Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
dc.contributor.author
dc.date.accessioned
2018-02-05T12:05:50Z
dc.date.available
2018-02-05T12:05:50Z
dc.date.issued
2017-10-09
dc.identifier.issn
0022-2828
dc.identifier.uri
dc.description.abstract
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
dc.format.extent
10 p.
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application/pdf
dc.language.iso
eng
dc.publisher
Elsevier
dc.relation.isformatof
Reproducció digital del document publicat a: https://doi.org/10.1016/j.yjmcc.2017.10.002
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Journal of Molecular and Cellular Cardiology, 2017, vol. 114, p. 10-19
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Articles publicats (D-CM)
dc.rights
Reconeixement 4.0 Internacional
dc.rights.uri
dc.source
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
dc.subject
dc.title
Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.type.version
info:eu-repo/semantics/acceptedVersion
dc.identifier.doi
dc.identifier.idgrec
027345