R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome
- Autores
- Mesquita, Fernanda C. P.; Arantes, Paulo C.; Kasai Brunswick, Tais H.; Araujo, Dayana S.; Gubert, Fernanda; Monnerat, Gustavo; Silva dos Santos, Danúbia; Neiman, Gabriel; Leitão, Isabela C.; Barbosa, Raiana A. Q.; Coutinho, Jorge L.; Vaz, Isadora M.; dos Santos, Marcus N.; Borgonovo, Tamara; Cruz, Fernando E. S.; Miriuka, Santiago Gabriel; Medei, Emiliano H.; Campos de Carvalho, Antonio C.; Carvalho, Adriana B.
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the IKr inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of IKr on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.
Fil: Mesquita, Fernanda C. P.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Arantes, Paulo C.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Kasai Brunswick, Tais H.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Araujo, Dayana S.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Gubert, Fernanda. Universidade Federal do Rio de Janeiro; Brasil
Fil: Monnerat, Gustavo. Universidade Federal do Rio de Janeiro; Brasil
Fil: Silva dos Santos, Danúbia. Universidade Federal do Rio de Janeiro; Brasil
Fil: Neiman, Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina
Fil: Leitão, Isabela C.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Barbosa, Raiana A. Q.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Coutinho, Jorge L.. National Institute Of Cardiology; Brasil
Fil: Vaz, Isadora M.. Pontificia Universidad Catolica de Parana; Brasil
Fil: dos Santos, Marcus N.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Borgonovo, Tamara. Pontificia Universidad Catolica de Parana; Brasil
Fil: Cruz, Fernando E. S.. National Institute of Cardiology; Brasil
Fil: Miriuka, Santiago Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina
Fil: Medei, Emiliano H.. Universidade Federal do Rio de Janeiro; Brasil
Fil: Campos de Carvalho, Antonio C.. Universidade Federal do Rio de Janeiro; Brasil. National Institute of Cardiology; Brasil. National Institute for Science and Technology in Regenerative Medicine; Brasil
Fil: Carvalho, Adriana B.. Universidade Federal do Rio de Janeiro; Brasil. National Institute for Science and Technology in Regenerative Medicine; Brasil - Materia
-
LONG QT SYNDROME
IPS - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/175631
Ver los metadatos del registro completo
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oai:ri.conicet.gov.ar:11336/175631 |
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CONICET Digital (CONICET) |
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R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndromeMesquita, Fernanda C. P.Arantes, Paulo C.Kasai Brunswick, Tais H.Araujo, Dayana S.Gubert, FernandaMonnerat, GustavoSilva dos Santos, DanúbiaNeiman, GabrielLeitão, Isabela C.Barbosa, Raiana A. Q.Coutinho, Jorge L.Vaz, Isadora M.dos Santos, Marcus N.Borgonovo, TamaraCruz, Fernando E. S.Miriuka, Santiago GabrielMedei, Emiliano H.Campos de Carvalho, Antonio C.Carvalho, Adriana B.LONG QT SYNDROMEIPShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the IKr inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of IKr on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane.Fil: Mesquita, Fernanda C. P.. Universidade Federal do Rio de Janeiro; BrasilFil: Arantes, Paulo C.. Universidade Federal do Rio de Janeiro; BrasilFil: Kasai Brunswick, Tais H.. Universidade Federal do Rio de Janeiro; BrasilFil: Araujo, Dayana S.. Universidade Federal do Rio de Janeiro; BrasilFil: Gubert, Fernanda. Universidade Federal do Rio de Janeiro; BrasilFil: Monnerat, Gustavo. Universidade Federal do Rio de Janeiro; BrasilFil: Silva dos Santos, Danúbia. Universidade Federal do Rio de Janeiro; BrasilFil: Neiman, Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Leitão, Isabela C.. Universidade Federal do Rio de Janeiro; BrasilFil: Barbosa, Raiana A. Q.. Universidade Federal do Rio de Janeiro; BrasilFil: Coutinho, Jorge L.. National Institute Of Cardiology; BrasilFil: Vaz, Isadora M.. Pontificia Universidad Catolica de Parana; BrasilFil: dos Santos, Marcus N.. Universidade Federal do Rio de Janeiro; BrasilFil: Borgonovo, Tamara. Pontificia Universidad Catolica de Parana; BrasilFil: Cruz, Fernando E. S.. National Institute of Cardiology; BrasilFil: Miriuka, Santiago Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; ArgentinaFil: Medei, Emiliano H.. Universidade Federal do Rio de Janeiro; BrasilFil: Campos de Carvalho, Antonio C.. Universidade Federal do Rio de Janeiro; Brasil. National Institute of Cardiology; Brasil. National Institute for Science and Technology in Regenerative Medicine; BrasilFil: Carvalho, Adriana B.. Universidade Federal do Rio de Janeiro; Brasil. National Institute for Science and Technology in Regenerative Medicine; BrasilNature Publishing Group2019-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/175631Mesquita, Fernanda C. P.; Arantes, Paulo C.; Kasai Brunswick, Tais H.; Araujo, Dayana S.; Gubert, Fernanda; et al.; R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome; Nature Publishing Group; Scientific Reports; 9; 1; 12-2019; 1-92045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-55837-winfo:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-019-55837-winfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:06:13Zoai:ri.conicet.gov.ar:11336/175631instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:06:14.05CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
title |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
spellingShingle |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome Mesquita, Fernanda C. P. LONG QT SYNDROME IPS |
title_short |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
title_full |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
title_fullStr |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
title_full_unstemmed |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
title_sort |
R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome |
dc.creator.none.fl_str_mv |
Mesquita, Fernanda C. P. Arantes, Paulo C. Kasai Brunswick, Tais H. Araujo, Dayana S. Gubert, Fernanda Monnerat, Gustavo Silva dos Santos, Danúbia Neiman, Gabriel Leitão, Isabela C. Barbosa, Raiana A. Q. Coutinho, Jorge L. Vaz, Isadora M. dos Santos, Marcus N. Borgonovo, Tamara Cruz, Fernando E. S. Miriuka, Santiago Gabriel Medei, Emiliano H. Campos de Carvalho, Antonio C. Carvalho, Adriana B. |
author |
Mesquita, Fernanda C. P. |
author_facet |
Mesquita, Fernanda C. P. Arantes, Paulo C. Kasai Brunswick, Tais H. Araujo, Dayana S. Gubert, Fernanda Monnerat, Gustavo Silva dos Santos, Danúbia Neiman, Gabriel Leitão, Isabela C. Barbosa, Raiana A. Q. Coutinho, Jorge L. Vaz, Isadora M. dos Santos, Marcus N. Borgonovo, Tamara Cruz, Fernando E. S. Miriuka, Santiago Gabriel Medei, Emiliano H. Campos de Carvalho, Antonio C. Carvalho, Adriana B. |
author_role |
author |
author2 |
Arantes, Paulo C. Kasai Brunswick, Tais H. Araujo, Dayana S. Gubert, Fernanda Monnerat, Gustavo Silva dos Santos, Danúbia Neiman, Gabriel Leitão, Isabela C. Barbosa, Raiana A. Q. Coutinho, Jorge L. Vaz, Isadora M. dos Santos, Marcus N. Borgonovo, Tamara Cruz, Fernando E. S. Miriuka, Santiago Gabriel Medei, Emiliano H. Campos de Carvalho, Antonio C. Carvalho, Adriana B. |
author2_role |
author author author author author author author author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
LONG QT SYNDROME IPS |
topic |
LONG QT SYNDROME IPS |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.1 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the IKr inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of IKr on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane. Fil: Mesquita, Fernanda C. P.. Universidade Federal do Rio de Janeiro; Brasil Fil: Arantes, Paulo C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Kasai Brunswick, Tais H.. Universidade Federal do Rio de Janeiro; Brasil Fil: Araujo, Dayana S.. Universidade Federal do Rio de Janeiro; Brasil Fil: Gubert, Fernanda. Universidade Federal do Rio de Janeiro; Brasil Fil: Monnerat, Gustavo. Universidade Federal do Rio de Janeiro; Brasil Fil: Silva dos Santos, Danúbia. Universidade Federal do Rio de Janeiro; Brasil Fil: Neiman, Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Leitão, Isabela C.. Universidade Federal do Rio de Janeiro; Brasil Fil: Barbosa, Raiana A. Q.. Universidade Federal do Rio de Janeiro; Brasil Fil: Coutinho, Jorge L.. National Institute Of Cardiology; Brasil Fil: Vaz, Isadora M.. Pontificia Universidad Catolica de Parana; Brasil Fil: dos Santos, Marcus N.. Universidade Federal do Rio de Janeiro; Brasil Fil: Borgonovo, Tamara. Pontificia Universidad Catolica de Parana; Brasil Fil: Cruz, Fernando E. S.. National Institute of Cardiology; Brasil Fil: Miriuka, Santiago Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia; Argentina Fil: Medei, Emiliano H.. Universidade Federal do Rio de Janeiro; Brasil Fil: Campos de Carvalho, Antonio C.. Universidade Federal do Rio de Janeiro; Brasil. National Institute of Cardiology; Brasil. National Institute for Science and Technology in Regenerative Medicine; Brasil Fil: Carvalho, Adriana B.. Universidade Federal do Rio de Janeiro; Brasil. National Institute for Science and Technology in Regenerative Medicine; Brasil |
description |
Patient-specific cardiomyocytes obtained from induced pluripotent stem cells (CM-iPSC) offer unprecedented mechanistic insights in the study of inherited cardiac diseases. The objective of this work was to study a type 2 long QT syndrome (LQTS2)-associated mutation (c.1600C > T in KCNH2, p.R534C in hERG) in CM-iPSC. Peripheral blood mononuclear cells were isolated from two patients with the R534C mutation and iPSCs were generated. In addition, the same mutation was inserted in a control iPSC line by genome editing using CRISPR/Cas9. Cells expressed pluripotency markers and showed spontaneous differentiation into the three embryonic germ layers. Electrophysiology demonstrated that action potential duration (APD) of LQTS2 CM-iPSC was significantly longer than that of the control line, as well as the triangulation of the action potentials (AP), implying a longer duration of phase 3. Treatment with the IKr inhibitor E4031 only caused APD prolongation in the control line. Patch clamp showed a reduction of IKr on LQTS2 CM-iPSC compared to control, but channel activation was not significantly affected. Immunofluorescence for hERG demonstrated perinuclear staining in LQTS2 CM-iPSC. In conclusion, CM-iPSC recapitulated the LQTS2 phenotype and our findings suggest that the R534C mutation in KCNH2 leads to a channel trafficking defect to the plasma membrane. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-12 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/175631 Mesquita, Fernanda C. P.; Arantes, Paulo C.; Kasai Brunswick, Tais H.; Araujo, Dayana S.; Gubert, Fernanda; et al.; R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome; Nature Publishing Group; Scientific Reports; 9; 1; 12-2019; 1-9 2045-2322 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/175631 |
identifier_str_mv |
Mesquita, Fernanda C. P.; Arantes, Paulo C.; Kasai Brunswick, Tais H.; Araujo, Dayana S.; Gubert, Fernanda; et al.; R534C mutation in hERG causes a trafficking defect in iPSC-derived cardiomyocytes from patients with type 2 long QT syndrome; Nature Publishing Group; Scientific Reports; 9; 1; 12-2019; 1-9 2045-2322 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41598-019-55837-w info:eu-repo/semantics/altIdentifier/doi/10.1038/s41598-019-55837-w |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Nature Publishing Group |
publisher.none.fl_str_mv |
Nature Publishing Group |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
_version_ |
1844613908462043136 |
score |
13.070432 |