Isogenic Sets of hiPSC-CMs Harboring Distinct KCNH2 Mutations Differ Functionally and in Susceptibility to Drug-Induced Arrhythmias.

Autor:	Brandão KO; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., van den Brink L; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., Miller DC; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., Grandela C; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., van Meer BJ; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., Mol MPH; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., de Korte T; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., Tertoolen LGJ; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., Mummery CL; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands., Sala L; Istituto Auxologico Italiano, IRCCS, Laboratory of Cardiovascular Genetics, 20095 Milan, Italy., Verkerk AO; Department of Medical Biology, Amsterdam UMC, University of Amsterdam, 1105AZ Amsterdam, The Netherlands; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, 1105AZ Amsterdam, The Netherlands., Davis RP; Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands. Electronic address: r.p.davis@lumc.nl.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2020 Nov 10; Vol. 15 (5), pp. 1127-1139.
DOI:	10.1016/j.stemcr.2020.10.005
Abstrakt:	Mutations in KCNH2 can lead to long QT syndrome type 2. Variable disease manifestation observed with this channelopathy is associated with the location and type of mutation within the protein, complicating efforts to predict patient risk. Here, we demonstrated phenotypic differences in cardiomyocytes derived from isogenic human induced pluripotent stem cells (hiPSC-CMs) genetically edited to harbor mutations either within the pore or tail region of the ion channel. Electrophysiological analysis confirmed that the mutations prolonged repolarization of the hiPSC-CMs, with differences between the mutations evident in monolayer cultures. Blocking the hERG channel revealed that the pore-loop mutation conferred greater susceptibility to arrhythmic events. These findings showed that subtle phenotypic differences related to KCNH2 mutations could be captured by hiPSC-CMs under genetically matched conditions. Moreover, the results support hiPSC-CMs as strong candidates for evaluating the underlying severity of individual KCNH2 mutations in humans, which could facilitate patient risk stratification. (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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