Selectivity filter mutation in Na _V 1.5 promotes ventricular tachycardia

Loss-of-Function (LoF) mutations in the SCN5A gene, which encodes for the predominant cardiac Na _V isoform, Na _V 1.5 result in either deficiency in the channel expression or function. Impaired Na _V 1.5 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 _V 1.5 selectivity filter (DEKA motif), K1419E (DE E A) has been identified in patients with BrS. Despite early characterization of mutations in selectivity filter of other Na _V isoforms, little is known about the impact of DE E A on Na _V 1.5 function as well as on cardiac electrophysiology. Therefore, we generated a mouse heterozygous for Na _V 1.5 DE E A to characterize the mutation and investigate the outcome of this functionally deficient Na _V 1.5 variant on cardiac electrophysiology and arrhythmias. Heterologous expression system and isolated cardiomyocytes revealed lower current density and unchanged Na _V 1.5 expression in DE E A vs. wild type (DEKA). On the organ level, optical mapping revealed conduction velocity slowing in DE E A hearts, which was accentuated by flecainide resulting in vivo ventricular arrhythmias. Overall, to our knowledge, we provide the first mechanistic insight into the proarrhythmic consequences of a functionally deficient BrS mutation in Na _V 1.5.