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J. Clin. Med. 2018, 7(11), 423; https://doi.org/10.3390/jcm7110423

Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes

1
Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic
2
Department of Internal Medicine, Cardiology Division/Cardiac Electrophysiology Section and Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine and Medical Center, Beirut 1107 2020, Lebanon
3
NeuroMyoGène Institute, University of Claude Bernard Lyon 1, 69100 Villeurbanne, France
4
PhyMedExp, INSERM, University of Montpellier, CNRS, 371 Avenue du Doyen G. Giraud, 34295 Montpellier CEDEX 5, France
5
Department of Physiology and Cellular Biophysics, Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA
6
CEITEC, Masaryk University, Brno 62500, Czech Republic
7
CRBM, CNRS, University of Montpellier, 34293 Montpellier, France and University ITMO, St Petersburg 197101, Russia
8
Department of Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA
9
International Clinical Research Center, St. Anne’s University Hospital, Brno 60200, Czech Republic
10
San Francisco Medical Center, University of California, San Francisco, CA 94115, USA
*
Authors to whom correspondence should be addressed.
Received: 19 October 2018 / Revised: 31 October 2018 / Accepted: 4 November 2018 / Published: 8 November 2018
(This article belongs to the Section Molecular Medicine)
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Abstract

Background: Sarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. Objective: The aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome. Methods: Patient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied. Results: Exercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2. Conclusion: We identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband’s resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms. View Full-Text
Keywords: ryanodine receptor; CPVT; hiPSC-derived cardiomyocytes; calcium; β-adrenergic receptor blockade; flecainide; post-translational modifications ryanodine receptor; CPVT; hiPSC-derived cardiomyocytes; calcium; β-adrenergic receptor blockade; flecainide; post-translational modifications
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Acimovic, I.; Refaat, M.M.; Moreau, A.; Salykin, A.; Reiken, S.; Sleiman, Y.; Souidi, M.; Přibyl, J.; Kajava, A.V.; Richard, S.; Lu, J.T.; Chevalier, P.; Skládal, P.; Dvořak, P.; Rotrekl, V.; Marks, A.R.; Scheinman, M.M.; Lacampagne, A.; Meli, A.C. Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes. J. Clin. Med. 2018, 7, 423.

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