Gain-of-Function Mutation of the SCN5A Gene Causes Exercise-Induced Polymorphic Ventricular Arrhythmias

Abstract

Background-Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family. Methods and Results-A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Na v 1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells. Conclusions-Gain

In SilicoEvaluation of the Potential Antiarrhythmic Effect of Epigallocatechin-3-Gallate on Cardiac Channelopathies

“…In cardiac cells, mutations in more than 30 genes encoding ion channels have been associated with an increasingly wide range of inherited cardiac arrhythmias [1]. Examples of genetic cardiac disorders include congenital ectopic Purkinje-related premature contractions (MEPPC) and exercise induced polymorphic ventricular tachycardia (EPVT) which have been linked to the presence of the Na v1.5 -p.R222Q and Na v1.5 -p.I141V mutations [2–4]. …”

“…The observed arrhythmia disappears under exercise [2, 3]. For Na v1.5 -p.I141V carriers, the ECG is characterized by an increased sinus rate, atrial tachyarrhythmias, and an increased number of ventricular complexes during exercise [4]. On the molecular level, these mutations affect the biophysical properties of Na v1.5 by shifting its voltage dependence of steady state of activation towards more negative potentials and accelerating its activation and inactivation kinetics [2–6].…”

Functional interaction between S1 and S4 segments in voltage-gated sodium channels revealed by human channelopathies

“…1A-F). 3,4 For both channels, the presence of the p.I141V mutation shifted the voltage dependence of activation toward negative potentials (Na v 1.4-V 1/2 act : ¡18 § 1.4 mV, n D 9, versus ¡28 § 2.1 mV, n D 5, ***P < 0.001; slope: 5.3 § (E and F) Steady-state activation and inactivation curves for Na v 1.4 (E) and Na v 1.5 (F). Activation properties were determined from I/V relationships by normalizing peak I Na to driving force and maximal I Na .…”

“…[3][4][5][6] This study investigated the biophysical effects of the p.I141V mutant on these channels and demonstrated that the p.I141V substitution stabilized the activated state of the DI VSD, manifested by a negative shift of the voltage dependence of the activation curve.…”

“…myotonia, exercise-induced polymorphic ventricular arrhythmias and erythromelalgia. [1][2][3][4][5][6] The p.I141V mutation in Na V 1.4 and Na V 1.5, as well as its homologous p.I136V mutation in Na v 1.7, induce similar modifications in the biophysical properties of the voltage-gated sodium channels [3][4][5][6] by shifting the voltage-dependence of steady state activation toward more negative potentials and hastening the activation and inactivation kinetics. In addition, the I Na generated by these mutant channels have larger sodium window current peaks which are shifted toward more negative potentials.…”