Mutations in SCN10A are responsible for a large fraction of cases of brugada syndrome

Dan Hu, Hector Barajas-Martínez, Ryan Pfeiffer, Fabio Dezi, Jenna Pfeiffer, Tapan Buch, Matthew J. Betzenhauser, Luiz Belardinelli, Kristopher M. Kahlig, Sridharan Rajamani, Harry J. Deantonio, Robert J Myerburg, Hiroyuki Ito, Pramod Deshmukh, Mark Marieb, Gi Byoung Nam, Atul Bhatia, Can Hasdemir, Michel Haïssaguerre, Christian VeltmannRainer Schimpf, Martin Borggrefe, Sami Viskin, Charles Antzelevitch

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

BACKGROUND: BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Na v1.8, in the electrical function of the heart. OBJECTIVES: The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). METHODS: Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. RESULTS: We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Na v1.8 and Nav1.5 in the plasma membrane. CONCLUSIONS: Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

Original languageEnglish
Pages (from-to)66-79
Number of pages14
JournalJournal of the American College of Cardiology
Volume64
Issue number1
DOIs
StatePublished - Jul 8 2014

Fingerprint

Brugada Syndrome
Mutation
Sodium Channels
Genes
Aptitude
Sudden Cardiac Death
Genotype
Cell Membrane
Phenotype

Keywords

  • Brugada syndrome
  • cardiac arrhythmias
  • cardiac conduction disease
  • electrophysiology
  • genetics
  • sudden cardiac death

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Hu, D., Barajas-Martínez, H., Pfeiffer, R., Dezi, F., Pfeiffer, J., Buch, T., ... Antzelevitch, C. (2014). Mutations in SCN10A are responsible for a large fraction of cases of brugada syndrome. Journal of the American College of Cardiology, 64(1), 66-79. https://doi.org/10.1016/j.jacc.2014.04.032

Mutations in SCN10A are responsible for a large fraction of cases of brugada syndrome. / Hu, Dan; Barajas-Martínez, Hector; Pfeiffer, Ryan; Dezi, Fabio; Pfeiffer, Jenna; Buch, Tapan; Betzenhauser, Matthew J.; Belardinelli, Luiz; Kahlig, Kristopher M.; Rajamani, Sridharan; Deantonio, Harry J.; Myerburg, Robert J; Ito, Hiroyuki; Deshmukh, Pramod; Marieb, Mark; Nam, Gi Byoung; Bhatia, Atul; Hasdemir, Can; Haïssaguerre, Michel; Veltmann, Christian; Schimpf, Rainer; Borggrefe, Martin; Viskin, Sami; Antzelevitch, Charles.

In: Journal of the American College of Cardiology, Vol. 64, No. 1, 08.07.2014, p. 66-79.

Research output: Contribution to journalArticle

Hu, D, Barajas-Martínez, H, Pfeiffer, R, Dezi, F, Pfeiffer, J, Buch, T, Betzenhauser, MJ, Belardinelli, L, Kahlig, KM, Rajamani, S, Deantonio, HJ, Myerburg, RJ, Ito, H, Deshmukh, P, Marieb, M, Nam, GB, Bhatia, A, Hasdemir, C, Haïssaguerre, M, Veltmann, C, Schimpf, R, Borggrefe, M, Viskin, S & Antzelevitch, C 2014, 'Mutations in SCN10A are responsible for a large fraction of cases of brugada syndrome', Journal of the American College of Cardiology, vol. 64, no. 1, pp. 66-79. https://doi.org/10.1016/j.jacc.2014.04.032
Hu, Dan ; Barajas-Martínez, Hector ; Pfeiffer, Ryan ; Dezi, Fabio ; Pfeiffer, Jenna ; Buch, Tapan ; Betzenhauser, Matthew J. ; Belardinelli, Luiz ; Kahlig, Kristopher M. ; Rajamani, Sridharan ; Deantonio, Harry J. ; Myerburg, Robert J ; Ito, Hiroyuki ; Deshmukh, Pramod ; Marieb, Mark ; Nam, Gi Byoung ; Bhatia, Atul ; Hasdemir, Can ; Haïssaguerre, Michel ; Veltmann, Christian ; Schimpf, Rainer ; Borggrefe, Martin ; Viskin, Sami ; Antzelevitch, Charles. / Mutations in SCN10A are responsible for a large fraction of cases of brugada syndrome. In: Journal of the American College of Cardiology. 2014 ; Vol. 64, No. 1. pp. 66-79.
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abstract = "BACKGROUND: BrS is an inherited sudden cardiac death syndrome. Less than 35{\%} of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Na v1.8, in the electrical function of the heart. OBJECTIVES: The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). METHODS: Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. RESULTS: We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0{\%}) displayed overlapping phenotypes. SCN10A mutations were found in 16.7{\%} of BrS probands, approaching our yield for SCN5A mutations (20.1{\%}). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4{\%} and 84.4{\%} reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Na v1.8 and Nav1.5 in the plasma membrane. CONCLUSIONS: Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.",
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T1 - Mutations in SCN10A are responsible for a large fraction of cases of brugada syndrome

AU - Hu, Dan

AU - Barajas-Martínez, Hector

AU - Pfeiffer, Ryan

AU - Dezi, Fabio

AU - Pfeiffer, Jenna

AU - Buch, Tapan

AU - Betzenhauser, Matthew J.

AU - Belardinelli, Luiz

AU - Kahlig, Kristopher M.

AU - Rajamani, Sridharan

AU - Deantonio, Harry J.

AU - Myerburg, Robert J

AU - Ito, Hiroyuki

AU - Deshmukh, Pramod

AU - Marieb, Mark

AU - Nam, Gi Byoung

AU - Bhatia, Atul

AU - Hasdemir, Can

AU - Haïssaguerre, Michel

AU - Veltmann, Christian

AU - Schimpf, Rainer

AU - Borggrefe, Martin

AU - Viskin, Sami

AU - Antzelevitch, Charles

PY - 2014/7/8

Y1 - 2014/7/8

N2 - BACKGROUND: BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Na v1.8, in the electrical function of the heart. OBJECTIVES: The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). METHODS: Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. RESULTS: We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Na v1.8 and Nav1.5 in the plasma membrane. CONCLUSIONS: Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

AB - BACKGROUND: BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Na v1.8, in the electrical function of the heart. OBJECTIVES: The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). METHODS: Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. RESULTS: We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Na v1.8 and Nav1.5 in the plasma membrane. CONCLUSIONS: Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

KW - Brugada syndrome

KW - cardiac arrhythmias

KW - cardiac conduction disease

KW - electrophysiology

KW - genetics

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