Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient

Brugada syndrome predisposes to sudden death due to disruption of normal cardiac ion channel function, yet our understanding of the underlying cellular mechanisms is incomplete. Commonly used heterologous expression models lack many characteristics of native cardiomyocytes and, in particular, the in...

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Autores: Selga Coma, Elisabet, Sendfeld, Franziska, Martínez Moreno, Rebecca, Medine, Claire N., Tura-Ceide, Olga, Wilmut, Ian, Pérez González, Guillermo J., Scornik, Fabiana S., Brugada, Ramon, Mills, Nicholas L.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/14982
Acceso en línea:http://hdl.handle.net/10256/14982
Access Level:acceso abierto
Palabra clave:Electrofisiologia
Cardiologia
Cèl·lules mare
Electrophysiology
Cardiology
Stem cells
Brugada, Síndrome de
Brugada syndrome
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repository_id_str
spelling Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patientSelga Coma, ElisabetSendfeld, FranziskaMartínez Moreno, RebeccaMedine, Claire N.Tura-Ceide, OlgaWilmut, IanPérez González, Guillermo J.Scornik, Fabiana S.Brugada, RamonMills, Nicholas L.ElectrofisiologiaCardiologiaCèl·lules mareElectrophysiologyCardiologyStem cellsBrugada, Síndrome deBrugada syndromeBrugada syndrome predisposes to sudden death due to disruption of normal cardiac ion channel function, yet our understanding of the underlying cellular mechanisms is incomplete. Commonly used heterologous expression models lack many characteristics of native cardiomyocytes and, in particular, the individual genetic background of a patient. Patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPS-CM) may uncover cellular phenotypical characteristics not observed in heterologous models. Our objective was to determine the properties of the sodium current in iPS-CM with a mutation in SCN5A associated with Brugada syndrome. Dermal fibroblasts from a Brugada syndrome patient with a mutation in SCN5A (c.1100G>A, leading to Nav1.5_p.R367H) were reprogrammed to iPS cells. Clones were characterized and differentiated to form beating clusters and sheets. Patient and control iPS-CM were structurally indistinguishable. Sodium current properties of patient and control iPS-CM were compared. These results were contrasted with those obtained in tsA201 cells heterologously expressing sodium channels with the same mutation. Patient-derived iPS-CM showed a 33.1-45.5% reduction in INa density, a shift in both activation and inactivation voltage-dependence curves, and faster recovery from inactivation. Co-expression of wild-type and mutant channels in tsA201 cells did not compromise channel trafficking to the membrane, but resulted in a reduction of 49.8% in sodium current density without affecting any other parameters. Cardiomyocytes derived from iPS cells from a Brugada syndrome patient with a mutation in SCN5A recapitulate the loss of function of sodium channel current associated with this syndrome; including pro-arrhythmic changes in channel function not detected using conventional heterologous expression systemsElsevier2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion10 p.application/pdfhttp://hdl.handle.net/10256/14982Journal of Molecular and Cellular Cardiology, 2017, vol. 114, p. 10-19Articles publicats (D-CM)Selga Coma, Elisabet Sendfeld, Franziska Martínez Moreno, Rebecca Medine, Claire N. Tura Ceide, Olga Wilmut, Ian Pérez González, Guillermo J. Scornik, Fabiana S. Brugada, Ramon Mills, Nicholas L. 2017 Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient Journal of Molecular and Cellular Cardiology 114 10 19reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.yjmcc.2017.10.002info:eu-repo/semantics/altIdentifier/issn/0022-2828Reconeixement 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0info:eu-repo/semantics/openAccessoai:recercat.cat:10256/149822026-05-29T05:05:01Z
dc.title.none.fl_str_mv Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
title Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
spellingShingle Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
Selga Coma, Elisabet
Electrofisiologia
Cardiologia
Cèl·lules mare
Electrophysiology
Cardiology
Stem cells
Brugada, Síndrome de
Brugada syndrome
title_short Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
title_full Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
title_fullStr Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
title_full_unstemmed Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
title_sort Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
dc.creator.none.fl_str_mv Selga Coma, Elisabet
Sendfeld, Franziska
Martínez Moreno, Rebecca
Medine, Claire N.
Tura-Ceide, Olga
Wilmut, Ian
Pérez González, Guillermo J.
Scornik, Fabiana S.
Brugada, Ramon
Mills, Nicholas L.
author Selga Coma, Elisabet
author_facet Selga Coma, Elisabet
Sendfeld, Franziska
Martínez Moreno, Rebecca
Medine, Claire N.
Tura-Ceide, Olga
Wilmut, Ian
Pérez González, Guillermo J.
Scornik, Fabiana S.
Brugada, Ramon
Mills, Nicholas L.
author_role author
author2 Sendfeld, Franziska
Martínez Moreno, Rebecca
Medine, Claire N.
Tura-Ceide, Olga
Wilmut, Ian
Pérez González, Guillermo J.
Scornik, Fabiana S.
Brugada, Ramon
Mills, Nicholas L.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Electrofisiologia
Cardiologia
Cèl·lules mare
Electrophysiology
Cardiology
Stem cells
Brugada, Síndrome de
Brugada syndrome
topic Electrofisiologia
Cardiologia
Cèl·lules mare
Electrophysiology
Cardiology
Stem cells
Brugada, Síndrome de
Brugada syndrome
description Brugada syndrome predisposes to sudden death due to disruption of normal cardiac ion channel function, yet our understanding of the underlying cellular mechanisms is incomplete. Commonly used heterologous expression models lack many characteristics of native cardiomyocytes and, in particular, the individual genetic background of a patient. Patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (iPS-CM) may uncover cellular phenotypical characteristics not observed in heterologous models. Our objective was to determine the properties of the sodium current in iPS-CM with a mutation in SCN5A associated with Brugada syndrome. Dermal fibroblasts from a Brugada syndrome patient with a mutation in SCN5A (c.1100G>A, leading to Nav1.5_p.R367H) were reprogrammed to iPS cells. Clones were characterized and differentiated to form beating clusters and sheets. Patient and control iPS-CM were structurally indistinguishable. Sodium current properties of patient and control iPS-CM were compared. These results were contrasted with those obtained in tsA201 cells heterologously expressing sodium channels with the same mutation. Patient-derived iPS-CM showed a 33.1-45.5% reduction in INa density, a shift in both activation and inactivation voltage-dependence curves, and faster recovery from inactivation. Co-expression of wild-type and mutant channels in tsA201 cells did not compromise channel trafficking to the membrane, but resulted in a reduction of 49.8% in sodium current density without affecting any other parameters. Cardiomyocytes derived from iPS cells from a Brugada syndrome patient with a mutation in SCN5A recapitulate the loss of function of sodium channel current associated with this syndrome; including pro-arrhythmic changes in channel function not detected using conventional heterologous expression systems
publishDate 2017
dc.date.none.fl_str_mv 2017
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10256/14982
url http://hdl.handle.net/10256/14982
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.yjmcc.2017.10.002
info:eu-repo/semantics/altIdentifier/issn/0022-2828
dc.rights.none.fl_str_mv Reconeixement 4.0 Internacional
http://creativecommons.org/licenses/by/4.0
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Reconeixement 4.0 Internacional
http://creativecommons.org/licenses/by/4.0
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 10 p.
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Journal of Molecular and Cellular Cardiology, 2017, vol. 114, p. 10-19
Articles publicats (D-CM)
Selga Coma, Elisabet Sendfeld, Franziska Martínez Moreno, Rebecca Medine, Claire N. Tura Ceide, Olga Wilmut, Ian Pérez González, Guillermo J. Scornik, Fabiana S. Brugada, Ramon Mills, Nicholas L. 2017 Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient Journal of Molecular and Cellular Cardiology 114 10 19
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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