A mutation in the β3 subunit of the cardiac sodium channel associated with brugada ECG phenotype

Dan Hu, Hector Barajas-Martinez, Elena Burashnikov, Michael Springer, Yuesheng Wu, A. Varró, Ryan Pfeiffer, Tamara T. Koopmann, Jonathan M. Cordeiro, Alejandra Guerchicoff, Guido D. Pollevick, Charles Antzelevitch

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

Background-Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene. Methods and Results-A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction- based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium. Conclusions-Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.

Original languageEnglish
Pages (from-to)270-278
Number of pages9
JournalCirculation: Cardiovascular Genetics
Volume2
Issue number3
DOIs
Publication statusPublished - May 2009

Fingerprint

Sodium Channels
Electrocardiography
Phenotype
Mutation
Brugada Syndrome
Genes
Procainamide
Patch-Clamp Techniques
Missense Mutation
Green Fluorescent Proteins
Confocal Microscopy
Organelles
Cardiac Arrhythmias
Exons
Myocardium
Western Blotting
Sodium
Polymerase Chain Reaction
Proteins

Keywords

  • Arrhythmia
  • Brugada syndrome
  • Ion channels
  • Protein trafficking
  • SCN3B

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)
  • Genetics
  • Medicine(all)

Cite this

A mutation in the β3 subunit of the cardiac sodium channel associated with brugada ECG phenotype. / Hu, Dan; Barajas-Martinez, Hector; Burashnikov, Elena; Springer, Michael; Wu, Yuesheng; Varró, A.; Pfeiffer, Ryan; Koopmann, Tamara T.; Cordeiro, Jonathan M.; Guerchicoff, Alejandra; Pollevick, Guido D.; Antzelevitch, Charles.

In: Circulation: Cardiovascular Genetics, Vol. 2, No. 3, 05.2009, p. 270-278.

Research output: Contribution to journalArticle

Hu, D, Barajas-Martinez, H, Burashnikov, E, Springer, M, Wu, Y, Varró, A, Pfeiffer, R, Koopmann, TT, Cordeiro, JM, Guerchicoff, A, Pollevick, GD & Antzelevitch, C 2009, 'A mutation in the β3 subunit of the cardiac sodium channel associated with brugada ECG phenotype', Circulation: Cardiovascular Genetics, vol. 2, no. 3, pp. 270-278. https://doi.org/10.1161/CIRCGENETICS.108.829192
Hu, Dan ; Barajas-Martinez, Hector ; Burashnikov, Elena ; Springer, Michael ; Wu, Yuesheng ; Varró, A. ; Pfeiffer, Ryan ; Koopmann, Tamara T. ; Cordeiro, Jonathan M. ; Guerchicoff, Alejandra ; Pollevick, Guido D. ; Antzelevitch, Charles. / A mutation in the β3 subunit of the cardiac sodium channel associated with brugada ECG phenotype. In: Circulation: Cardiovascular Genetics. 2009 ; Vol. 2, No. 3. pp. 270-278.
@article{b9a7de417ec047449fa76979aef2ffa0,
title = "A mutation in the β3 subunit of the cardiac sodium channel associated with brugada ECG phenotype",
abstract = "Background-Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene. Methods and Results-A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction- based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6{\%} decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium. Conclusions-Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.",
keywords = "Arrhythmia, Brugada syndrome, Ion channels, Protein trafficking, SCN3B",
author = "Dan Hu and Hector Barajas-Martinez and Elena Burashnikov and Michael Springer and Yuesheng Wu and A. Varr{\'o} and Ryan Pfeiffer and Koopmann, {Tamara T.} and Cordeiro, {Jonathan M.} and Alejandra Guerchicoff and Pollevick, {Guido D.} and Charles Antzelevitch",
year = "2009",
month = "5",
doi = "10.1161/CIRCGENETICS.108.829192",
language = "English",
volume = "2",
pages = "270--278",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "3",

}

TY - JOUR

T1 - A mutation in the β3 subunit of the cardiac sodium channel associated with brugada ECG phenotype

AU - Hu, Dan

AU - Barajas-Martinez, Hector

AU - Burashnikov, Elena

AU - Springer, Michael

AU - Wu, Yuesheng

AU - Varró, A.

AU - Pfeiffer, Ryan

AU - Koopmann, Tamara T.

AU - Cordeiro, Jonathan M.

AU - Guerchicoff, Alejandra

AU - Pollevick, Guido D.

AU - Antzelevitch, Charles

PY - 2009/5

Y1 - 2009/5

N2 - Background-Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene. Methods and Results-A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction- based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium. Conclusions-Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.

AB - Background-Brugada syndrome, characterized by ST-segment elevation in the right precordial ECG leads and the development of life-threatening ventricular arrhythmias, has been associated with mutations in 6 different genes. We identify and characterize a mutation in a new gene. Methods and Results-A 64-year-old white male displayed a type 1 ST-segment elevation in V1 and V2 during procainamide challenge. Polymerase chain reaction- based direct sequencing was performed using a candidate gene approach. A missense mutation (L10P) was detected in exon 1 of SCN3B, the β3 subunit of the cardiac sodium channel, but not in any other gene known to be associated with Brugada syndrome or in 296 controls. Wild-type (WT) and mutant genes were expressed in TSA201 cells and studied using whole-cell patch-clamp techniques. Coexpression of SCN5A/WT+SCN1B/WT+SCN3B/L10P resulted in an 82.6% decrease in peak sodium current density, accelerated inactivation, slowed reactivation, and a -9.6-mV shift of half-inactivation voltage compared with SCN5A/WT+SCN1B/WT+SCN3B/WT. Confocal microscopy revealed that SCN5A/WT channels tagged with green fluorescent protein are localized to the cell surface when coexpressed with WT SCN1B and SCN3B but remain trapped in intracellular organelles when coexpressed with SCN1B/WT and SCN3B/L10P. Western blot analysis confirmed the presence of NaVβ3 in human ventricular myocardium. Conclusions-Our results provide support for the hypothesis that mutations in SCN3B can lead to loss of transport and functional expression of the hNav1.5 protein, leading to reduction in sodium channel current and clinical manifestation of a Brugada phenotype.

KW - Arrhythmia

KW - Brugada syndrome

KW - Ion channels

KW - Protein trafficking

KW - SCN3B

UR - http://www.scopus.com/inward/record.url?scp=69549145477&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69549145477&partnerID=8YFLogxK

U2 - 10.1161/CIRCGENETICS.108.829192

DO - 10.1161/CIRCGENETICS.108.829192

M3 - Article

VL - 2

SP - 270

EP - 278

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 3

ER -