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Article

Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

1
Department of Experimental Cardiology, Masonic Medical Research Institute, Utica, NY 13501, USA
2
Department of Cardiovascular Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA
3
Nanion Technologies, 1 Naylon Ave. Suite C, Livingston, NJ 07039, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Ofer Binah
Int. J. Mol. Sci. 2021, 22(13), 7108; https://doi.org/10.3390/ijms22137108
Received: 3 May 2021 / Revised: 7 June 2021 / Accepted: 24 June 2021 / Published: 1 July 2021
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are used for genetic models of cardiac diseases. We report an arrhythmia syndrome consisting of Early Repolarization Syndrome (ERS) and Short QT Syndrome (SQTS). The index patient (MMRL1215) developed arrhythmia-mediated syncope after electrocution and was found to carry six mutations. Functional alterations resulting from these mutations were examined in patient-derived hiPSC-CMs. Electrophysiological recordings were made in hiPSC-CMs from MMRL1215 and healthy controls. ECG analysis of the index patient showed slurring of the QRS complex and QTc = 326 ms. Action potential (AP) recordings from MMRL1215 myocytes showed slower spontaneous activity and AP duration was shorter. Field potential recordings from MMRL1215 hiPSC-CMs lack a “pseudo” QRS complex suggesting reduced inward current(s). Voltage clamp analysis of ICa showed no difference in the magnitude of current. Measurements of INa reveal a 60% reduction in INa density in MMRL1215 hiPSC-CMs. Steady inactivation and recovery of INa was unaffected. mRNA analysis revealed ANK2 and SCN5A are significantly reduced in hiPSC-CM derived from MMRL1215, consistent with electrophysiological recordings. The polygenic cause of ERS/SQTS phenotype is likely due to a loss of INa due to a mutation in PKP2 coupled with and a gain of function in IK,ATP due to a mutation in ABCC9. View Full-Text
Keywords: action potentials; depolarization; electrophysiology; sodium current; stem cells action potentials; depolarization; electrophysiology; sodium current; stem cells
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MDPI and ACS Style

Treat, J.A.; Pfeiffer, R.; Barajas-Martinez, H.; Goodrow, R.J.; Bot, C.; Haedo, R.J.; Knox, R.; Cordeiro, J.M. Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Int. J. Mol. Sci. 2021, 22, 7108. https://doi.org/10.3390/ijms22137108

AMA Style

Treat JA, Pfeiffer R, Barajas-Martinez H, Goodrow RJ, Bot C, Haedo RJ, Knox R, Cordeiro JM. Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. International Journal of Molecular Sciences. 2021; 22(13):7108. https://doi.org/10.3390/ijms22137108

Chicago/Turabian Style

Treat, Jacqueline A., Ryan Pfeiffer, Hector Barajas-Martinez, Robert J. Goodrow, Corina Bot, Rodolfo J. Haedo, Ronald Knox, and Jonathan M. Cordeiro 2021. "Overlap Arrhythmia Syndromes Resulting from Multiple Genetic Variations Studied in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes" International Journal of Molecular Sciences 22, no. 13: 7108. https://doi.org/10.3390/ijms22137108

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