Gene mutations in cardiac arrhythmias: A review of recent evidence in ion channelopathies
Journal
Application of Clinical Genetics
Journal Volume
6
Date Issued
2013
Author(s)
Abstract
Over the past 15 years, molecular genetic studies have linked gene mutations to many inherited arrhythmogenic disorders, in particular, "ion channelopathies", in which mutations in genes encode functional units of ion channels and/or their transporter-associated proteins in patients without primary cardiac structural abnormalities. These disorders are exemplified by congenital long QT syndrome (LQTS), short QT syndrome, Brugada syndrome (BrS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). Functional and pathophysiological studies have led to better understanding of the clinical spectrum, ion channel structures and cellular electrophysiology involving dynamics of intracellular calcium cycling in many subtypes of these disorders and more importantly, development of potentially more effective pharmacological agents and even curative gene therapy. In this review, we have summarized (1) the significance of unveiling mutations in genes encoding transporter-associated proteins as the cause of congenital LQTS, (2) the technique of catheter ablation applied at the right ventricular outflow tract may be curative for severely symptomatic BrS, (3) mutations with channel function modulated by protein Kinase A-dependent phosphorylation can be the culprit of CPVT mimicry in Andersen-Tawil syndrome (LQT7), (4) ablation of the ion channel anchoring protein may prevent arrhythmogenesis in Timothy syndrome (LQT8), (5) altered intracellular Ca2+ cycling can be the basis of effective targeted pharmacotherapy in CPVT, and (6) the technology of induced pluripotent stem cells is a promising diagnostic and research tool as it has become a new paradigm for pathophysiological study of patient- and disease-specific cells aimed at screening new drugs and eventual clinical application of gene therapy. Lastly, we have discussed (7) genotype-phenotype correlation in relation to risk stratification of patients with congenital LQTS in clinical practice. ? 2013 Hsiao et al, publisher and licensee Dove Medical Press Ltd.
SDGs
Other Subjects
adenosine triphosphatase (calcium); alpha 1 syntrophin; amiodarone; beta adrenergic receptor blocking agent; calcium channel blocking agent; calcium ion; cyclic AMP dependent protein kinase; flecainide; membrane protein; quinidine; unclassified drug; verapamil; AKAP150 gene; AKAP9 gene; Andersen syndrome; Brugada syndrome; Cacna1c gene; calcium transport; cardioversion; CASQ2 gene; catecholaminergic polymorphic ventricular tachycardia; catheter ablation; causal attribution; CAV3 gene; channelopathy; drug efficacy; drug treatment failure; gene; gene expression; gene frequency; gene function; gene mutation; genetic susceptibility; genotype phenotype correlation; heart arrhythmia; heart ventricle arrhythmia; heterozygosity; human; KCNH2 gene; KCNJ2 gene; KCNQ1 gene; long QT syndrome; LQT3 gene; LQT8 gene; missense mutation; nonhuman; pluripotent stem cell; protein phosphorylation; review; RYR2 gene; SCNA5A gene; Timothy syndrome; treatment response; Phleum pratense
Type
review