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
Mutations within the gene, which encodes the α-subunit 5 (Na 1.5) 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 mutat...
Gespeichert in:
Veröffentlicht in: | The Korean journal of physiology & pharmacology 2024, 28(4), , pp.313-322 |
---|---|
Hauptverfasser: | , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | Mutations within the
gene, which encodes the α-subunit 5 (Na
1.5) 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 Na
1.5 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 Na
1.5, respectively. |
---|---|
ISSN: | 1226-4512 2093-3827 |
DOI: | 10.4196/kjpp.2024.28.4.313 |