmias with an “apparently normal heart”. In 2003 a new form of dilated cardiomyopathy was identified associated with mutations in the SCN5A gene. Recently mutations have been also found in patients with arrhythmogenic right ventricular cardiomyopathy and atrial standstill. The purpose of this review is to outline and analyze the following four topics: 1) SCN5A genetic variants linked to different cardiomyopathies; 2) clinical manifestations of the known mutations; 3) possible molecular mechanisms of myocardial remodeling; and 4) the potential implications of gene-specific treatment for those disorders. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Abbreviations

AF
atrial fibrillation
AHA
American Heart Association
AP
action potential
ARVC
arrhythmogenic right ventricular cardiomyopathy
AtSt
Atrial standstill
AV
atrio-ventricular
AVB
artio-venrticular block
CMP
cardiomyopathy
CP
cytoplasmic
CRT
cardiac resynchronization therapy
CRT-D
cardiac resynchronization therapy with defibrillator function
CRT-P
cardiac resynchronization therapy with pacemaker function
DCM
dilated cardiomyopathy
EC
extracellular
ECG
electrocardiogram
ESC
European Society of Cardiology
EHRA
European Heart Rhythm Association
ICD
implantable cardioverter defibrillator
ISFC
International Society and Federation of Cardiology
LQT3
Long QT syndrome, type 3
LQTS
Long QT syndrome
HCM
hypertrophic cardiomyopathy
HRS
Heart Rhythm Society
LVNC
left ventricular non-compaction
NGS
new generation sequencing
PVC
premature ventricular contractions
RVOT
right ventricular outflow tract
SCD
sudden cardiac death
SIDS
sudden infant death syndrome
SSS
sick sinus syndrome
TM
transmembrane
VT
ventricular tachycardia
WHF
World Heart Federation
WHO
World Health Organization

Keywords

SCN5A
Nav1.5
Dilated cardiomyopathy
Hypertrophic cardiomyopathy
Arrhythmogenic right ventricular cardiomyopathy
Cardiac remodeling

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This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.