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

Stem Cell Reports, vol. 15, pp. 1127–1139

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.

Authors 12

1. Karina O. Brandão Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

2. Lettine van den Brink Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

3. Duncan C. Miller Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

4. Catarina Grandela Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

5. Berend J. van Meer Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

6. Mervyn P.H. Mol Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

7. Tessa de Korte Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

8. Leon G.J. Tertoolen Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

9. Christine L. Mummery Aachen Department of Anatomy and Embryology

   Leiden University Medical Center

   Affiliation as printed

   Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands

10. Luca Sala

    IRCCS Istituto Auxologico Italiano

    Affiliation as printed

    Istituto Auxologico Italiano, IRCCS, Laboratory of Cardiovascular Genetics, 20095 Milan, Italy

11. Arie O. Verkerk

    Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers · University of Amsterdam

    Affiliation as printed

    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

    Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, 1105AZ Amsterdam, The Netherlands

    Department of Medical Biology, Amsterdam UMC, University of Amsterdam, 1105AZ Amsterdam, The Netherlands

12. Richard P. Davis corresponding Aachen Department of Anatomy and Embryology

    Leiden University Medical Center

    Affiliation as printed

    Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands. Electronic address: r.p.davis@lumc.nl

    Department of Anatomy and Embryology, Leiden University Medical Center, 2300RC Leiden, The Netherlands