title: The disease-specific phenotype in cardiomyocytes derived from induced pluripotent stem cells of two long QT syndrome type 3 patients.
abstract: 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.
authors.affiliation: Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany.
authors.forename: Azra
authors.initials: A
authors.lastname: Fatima
authors.affiliation: Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany.
authors.forename: Shao
authors.initials: S
authors.lastname: Kaifeng
authors.affiliation: Heart and Diabetes Center NRW, University Hospital of the Ruhr-University of Bochum, Bad Oeynhausen, Germany ; Erich & Hanna Klessmann-Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Dittmann
authors.affiliation: Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany.
authors.forename: Guoxing
authors.initials: G
authors.lastname: Xu
authors.affiliation: Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: Institute for Human Genetics, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Linke
authors.affiliation: Institute for Human Genetics, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zechner
authors.affiliation: Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany.
authors.forename: Filomain
authors.initials: F
authors.lastname: Nguemo
authors.affiliation: Heart and Diabetes Center NRW, University Hospital of the Ruhr-University of Bochum, Bad Oeynhausen, Germany ; Erich & Hanna Klessmann-Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
authors.affiliation: Heart and Diabetes Center NRW, University Hospital of the Ruhr-University of Bochum, Bad Oeynhausen, Germany ; Erich & Hanna Klessmann-Institute for Cardiovascular Research and Development, Bad Oeynhausen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Farr
authors.affiliation: Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Institute for Neurophysiology, Medical Center, University of Cologne, Cologne, Germany.
authors.forename: Tomo
authors.initials: T
authors.lastname: Sarić
mesh_terms: D000200:Action Potentials / Q000235:genetics*; D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human