Abstract Body (Do not enter title and authors here): Background: Mutations in the SCN5A gene, encoding the cardiac voltage-gates sodium channels (Na_v1.5) are associated with life threatening arrhythmias. Recently a missense mutation in the selectivity filter, SCN5A-K1419E, has been identified in patients with Brugada syndrome and has also been linked to long QT. Prior studies demonstrated that SCN5A-K1419E substitution alters ion selectivity of Na_V1.5, conferring Ca²⁺ permeability, and thereby lowering overall conductance. However, the arrhythmogenic mechanism of selectivity filter mutations have not been established.
Methods and results: To address this, we generated heterozygous Scn5a-K1421E mice (homolog of human SCN5A-K1419E). Cardiomyocytes from these mice exhibited reduced peak Na⁺ current (I_Na) density with a reversal potential consistent with altered permeability to other ions relative to wild type (WT). Importantly, Na_V1.5 expression in Scn5a-K1421E hearts was unchanged compared to WT as revealed by confocal immunolabeling studies. Consistent with reduced I_Na density in Scn5a-K1421E, conduction velocity (CV) slowing was observed in optical mapping experiments. Notably, flecainide (1µM) challenge profoundly slowed CV in Scn5a-K1421E relative to WT hearts, resulting in ventricular tachyarrhythmias (VT) in vivo. Intriguingly, despite reduction in peak I_Na, Scn5a-K1421E cardiomyocytes exhibited enhanced late Na⁺ influx relative to WT, which translated to prolonged QT interval in vivo.
Conclusion: Overall, Scn5a-K1421E mice exhibit an overlap phenotype consistent with Brugada and long QT type 3 syndromes revealing complex effects of K1421E on Na_V1.5 function.