SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of Na_V1.5 channel

Background Brugada syndrome (BrS) is an inherited lethal arrhythmic disorder characterized by syncope and sudden cardiac death from ventricular tachyarrhythmias. Here we identified a novel K817E mutation of SCN5A gene in a man with type 1 BrS electrocardiogram pattern using next-generation sequencing targeted for 73 cardiac disorder-related genes. SCN5A encodes the α-subunit of Na_V1.5 voltage-gated Na⁺ channel, and some of its mutations are linked to BrS. The proband had no mutation in any of the other arrhythmia-related genes sequenced. Objective We investigated whether the K817E mutation causes a functional change of Na_V1.5 channel responsible for the BrS phenotype. Methods We compared the electrophysiological properties of the whole-cell currents mediated by wild-type and mutant channels heterologously expressed in human embryonic kidney 293 cells by using a voltage-clamp technique. Results The K817E mutation reduced the Na⁺ current density by 39.0%-91.4% at membrane potentials from -55 to -5 mV. This reduction resulted from a ∼24-mV positive shift in the voltage dependence of activation. The mutation also decelerated recovery from both fast and intermediate inactivation, whereas it had little effect on the cell surface expression, single-channel conductance, voltage-dependence of fast inactivation, entry into intermediate inactivation, use-dependent loss of channel availability, or closed-state inactivation. Conclusion The K817E mutation of SCN5A gene leads to loss of function of Na_V1.5 channel and may underlie the BrS phenotype of the proband.