SCN5A(K817E), A Novel Brugada Syndrome-Associated Mutation that Alters the Activation Gating of NaV1.5 Channel.

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 male with type 1 BrS ECG pattern using next-generation sequencing targeted for 73 cardiac disorder-related genes. SCN5A encodes the α-subunit of NaV1.5 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.We investigated whether the K817E mutation causes a functional change of NaV1.5 channel responsible for the BrS phenotype.We compared the electrophysiological properties of the whole-cell currents mediated by the wild-type and mutant channels heterologously expressed in HEK-293T cells using a voltage-clamp technique.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.The K817E mutation of SCN5A gene leads to loss of function of NaV1.5 channel and may underlie the BrS phenotype of the proband.