Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies

The Application of Clinical Genetics Dovepress open access to scientific and medical research R e v iew The Application of Clinical Genetics downloaded from https://www.dovepress.com/ by 5.135.254.153 on 12-Jul-2018 For personal use only. Open Access Full Text Article Gene mutations in cardiac arrhythmias: a review of recent evidence in ion channelopathies This article was published in the following Dove Press journal: The Application of Clinical Genetics 17 January 2013 Number of times this article has been viewed Pi-Yin Hsiao 1 Hui-Chun Tien 2 Chu-Pin Lo 2 Jyh-Ming Jimmy Juang 3 Yi-Hsin Wang 2 Ruey J Sung 4 Institute of Life Sciences, National Central University, Taoyuan, Taiwan; 2Department of Financial and Computational Mathematics, Providence University, Taichung, Taiwan; 3Cardiovascular Center and Department of Cardiology, National Taiwan University, Taipei, Taiwan; 4Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA 1 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. Keywords: Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, induced pluripotent stem cells, long QT syndrome, short QT syndrome. Introduction Correspondence: Ruey Jen Sung 100 Rowan Tree Lane, Hillsborough, CA 94305, USA Tel +1 650 685 1865 Fax +1 650 685 1865 Email submit your manuscript | www.dovepress.com Dovepress http://dx.doi.org/10.2147/TACG.S29676 Powered by TCPDF (www.tcpdf.org) Applying the technology of DNA sequencing,1 Curran et al2 and Wang et al3,4 noted that mutations in the KCNQ1, KCNH2, and SCN5A genes, encoding the α-subunit of ion channels that conduct potassium delayed-rectifier currents (IKs and IKr) and the sodium current (INa), respectively, could be responsible for three subtypes (LQT13) of congenital long-QT syndrome (LQTS). These seminal works have inspired many investigators and prompted extensive basic research, leading to subsequent identification of various gene mutations causing cardiac arrhythmias referred to as “inherited arrhythmogenic disorders” (Table 1). These arrhythmogenic disorders with mutations in genes encoding developmental components of cardiac structures produce diseases associated with a structurally abnormal heart, exemplified by hypertrophic The Application of Clinical Genetics 2013:6 1–13 © 2013 Hsiao et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. 1 Dovepress Hsiao et al The Application of Clinical Genetics downloaded from https://www.dovepress.com/ by 5.135.254.153 on 12-Jul-2018 For personal use only. Table 1 Inherited arrhythmogenic disorders Mutations in genes encoding developmental components of the heart Hypertrophic cardiomyopathy (HCM) Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) Dilated cardiomyopathy (DC) Mutations in genes encoding functional units of ion channels and/or transporter-associated proteins (“ion channelopathies”) Congenital long-QT syndrome (LQTS) Brugada syndrome (BrS) Catecholaminergic polymorphic ventricular tachycardia (CPVT) Short-QT syndrome (SQTS) cardiomyopathy, arrhythmogenic right ventricular dysplasia (cardiomyopathy), and dilated cardiomyopathy, whereas those with mutations in genes encoding functional units of ion channels and/or their transporter-associated proteins produce diseases associated with a structurally normal heart, such as congenital LQTS, short-QT syndrome, Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT), known as “ion channelopathies” (Tables 2–5). All these arrhythmogenic disorders are usually genetically heterogeneous, and their clinical courses are underscored by variable clinical expressivity ranging from being asymptomatic to episodic syncope, abortive cardiac arrest, and sudden cardiac death (SCD). To confirm that a specific gene mutation is linked to cardiac arrhythmias, functional studies to illustrate consequences of the mutation are required. These functional studies usually use heterologous expression systems, primarily Xenopus oocytes, human embryonic kidney (HEK) cells, and Chinese hamster ovary cells.5 Electrophysiological effects of the mutant ion channel are then compared to those of the wild-type counterpart. However, in order to include important constituents of the macromolecular complex of an ion channel in the complex living environment so as to reproduce the exact molecular and electrophysiological phenotype, it is often necessary to generate a transgenic mouse model carrying the specific gene mutation.6 Through collaborative endeavors between clinical and basic science researchers over the past 15 years, we now have better understanding of the clinical spectrum, molecular genetics, ion-channel structures, and cellular electrophysiology relating to these inherited arrhythmogenic disorders. Taking ion channelopathies as an example, the discovery of genetic defects involving the L-type Ca2+ channel (Cav1.2), (...truncated)