A Proton Leak Current through the Cardiac Sodium Channel Linked to Mixed Arrhythmia and Dilated Cardiomyopathy Phenotypes

Cardiac Na+ channels encoded by SCN5A gene are essential for initiating heart beats and maintaining a regular heart rhythm. Mutations in these channels have recently been associated to atrial fibrillation, ventricular arrhythmias, conduction disorders and dilated cardiomyopathy (DCM).We investigated a young male patient with a mixed phenotype composed of documented conduction disorder, atrial flutter, and ventricular tachycardia and DCM. Further family screening revealed DCM in the patient's mother his sister and in three of the mother's sisters. Because of the complex clinical phenotypes, we screened SCN5A and identified a novel mutation, R219H, which is located on a highly conserved region on the fourth helix of the voltage sensor domain of Nav1.5. Three family members with DCM carried the R219H mutation.The wild-type (WT) and mutant Na channels were expressed in a heterologous expression system and intracellular pH (pHi) was measured using a pH-sensitive electrode. The biophysical characterization of this mutant channel revealed an unexpected selective proton leak without any effect on the channel's biophysical properties. This H+ leak through the mutated Nav1.5 channel was not related to the Na+ permeation pathway but occurred through an alternative pore. This pore most probably involves a proton wire on the voltage sensor domain.We suggest that an acidification of cardiac myocytes and/or downstream events may cause the DCM phenotype and other electrical problems in affected family members. The identification of this clinically significant H+ leak may lead to the development of more targeted treatment.