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J Am Coll Cardiol. 2012 Oct 16;60(16):1566-73. doi: 10.1016/j.jacc.2012.05.050. Epub 2012 Sep 19.

R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy.

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Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.



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).


Treatment guidelines for familial DCM are based on conventional heart failure therapies, and no gene-based interventions have been established.


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.


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.


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.

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