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Open AccessArticle

hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells

1
Faculty of Medicine and Health Technology and BioMediTech Institute, Tampere University, 33520 Tampere, Finland
2
Heart Hospital, Tampere University Hospital, 33520 Tampere, Finland
*
Author to whom correspondence should be addressed.
Cells 2020, 9(5), 1153; https://doi.org/10.3390/cells9051153
Received: 26 February 2020 / Revised: 29 April 2020 / Accepted: 2 May 2020 / Published: 7 May 2020
(This article belongs to the Special Issue Stem Cell-based Therapy and Disease Modeling)
Mutations in the HERG gene encoding the potassium ion channel HERG, represent one of the most frequent causes of long QT syndrome type-2 (LQT2). The same genetic mutation frequently presents different clinical phenotypes in the family. Our study aimed to model LQT2 and study functional differences between the mutation carriers of variable clinical phenotypes. We derived human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) from asymptomatic and symptomatic HERG mutation carriers from the same family. When comparing asymptomatic and symptomatic single LQT2 hiPSC-CMs, results from allelic imbalance, potassium current density, and arrhythmicity on adrenaline exposure were similar, but a difference in Ca2+ transients was observed. The major differences were, however, observed at aggregate level with increased susceptibility to arrhythmias on exposure to adrenaline or potassium channel blockers on CM aggregates derived from the symptomatic individual. The effect of this mutation was modeled in-silico which indicated the reactivation of an inward calcium current as one of the main causes of arrhythmia. Our in-vitro hiPSC-CM model recapitulated major phenotype characteristics observed in LQT2 mutation carriers and strong phenotype differences between LQT2 asymptomatic vs. symptomatic were revealed at CM-aggregate level. View Full-Text
Keywords: HERG; LQT2; channelopathies; in vitro electrophysiology; arrhythmia; induced pluripotent stem cells; in-silico modeling HERG; LQT2; channelopathies; in vitro electrophysiology; arrhythmia; induced pluripotent stem cells; in-silico modeling
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Shah, D.; Prajapati, C.; Penttinen, K.; Cherian, R.M.; Koivumäki, J.T.; Alexanova, A.; Hyttinen, J.; Aalto-Setälä, K. hiPSC-Derived Cardiomyocyte Model of LQT2 Syndrome Derived from Asymptomatic and Symptomatic Mutation Carriers Reproduces Clinical Differences in Aggregates but Not in Single Cells. Cells 2020, 9, 1153.

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