Requirement of β subunit for the reduced voltage-gated Na current of a Brugada syndrome patient having novel double missense mutation (p.A385T/R504T) of .

Mutations within the gene, which encodes the α-subunit 5 (Na1.5) of the voltage-gated Na channel, have been linked to three distinct cardiac arrhythmia disorders: long QT syndrome type 3, Brugada syndrome (BrS), and cardiac conduction disorder. In this study, we have identified novel missense mutations (p.A385T/R504T) within in a patient exhibiting overlap arrhythmia phenotypes. This study aims to elucidate the functional consequences of mutants (p.A385T/R504T) to understand the clinical phenotypes. Whole-cell patch-clamp technique was used to analyze the Na1.5 current (I) in HEK293 cells transfected with the wild-type and mutant with or without co-expression. The amplitude of I was not altered in mutant (p.A385T/R504T) alone. Furthermore, a rightward shift of the voltage-dependent inactivation and faster recovery from inactivation was observed, suggesting a gain-of-function state. Intriguingly, the coexpression of with p.A385T/R504T revealed significant reduction of I and slower recovery from inactivation, consistent with the loss-of-function in Na channels. The dependent reduction of I was also observed in a single mutation p.R504T, but p.A385T co-expressed with showed no reduction. In contrast, the slower recovery from inactivation with was observed in A385T while not in R504T. The expression of is indispensable for the electrophysiological phenotype of BrS with the novel double mutations; p.A385T and p.R504T contributed to the slower recovery from inactivation and reduced current density of Na1.5, respectively.