Selectivity filter mutation in Na_V1.5 promotes ventricular tachycardia

Loss-of-Function (LoF) mutations in theSCN5Agene, which encodes for the predominant cardiac Na_Visoform, Na_V1.5 result in either deficiency in the channel expression or function. Impaired Na_V1.5 expression and function underlie reduced peak Na⁺current (I_Na) and result in ventricular conduction velocity slowing, predisposing the heart to conduction block and ventricular arrhythmias clinically associated with Brugada syndrome (BrS). Recently, a missense mutation in Na_V1.5 selectivity filter (DEKA motif), K1419E (DEEA) has been identified in patients with BrS. Despite early characterization of mutations in selectivity filter of other Na_Visoforms, little is known about the impact of DEEA on Na_V1.5 function as well as on cardiac electrophysiology. Therefore, we generated a mouse heterozygous for Na_V1.5 DEEA to characterize the mutation and investigate the outcome of this functionally deficient Na_V1.5 variant on cardiac electrophysiology and arrhythmias. Heterologous expression system and isolated cardiomyocytes revealed lower current density and unchanged Na_V1.5 expression in DEEA vs. wild type (DEKA). On the organ level, optical mapping revealed conduction velocity slowing in DEEA hearts, which was accentuated by flecainide resultingin vivoventricular arrhythmias. Overall, to our knowledge, we provide the first mechanistic insight into the proarrhythmic consequences of a functionally deficient BrS mutation in Na_V1.5.