@article{fdb51913b20f4c2e852477402cb39ee2,
title = "Isogenic Sets of hiPSC-CMs Harboring Distinct KCNH2 Mutations Differ Functionally and in Susceptibility to Drug-Induced Arrhythmias",
abstract = "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.",
keywords = "arrhythmia, disease modeling, electrophysiology, genome editing, induced pluripotent stem cells, isogenic, long QT syndrome 2, risk stratification",
author = "Brand{\~a}o, {Karina O.} and {van den Brink}, Lettine and Miller, {Duncan C.} and Catarina Grandela and {van Meer}, {Berend J.} and Mol, {Mervyn P.H.} and {de Korte}, Tessa and Tertoolen, {Leon G.J.} and Mummery, {Christine L.} and Luca Sala and Verkerk, {Arie O.} and Davis, {Richard P.}",
note = "Funding Information: We thank M. Gomes Fernandes for assistance with immunofluorescence images, J. Goeman for statistical advice, A. Krotenberg for technical assistance in performing the optical recordings, Y. Ge for help with western blots, and M. Bellin for providing the control (LUMC0020iCTRL) hiPSC line and constructive comments on the manuscript. We also acknowledge Niels Geijsen for providing the Cas9 protein. The graphical abstract was created with BioRender.com . Funding: This work was supported by a Starting Grant (STEMCARDIORISK) from the European Research Council (ERC) under the European Union's Horizon 2020 Research And Innovation Programme (H2020 European Research Council; grant agreement no. 638030 ), and a VIDI fellowship from the Netherlands Organisation for Scientific Research ( Nederlandse Organisatie voor Wetenschappelijk Onderzoek NWO; ILLUMINATE; no. 91715303 ), and the Marie Sk{\l}odowska-Curie Individual Fellowship (H2020-MSCA-IF-2017; no. 795209 to L.S.). Publisher Copyright: {\textcopyright} 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = nov,
day = "10",
doi = "10.1016/j.stemcr.2020.10.005",
language = "English",
volume = "15",
pages = "1127--1139",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "5",
}