Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndrome

• Published in: Annals of noninvasive electrocardiology 2021-05, Vol.26 (3), p.e12828-n/a
• Main Authors: Nakajima, Tadashi, Dharmawan, Tommy, Kawabata‐Iwakawa, Reika, Tamura, Shuntaro, Hasegawa, Hiroshi, Kobari, Takashi, Ota, Masaki, Tange, Shoichi, Nishiyama, Masahiko, Kaneko, Yoshiaki, Kurabayashi, Masahiko
• Format: Article
• Language: English
• Subjects: Brugada syndrome; Channel gating; Current density; Defects; Depolarization; mexiletine; Mutation; Original; rescue; SCN5A; Sodium currents; Syncope; trafficking defect
• ISSN: 1082-720X; 1542-474X
• DOI: 10.1111/anec.12828

Background SCN5A‐related Brugada syndrome (BrS) can be caused by multiple mechanisms including trafficking defects and altered channel gating properties. Most SCN5A mutations at pore region cause trafficking defects, and some of them can be rescued by mexiletine (MEX). Objective We recently encountered symptomatic siblings with BrS and sought to identify a responsible mutation and reveal its biophysical defects. Methods Target panel sequencing was performed. Wild‐type (WT) or identified mutant SCN5A was transfected into tsA201 cells. After incubation of transfected cells with or without 0.1 mM MEX for 24–36 hr, whole‐cell sodium currents (INa) were recorded using patch‐clamp techniques. Results The proband was 29‐year‐old male who experienced cardiopulmonary arrest. Later, his 36‐year‐old sister, who had been suffering from recurrent episodes of syncope since 12 years, was diagnosed with BrS. An SCN5A W374G mutation, located at pore region of domain 1 (D1 pore), was identified in both. The peak density of W374G‐INa was markedly reduced (WT: 521 ± 38 pA/pF, W374G: 60 ± 10 pA/pF, p