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

Abstract 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...

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Main Authors: Tadashi Nakajima, Tommy Dharmawan, Reika Kawabata‐Iwakawa, Shuntaro Tamura, Hiroshi Hasegawa, Takashi Kobari, Masaki Ota, Shoichi Tange, Masahiko Nishiyama, Yoshiaki Kaneko, Masahiko Kurabayashi
Format: Article
Language:English
Published: Wiley 2021-05-01
Series:Annals of Noninvasive Electrocardiology
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Online Access:https://doi.org/10.1111/anec.12828
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spelling doaj-7f581cf3e4594759af2b0237dd9422a72021-06-16T06:25:24ZengWileyAnnals of Noninvasive Electrocardiology1082-720X1542-474X2021-05-01263n/an/a10.1111/anec.12828Reduced current density, partially rescued by mexiletine, and depolarizing shift in activation of SCN5A W374G channels as a cause of severe form of Brugada syndromeTadashi Nakajima0Tommy Dharmawan1Reika Kawabata‐Iwakawa2Shuntaro Tamura3Hiroshi Hasegawa4Takashi Kobari5Masaki Ota6Shoichi Tange7Masahiko Nishiyama8Yoshiaki Kaneko9Masahiko Kurabayashi10Department of Cardiovascular Medicine Gunma University Graduate School of Medicine Maebashi JapanDepartment of Cardiovascular Medicine Gunma University Graduate School of Medicine Maebashi JapanDivision of Integrated Oncology Research Gunma University Initiative for Advanced Research Maebashi JapanDepartment of Cardiovascular Medicine Gunma University Graduate School of Medicine Maebashi JapanDepartment of Cardiovascular Medicine Gunma University Graduate School of Medicine Maebashi JapanDepartment of Cardiovascular Medicine Gunma University Graduate School of Medicine Maebashi JapanDepartment of Cardiovascular Medicine National Hospital Organization Takasaki General Medical Center Takasaki JapanDepartment of Cardiovascular Medicine Japanese Red Cross Maebashi Hospital Maebashi JapanGunma University Maebashi JapanDepartment of Cardiovascular Medicine Gunma University Graduate School of Medicine Maebashi JapanDepartment of Cardiovascular Medicine Gunma University Graduate School of Medicine Maebashi JapanAbstract 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 < .01), and steady‐state activation (SSA) was shifted to depolarizing potentials compared with WT‐INa (V1/2‐WT: −39.1 ± 0.8 mV, W374G: −30.9 ± 1.1 mV, p < .01). Incubation of W374G‐transfected cells with MEX (W374G‐MEX) increased INa density, but it was still reduced compared with WT‐INa (W374G‐MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G‐MEX‐INa was comparable to W374G‐INa (V1/2‐W374G‐MEX: −31.6 ± 0.7 mV, P = NS). Conclusions Reduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.https://doi.org/10.1111/anec.12828Brugada syndromemexiletinerescueSCN5Atrafficking defect
collection DOAJ
language English
format Article
sources DOAJ
author Tadashi Nakajima
Tommy Dharmawan
Reika Kawabata‐Iwakawa
Shuntaro Tamura
Hiroshi Hasegawa
Takashi Kobari
Masaki Ota
Shoichi Tange
Masahiko Nishiyama
Yoshiaki Kaneko
Masahiko Kurabayashi
spellingShingle Tadashi Nakajima
Tommy Dharmawan
Reika Kawabata‐Iwakawa
Shuntaro Tamura
Hiroshi Hasegawa
Takashi Kobari
Masaki Ota
Shoichi Tange
Masahiko Nishiyama
Yoshiaki Kaneko
Masahiko Kurabayashi
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
Annals of Noninvasive Electrocardiology
Brugada syndrome
mexiletine
rescue
SCN5A
trafficking defect
author_facet Tadashi Nakajima
Tommy Dharmawan
Reika Kawabata‐Iwakawa
Shuntaro Tamura
Hiroshi Hasegawa
Takashi Kobari
Masaki Ota
Shoichi Tange
Masahiko Nishiyama
Yoshiaki Kaneko
Masahiko Kurabayashi
author_sort Tadashi Nakajima
title 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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publisher Wiley
series Annals of Noninvasive Electrocardiology
issn 1082-720X
1542-474X
publishDate 2021-05-01
description Abstract 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 < .01), and steady‐state activation (SSA) was shifted to depolarizing potentials compared with WT‐INa (V1/2‐WT: −39.1 ± 0.8 mV, W374G: −30.9 ± 1.1 mV, p < .01). Incubation of W374G‐transfected cells with MEX (W374G‐MEX) increased INa density, but it was still reduced compared with WT‐INa (W374G‐MEX: 174 ± 19 pA/pF, p < .01 versus W374G, p < .01 versus WT). The SSA of W374G‐MEX‐INa was comparable to W374G‐INa (V1/2‐W374G‐MEX: −31.6 ± 0.7 mV, P = NS). Conclusions Reduced current density, possibly due to a trafficking defect, and depolarizing shift in activation of SCN5A W374G are underlying biophysical defects in this severe form of BrS. Trafficking defects of SCN5A mutations at D1 pore may be commonly rescued by MEX.
topic Brugada syndrome
mexiletine
rescue
SCN5A
trafficking defect
url https://doi.org/10.1111/anec.12828
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