The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients

Long QT syndromes (LQTS) are heritable diseases characterized by prolongation of the QT interval on an electrocardiogram, which often leads to syncope and sudden cardiac death. Here we report the generation of induced pluripotent stems (iPS) cells from two patients with LQTS type 3 carrying a differ...

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Main Authors:	Fatima, Azra, Kaifeng, Shao, Dittmann, Sven, Xu, Guoxing, Gupta, Manoj K., Linke, Matthias, Zechner, Ulrich, Nguemo, Filomain, Milting, Hendrik, Farr, Martin, Hescheler, Jürgen, Šarić, Tomo
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859612/

id	pubmed-3859612
recordtype	oai_dc
spelling	pubmed-38596122013-12-13 The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients Fatima, Azra Kaifeng, Shao Dittmann, Sven Xu, Guoxing Gupta, Manoj K. Linke, Matthias Zechner, Ulrich Nguemo, Filomain Milting, Hendrik Farr, Martin Hescheler, Jürgen Šarić, Tomo Research Article Long QT syndromes (LQTS) are heritable diseases characterized by prolongation of the QT interval on an electrocardiogram, which often leads to syncope and sudden cardiac death. Here we report the generation of induced pluripotent stems (iPS) cells from two patients with LQTS type 3 carrying a different point mutation in a sodium channel Nav1.5 (p.V240M and p.R535Q) and functional characterization of cardiomyocytes (CM) derived from them. The iPS cells exhibited all characteristic properties of pluripotent stem cells, maintained the disease-specific mutation and readily differentiated to CM. The duration of action potentials at 50% and 90% repolarization was longer in LQTS-3 CM as compared to control CM but this difference did not reach statistical significance due to high variations among cells. Sodium current recordings demonstrated longer time to peak and longer time to 90% of inactivation of the Na+ channel in the LQTS-3 CM. This hints at a defective Na+ channel caused by deficiency in open-state inactivation of the Na+ channel that is characteristic of LQTS-3. These analyses suggest that the effect of channel mutation in the diseased CM is demonstrated in vitro and that the iPS cell-derived CM can serve as a model system for studying the pathophysiology of LQTS-3, toxicity testing and design of novel therapeutics. However, further improvements in the model are still required to reduce cell-to-cell and cell line-to-cell line variability. Public Library of Science 2013-12-11 /pmc/articles/PMC3859612/ /pubmed/24349418 http://dx.doi.org/10.1371/journal.pone.0083005 Text en © 2013 Fatima et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Fatima, Azra Kaifeng, Shao Dittmann, Sven Xu, Guoxing Gupta, Manoj K. Linke, Matthias Zechner, Ulrich Nguemo, Filomain Milting, Hendrik Farr, Martin Hescheler, Jürgen Šarić, Tomo
spellingShingle	Fatima, Azra Kaifeng, Shao Dittmann, Sven Xu, Guoxing Gupta, Manoj K. Linke, Matthias Zechner, Ulrich Nguemo, Filomain Milting, Hendrik Farr, Martin Hescheler, Jürgen Šarić, Tomo The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients
author_facet	Fatima, Azra Kaifeng, Shao Dittmann, Sven Xu, Guoxing Gupta, Manoj K. Linke, Matthias Zechner, Ulrich Nguemo, Filomain Milting, Hendrik Farr, Martin Hescheler, Jürgen Šarić, Tomo
author_sort	Fatima, Azra
title	The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients
title_short	The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients
title_full	The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients
title_fullStr	The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients
title_full_unstemmed	The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients
title_sort	disease-specific phenotype in cardiomyocytes derived from induced pluripotent stem cells of two long qt syndrome type 3 patients
description	Long QT syndromes (LQTS) are heritable diseases characterized by prolongation of the QT interval on an electrocardiogram, which often leads to syncope and sudden cardiac death. Here we report the generation of induced pluripotent stems (iPS) cells from two patients with LQTS type 3 carrying a different point mutation in a sodium channel Nav1.5 (p.V240M and p.R535Q) and functional characterization of cardiomyocytes (CM) derived from them. The iPS cells exhibited all characteristic properties of pluripotent stem cells, maintained the disease-specific mutation and readily differentiated to CM. The duration of action potentials at 50% and 90% repolarization was longer in LQTS-3 CM as compared to control CM but this difference did not reach statistical significance due to high variations among cells. Sodium current recordings demonstrated longer time to peak and longer time to 90% of inactivation of the Na+ channel in the LQTS-3 CM. This hints at a defective Na+ channel caused by deficiency in open-state inactivation of the Na+ channel that is characteristic of LQTS-3. These analyses suggest that the effect of channel mutation in the diseased CM is demonstrated in vitro and that the iPS cell-derived CM can serve as a model system for studying the pathophysiology of LQTS-3, toxicity testing and design of novel therapeutics. However, further improvements in the model are still required to reduce cell-to-cell and cell line-to-cell line variability.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3859612/
_version_	1612037503218352128

The Disease-Specific Phenotype in Cardiomyocytes Derived from Induced Pluripotent Stem Cells of Two Long QT Syndrome Type 3 Patients

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