0265: A novel SCN5A mutation associated with exercise-induced polymorphic ventricular arrhythmias resembling CPVT

Abstract

Cardiac sodium channel is a complex which includes the poreforming alpha subunit and regulatory proteins that allow sodium influx during the depolarization phase of the ventricular action potential. The alpha subunit, Nav1.5, is encoded by SCN5A . Mutations in this gene are responsible for a wide spectrum of hereditary arrhythmias such as cardiac conduction disease and atrial fibrillation. A mutation in SCN5A , leading to a p.I141V substitution, was identified in a large multigenerational family with an arrhythmia syndrome resembling catecholaminergic polymorphic ventricular tachycardia through whole-exome sequencing. The purpose of this study was to identify the molecular mechanisms linking the p.I141V mutation to this arrhythmia. To evaluate the incidence of this substitution on Nav1.5 function, whole-cell patch-clamp experiments were performed on HEK293 cells transfected with the human alpha and beta subunits. The presence of the p.I141V mutation shifted the voltage-dependence of steady state activation towards more negative potentials. Thus, we studied the effect of this mutation on the sodium window current. Compared to the WT, the p.I141V window current exhibited a larger peak and this peak was shifted towards more negative potentials. To investigate the functional consequences of the cardiac hyperexcitability due to the p.I141V mutation, we incorporated biophysical properties of the mutant into atrial, Purkinje and ventricular cell models. The computational analyses imply that the biophysical changes caused by the p.I141V mutation accelerates the spontaneous rate in the Purkinje cell model, and reduce the excitation threshold leading to an increase of the excitability of the cardiac cells. In conclusion, the present study demonstrates that mutations in SCN5A also may result in exercise-induced polymorphic ventricular premature complexes and tachycardia resembling CPVT.