Article

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: 15.34). 10/2012; 60(16). DOI: 10.1016/j.jacc.2012.05.050

ABSTRACT Our aim 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 ar-rhythmias, including premature ventricular complexes (PVCs).

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    ABSTRACT: Mutations in SCN5A, encoding the cardiac sodium channel (NaV1.5) typically cause ventricular arrhythmia or conduction slowing. Recently, SCN5A mutations have been associated with heart failure combined with variable atrial and ventricular arrhythmia. Here we present the clinical, genetic and functional features of an amiodarone-responsive multifocal ventricular ectopy-related cardiomyopathy associated with a novel mutation in a NaV1.5 voltage sensor domain. A novel, de novo SCN5A mutation (NaV1.5-R225P) was identified in a boy with prenatal arrhythmia and impaired cardiac contractility followed by postnatal multifocal ventricular ectopy suppressible by amiodarone. We investigated the functional consequences of NaV1.5-R225P expressed heterologously in tsA201 cells. Mutant channels exhibited significant abnormalities in both activation and inactivation leading to large, hyperpolarized window- and ramp-currents that predict aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. Mutant channels also exhibited significantly increased persistent (late) sodium current. This profile of channel dysfunction shares features with other SCN5A voltage sensor mutations associated with cardiomyopathy and overlapped that of congenital long-QT syndrome. Amiodarone stabilized fast inactivation, suppressed persistent sodium current and enhanced frequency-dependent rundown of channel availability. We determined the functional consequences and pharmacological responses of a novel SCN5A mutation associated with an arrhythmia-associated cardiomyopathy. Comparisons with other cardiomyopathy-associated NaV1.5 voltage sensor mutations revealed a pattern of abnormal voltage dependence of activation as a shared molecular mechanism of the syndrome.
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