Gating Pore Currents are Common Defects of Two Nav1.5 Mutations in Patients with Mixed Arrhythmias and Dilated Cardiomyopathy

Abstract

The gating pore current, also called omega current, consists of a cation leak through the typically non-conductive voltage sensor domain (VSD) of voltage gated ion channels (VGIC). While the study of gating pore current refined the knowledge of the structure and the function of VGIC, their implication in cardiac disorders has not been established. Two Nav1.5 mutations (R222Q and R225W) localized in the VSD are associated with 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 atypical clinical phenotypes. Our findings suggest that the gating pore current generated by the R222Q and R225W mutations could constitute the yet unrevealed pathological mechanism linking Nav1.5 VSD mutations with cardiac arrhythmias and dilatation of cardiac chambers in humans.