SCN5A(K817E), a novel Brugada syndrome-associated mutation that alters the activation gating of NaV1.5 channel

Heart Rhythm : the Official Journal of the Heart Rhythm Society
Koshi KinoshitaNaoki Nishida

Abstract

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 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 wild-type and mutant channels heterologously expressed in human embryonic kidney 293 cells by 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 conductanc...Continue Reading

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Citations

Dec 30, 2016·International Journal of Legal Medicine·Lei HuangJianding Cheng
Oct 27, 2018·Frontiers in Physiology·Wenjia LiAijun Sun

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