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Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome

Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndro...

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Autores principales: Bellin, Milena, Casini, Simona, Davis, Richard P, D'Aniello, Cristina, Haas, Jessica, Ward-van Oostwaard, Dorien, Tertoolen, Leon G J, Jung, Christian B, Elliott, David A, Welling, Andrea, Laugwitz, Karl-Ludwig, Moretti, Alessandra, Mummery, Christine L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: European Molecular Biology Organization 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981141/
https://www.ncbi.nlm.nih.gov/pubmed/24213244
http://dx.doi.org/10.1038/emboj.2013.240
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author Bellin, Milena
Casini, Simona
Davis, Richard P
D'Aniello, Cristina
Haas, Jessica
Ward-van Oostwaard, Dorien
Tertoolen, Leon G J
Jung, Christian B
Elliott, David A
Welling, Andrea
Laugwitz, Karl-Ludwig
Moretti, Alessandra
Mummery, Christine L
author_facet Bellin, Milena
Casini, Simona
Davis, Richard P
D'Aniello, Cristina
Haas, Jessica
Ward-van Oostwaard, Dorien
Tertoolen, Leon G J
Jung, Christian B
Elliott, David A
Welling, Andrea
Laugwitz, Karl-Ludwig
Moretti, Alessandra
Mummery, Christine L
author_sort Bellin, Milena
collection PubMed
description Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (I(Kr)) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced I(Kr) and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype.
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spelling pubmed-39811412014-04-09 Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome Bellin, Milena Casini, Simona Davis, Richard P D'Aniello, Cristina Haas, Jessica Ward-van Oostwaard, Dorien Tertoolen, Leon G J Jung, Christian B Elliott, David A Welling, Andrea Laugwitz, Karl-Ludwig Moretti, Alessandra Mummery, Christine L EMBO J Article Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (I(Kr)) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced I(Kr) and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype. European Molecular Biology Organization 2013-12-11 2013-11-08 /pmc/articles/PMC3981141/ /pubmed/24213244 http://dx.doi.org/10.1038/emboj.2013.240 Text en Copyright © 2013, European Molecular Biology Organization https://creativecommons.org/licenses/by/3.0/This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/ (https://creativecommons.org/licenses/by/3.0/) .
spellingShingle Article
Bellin, Milena
Casini, Simona
Davis, Richard P
D'Aniello, Cristina
Haas, Jessica
Ward-van Oostwaard, Dorien
Tertoolen, Leon G J
Jung, Christian B
Elliott, David A
Welling, Andrea
Laugwitz, Karl-Ludwig
Moretti, Alessandra
Mummery, Christine L
Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome
title Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome
title_full Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome
title_fullStr Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome
title_full_unstemmed Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome
title_short Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome
title_sort isogenic human pluripotent stem cell pairs reveal the role of a kcnh2 mutation in long-qt syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3981141/
https://www.ncbi.nlm.nih.gov/pubmed/24213244
http://dx.doi.org/10.1038/emboj.2013.240
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