R222Q SCN5A Mutation Is Associated With Reversible Ventricular Ectopy and Dilated Cardiomyopathy

Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
Journal of the American College of Cardiology (Impact Factor: 16.5). 10/2012; 60(16). DOI: 10.1016/j.jacc.2012.05.050


Objectives The goal of this study was to characterize a variant in the SCN5A gene that encodes the alpha-subunit of the cardiac sodium channel, Nav1.5, which was identified in 1 large kindred with dilated cardiomyopathy (DCM) and multiple arrhythmias, including premature ventricular complexes (PVCs). Background Treatment guidelines for familial DCM are based on conventional heart failure therapies, and no gene-based interventions have been established. Methods Family members underwent clinical evaluation and screening of the SCN5A and LMNA genes. Cellular electrophysiology and computational modeling were used to determine the functional consequences of the mutant Nav1.5 protein. Results An R222Q missense variant located in a Nav1.5 voltage-sensing domain was identified in affected family members. Patch-clamp studies showed that R222Q Nav1.5 did not alter sodium channel current density, but did left shift steady-state parameters of activation and inactivation. Using a voltage ramp protocol, normalized current responses of R222Q channels were of earlier onset and greater magnitude than wild-type channels. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant and a potential cause of DCM. In R222Q carriers, there were only modest responses to heart failure therapies, but PVCs and DCM were substantially reduced by amiodarone or flecainide, which are drugs that have sodium channel-blocking properties. Conclusions The R222Q SCN5A variant has an activating effect on sodium channel function and is associated with reversible ventricular ectopy and DCM. Elucidation of the genetic basis of familial DCM can enable effective gene-targeted therapy to be implemented. (J Am Coll Cardiol 2012;60:1566-73) (c) 2012 by the American College of Cardiology Foundation

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    • "These highly conserved R222 and R225 residues are located on the S4 segment of DI of the channel protein (Fig. 1). Although their clinical phenotypes share major similarities, highly divergent biophysical properties have also been observed (Table S1) (Bezzina et al., 2003; Cheng et al., 2010; Laurent et al., 2012; Mann et al., 2012; Nair et al., 2012). Indeed, the R222Q mutant channel exhibits gain of function characteristics, whereas the markedly lower current density observed for the R225W mutant channel leads to loss of function. "
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    ABSTRACT: The gating pore current, also called omega current, consists of a cation leak through the typically nonconductive voltage-sensor domain (VSD) of voltage-gated ion channels. Although the study of gating pore currents has refined our knowledge of the structure and the function of voltage-gated ion channels, their implication in cardiac disorders has not been established. Two Nav1.5 mutations (R222Q and R225W) located in the VSD are associated with atypical clinical phenotypes involving complex arrhythmias and dilated cardiomyopathy. Using the patch-clamp technique, in silico mutagenesis, and molecular dynamic simulations, we tested the hypothesis that these two mutations may generate gating pore currents, potentially accounting for their clinical phenotypes. Our findings suggest that the gating pore current generated by the R222Q and R225W mutations could constitute the underlying pathological mechanism that links Nav1.5 VSD mutations with human cardiac arrhythmias and dilatation of cardiac chambers. © 2015 Moreau et al.
    The Journal of General Physiology 02/2015; 145(2):93-106. DOI:10.1085/jgp.201411304 · 4.79 Impact Factor
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    • "Our findings further suggest that the S4 segments in DIV may affect intermediate inactivation gating process and its stability of sodium channels. Moreover, there are a growing number of reports that mutations associated with SCN5A channelopathies resided in the voltage-sensor domain [10].For example, SCN5A mutations preferentially inclined to occur in the S4 segment in DCM patients, and among positive charge clusters acted as voltage sensor [35,36]. These mutations resulted in the functional defects of sodium channels with synthesis of a channel protein altered gating kinetics rather than reduced the current density [10,37]. "
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    ABSTRACT: Brugada syndrome (BrS) is an inherited arrhythmogenic syndrome leading to sudden cardiac death, partially associated with autosomal dominant mutations in SCN5A, which encodes the cardiac sodium channel alpha-subunit (Nav1.5). To date some SCN5A mutations related with BrS have been identified in voltage sensor of Nav1.5. Here, we describe a dominant missense mutation (R1629Q) localized in the fourth segment of domain IV region (DIV-S4) in a Chinese Han family. The mutation was identified by direct sequencing of SCN5A from the proband's DNA. Co-expression of Wild-type (WT) or R1629Q Nav1.5 channel and hβ1 subunit were achieved in human embryonic kidney cells by transient transfection. Sodium currents were recorded using whole cell patch-clamp protocols. No significant changes between WT and R1629Q currents were observed in current density or steady-state activation. However, hyperpolarized shift of steady-state inactivation curve was identified in cells expressing R1629Q channel (WT: V1/2 = -81.1 ± 1.3 mV, n = 13; R1629Q: V1/2 = -101.7 ± 1.2 mV, n = 18). Moreover, R1629Q channel showed enhanced intermediate inactivation and prolonged recovery time from inactivation. In summary, this study reveals that R1629Q mutation causes a distinct loss-of-function of the channel due to alter its electrophysiological characteristics, and facilitates our understanding of biophysical mechanisms of BrS.
    PLoS ONE 10/2013; 8(10):e78382. DOI:10.1371/journal.pone.0078382 · 3.23 Impact Factor
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    • "Mutations in the sodium channel gene, SCN5A, are found in patients with a variety of cardiac diseases, such as congenital long QT syndrome type 3 and Brugada syndrome (Wang et al., 1995a,b; Antzelevitch , 2001; Moric et al., 2003). Recent studies have associated mutations in SCN5A with dilated cardiomyopathy (Mcnair et al., 2004; Hesse et al., 2007; Mann et al., 2012). Many investigators have characterized naturally occurring SCN5A mutations, but little is known about the regulation of expression of Na v 1.5 in cardiac cells. "
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    ABSTRACT: The cardiac voltage-gated sodium channel, Nav1.5, plays a central role in cardiac excitability and impulse propagation and associates with the dystrophin multiprotein complex at the lateral membrane of cardiomyocytes. It was previously shown that Nav1.5 protein content and the sodium current (l Na) were both decreased in cardiomyocytes of dystrophin-deficient mdx (5cv) mice. In this study, wild-type and mdx (5cv) mice were treated for 7 days with the proteasome inhibitor MG132 (10 μg/Kg/24 h) using implanted osmotic mini pumps. MG132 rescued both the total amount of Nav1.5 protein and l Na but, unlike in previous studies, de novo expression of dystrophin was not observed in skeletal or cardiac muscle. This study suggests that the reduced expression of Nav1.5 in dystrophin-deficient cells is dependent on proteasomal degradation.
    Frontiers in Physiology 03/2013; 4:51. DOI:10.3389/fphys.2013.00051 · 3.53 Impact Factor
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