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Original Article

Korean J Physiol Pharmacol 2024; 28(4): 313-322

Published online July 1, 2024 https://doi.org/10.4196/kjpp.2024.28.4.313

Copyright © Korean J Physiol Pharmacol.

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 SCN5A

Na Kyeong Park1,#, Seong Woo Choi2,3,#, Soon-Jung Park4,#, JooHan Woo2,3, Hyun Jong Kim2,3, Woo Kyung Kim3,5, Sung-Hwan Moon6,*, Hun-Jun Park7,*, and Sung Joon Kim1,8,*

1Department of Physiology, Seoul National University College of Medicine, Seoul 03080, 2Department of Physiology, Dongguk University College of Medicine, Gyeongju 38066, 3Channelopathy Research Center (CRC), Dongguk University College of Medicine, Goyang 10326, 4R&D Center, Biosolvix Co. Ltd, Seoul 08502, 5Department of Internal Medicine Graduate School of Medicine, Dongguk University, Goyang 10326, 6Department of Animal Science and Technology, Chung-Ang University, Anseong 17546, 7Division of Cardiology, Department of Internal Medicine, Uijeonbu St.Mary’s Hospital, The Catholic University of Korea, Seoul 11765, 8Department of Physiology & Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea

Correspondence to:Sung-Hwan Moon
E-mail: moonsh@cau.ac.kr
Hun-Jun Park
E-mail: cardioman@catholic.ac.kr
Sung Joon Kim
E-mail: sjoonkim@snu.ac.kr

#These authors contributed equally to this work.

Received: March 25, 2024; Revised: April 2, 2024; Accepted: April 2, 2024

Abstract

Mutations within the SCN5A gene, which encodes the α-subunit 5 (NaV1.5) 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 SCN5A in a patient exhibiting overlap arrhythmia phenotypes. This study aims to elucidate the functional consequences of SCN5A mutants (p.A385T/R504T) to understand the clinical phenotypes. Whole-cell patch-clamp technique was used to analyze the NaV1.5 current (INa) in HEK293 cells transfected with the wild-type and mutant SCN5A with or without SCN1B co-expression. The amplitude of INa was not altered in mutant SCN5A (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 SCN1B with p.A385T/R504T revealed significant reduction of INa and slower recovery from inactivation, consistent with the loss-of-function in Na+ channels. The SCN1B dependent reduction of INa was also observed in a single mutation p.R504T, but p.A385T co-expressed with SCN1B showed no reduction. In contrast, the slower recovery from inactivation with SCN1B was observed in A385T while not in R504T. The expression of SCN1B 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 NaV1.5, respectively.

Keywords: Cardiac arrhythmia, Brugada syndrome, Missense mutation, NAV1.5 voltage-gated sodium channel, Sodium channel beta subunit

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