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Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome

BACKGROUND: The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown. METHODS AND RESULTS: We combined whole...

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Autores principales: Portero, Vincent, Le Scouarnec, Solena, Es‐Salah‐Lamoureux, Zeineb, Burel, Sophie, Gourraud, Jean‐Baptiste, Bonnaud, Stéphanie, Lindenbaum, Pierre, Simonet, Floriane, Violleau, Jade, Baron, Estelle, Moreau, Eléonore, Scott, Carol, Chatel, Stéphanie, Loussouarn, Gildas, O'Hara, Thomas, Mabo, Philippe, Dina, Christian, Le Marec, Hervé, Schott, Jean‐Jacques, Probst, Vincent, Baró, Isabelle, Marionneau, Céline, Charpentier, Flavien, Redon, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937261/
https://www.ncbi.nlm.nih.gov/pubmed/27287695
http://dx.doi.org/10.1161/JAHA.115.003122
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author Portero, Vincent
Le Scouarnec, Solena
Es‐Salah‐Lamoureux, Zeineb
Burel, Sophie
Gourraud, Jean‐Baptiste
Bonnaud, Stéphanie
Lindenbaum, Pierre
Simonet, Floriane
Violleau, Jade
Baron, Estelle
Moreau, Eléonore
Scott, Carol
Chatel, Stéphanie
Loussouarn, Gildas
O'Hara, Thomas
Mabo, Philippe
Dina, Christian
Le Marec, Hervé
Schott, Jean‐Jacques
Probst, Vincent
Baró, Isabelle
Marionneau, Céline
Charpentier, Flavien
Redon, Richard
author_facet Portero, Vincent
Le Scouarnec, Solena
Es‐Salah‐Lamoureux, Zeineb
Burel, Sophie
Gourraud, Jean‐Baptiste
Bonnaud, Stéphanie
Lindenbaum, Pierre
Simonet, Floriane
Violleau, Jade
Baron, Estelle
Moreau, Eléonore
Scott, Carol
Chatel, Stéphanie
Loussouarn, Gildas
O'Hara, Thomas
Mabo, Philippe
Dina, Christian
Le Marec, Hervé
Schott, Jean‐Jacques
Probst, Vincent
Baró, Isabelle
Marionneau, Céline
Charpentier, Flavien
Redon, Richard
author_sort Portero, Vincent
collection PubMed
description BACKGROUND: The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown. METHODS AND RESULTS: We combined whole‐exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB2, which encodes the voltage‐gated K(+) channel β2‐subunit (Kvβ2‐R12Q). Kvβ2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K(+) channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB2 variants by using cellular electrophysiology and biochemistry. Patch‐clamp experiments performed in COS‐7 cells expressing both Kv4.3 and Kvβ2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvβ2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvβ2‐R12Q were significantly increased in comparison with wild‐type Kvβ2. CONCLUSIONS: Altogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern.
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spelling pubmed-49372612016-07-18 Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome Portero, Vincent Le Scouarnec, Solena Es‐Salah‐Lamoureux, Zeineb Burel, Sophie Gourraud, Jean‐Baptiste Bonnaud, Stéphanie Lindenbaum, Pierre Simonet, Floriane Violleau, Jade Baron, Estelle Moreau, Eléonore Scott, Carol Chatel, Stéphanie Loussouarn, Gildas O'Hara, Thomas Mabo, Philippe Dina, Christian Le Marec, Hervé Schott, Jean‐Jacques Probst, Vincent Baró, Isabelle Marionneau, Céline Charpentier, Flavien Redon, Richard J Am Heart Assoc Original Research BACKGROUND: The Brugada syndrome is an inherited cardiac arrhythmia associated with high risk of sudden death. Although 20% of patients with Brugada syndrome carry mutations in SCN5A, the molecular mechanisms underlying this condition are still largely unknown. METHODS AND RESULTS: We combined whole‐exome sequencing and linkage analysis to identify the genetic variant likely causing Brugada syndrome in a pedigree for which SCN5A mutations had been excluded. This approach identified 6 genetic variants cosegregating with the Brugada electrocardiographic pattern within the pedigree. In silico gene prioritization pointed to 1 variant residing in KCNAB2, which encodes the voltage‐gated K(+) channel β2‐subunit (Kvβ2‐R12Q). Kvβ2 is widely expressed in the human heart and has been shown to interact with the fast transient outward K(+) channel subunit Kv4.3, increasing its current density. By targeted sequencing of the KCNAB2 gene in 167 unrelated patients with Brugada syndrome, we found 2 additional rare missense variants (L13F and V114I). We then investigated the physiological effects of the 3 KCNAB2 variants by using cellular electrophysiology and biochemistry. Patch‐clamp experiments performed in COS‐7 cells expressing both Kv4.3 and Kvβ2 revealed a significant increase in the current density in presence of the R12Q and L13F Kvβ2 mutants. Although biotinylation assays showed no differences in the expression of Kv4.3, the total and submembrane expression of Kvβ2‐R12Q were significantly increased in comparison with wild‐type Kvβ2. CONCLUSIONS: Altogether, our results indicate that Kvβ2 dysfunction can contribute to the Brugada electrocardiographic pattern. John Wiley and Sons Inc. 2016-06-10 /pmc/articles/PMC4937261/ /pubmed/27287695 http://dx.doi.org/10.1161/JAHA.115.003122 Text en © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Portero, Vincent
Le Scouarnec, Solena
Es‐Salah‐Lamoureux, Zeineb
Burel, Sophie
Gourraud, Jean‐Baptiste
Bonnaud, Stéphanie
Lindenbaum, Pierre
Simonet, Floriane
Violleau, Jade
Baron, Estelle
Moreau, Eléonore
Scott, Carol
Chatel, Stéphanie
Loussouarn, Gildas
O'Hara, Thomas
Mabo, Philippe
Dina, Christian
Le Marec, Hervé
Schott, Jean‐Jacques
Probst, Vincent
Baró, Isabelle
Marionneau, Céline
Charpentier, Flavien
Redon, Richard
Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome
title Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome
title_full Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome
title_fullStr Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome
title_full_unstemmed Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome
title_short Dysfunction of the Voltage‐Gated K(+) Channel β2 Subunit in a Familial Case of Brugada Syndrome
title_sort dysfunction of the voltage‐gated k(+) channel β2 subunit in a familial case of brugada syndrome
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937261/
https://www.ncbi.nlm.nih.gov/pubmed/27287695
http://dx.doi.org/10.1161/JAHA.115.003122
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