{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:42:23Z","timestamp":1792114943927,"version":"4.4.0"},"reference-count":38,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,8]],"date-time":"2018-11-08T00:00:00Z","timestamp":1541635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"South Moravian Centre for International Mobility","award":["2SGA2744"],"award-info":[{"award-number":["2SGA2744"]}]},{"DOI":"10.13039\/501100000860","name":"European Society of Cardiology","doi-asserted-by":"publisher","award":["R12042FF"],"award-info":[{"award-number":["R12042FF"]}],"id":[{"id":"10.13039\/501100000860","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007393","name":"Association Fran\u00e7aise contre les Myopathies","doi-asserted-by":"publisher","award":["16073"],"award-info":[{"award-number":["16073"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007393","name":"Association Fran\u00e7aise contre les Myopathies","doi-asserted-by":"publisher","award":["20225"],"award-info":[{"award-number":["20225"]}],"id":[{"id":"10.13039\/100007393","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["SPF20130526710"],"award-info":[{"award-number":["SPF20130526710"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["P302\/12\/G157"],"award-info":[{"award-number":["P302\/12\/G157"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/jcm7110423","type":"journal-article","created":{"date-parts":[[2018,11,9]],"date-time":"2018-11-09T03:08:02Z","timestamp":1541732882000},"page":"423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes"],"prefix":"10.3390","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6992-3274","authenticated-orcid":false,"given":"Ivana","family":"Acimovic","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwan","family":"Refaat","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrien","family":"Moreau","sequence":"additional","affiliation":[{"name":"NeuroMyoG\u00e8ne Institute, University of Claude Bernard Lyon 1, 69100 Villeurbanne, France"},{"name":"PhyMedExp, INSERM, University of Montpellier, CNRS, 371 Avenue du Doyen G. Giraud, 34295 Montpellier CEDEX 5, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anton","family":"Salykin","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Reiken","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1550-8945","authenticated-orcid":false,"given":"Yvonne","family":"Sleiman","sequence":"additional","affiliation":[{"name":"PhyMedExp, INSERM, University of Montpellier, CNRS, 371 Avenue du Doyen G. Giraud, 34295 Montpellier CEDEX 5, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monia","family":"Souidi","sequence":"additional","affiliation":[{"name":"PhyMedExp, INSERM, University of Montpellier, CNRS, 371 Avenue du Doyen G. Giraud, 34295 Montpellier CEDEX 5, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1232-3694","authenticated-orcid":false,"given":"Jan","family":"P\u0159ibyl","sequence":"additional","affiliation":[{"name":"CEITEC, Masaryk University, Brno 62500, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2342-6886","authenticated-orcid":false,"given":"Andrey","family":"Kajava","sequence":"additional","affiliation":[{"name":"CRBM, CNRS, University of Montpellier, 34293 Montpellier, France and University ITMO, St Petersburg 197101, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9460-6705","authenticated-orcid":false,"given":"Sylvain","family":"Richard","sequence":"additional","affiliation":[{"name":"PhyMedExp, INSERM, University of Montpellier, CNRS, 371 Avenue du Doyen G. Giraud, 34295 Montpellier CEDEX 5, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Chevalier","sequence":"additional","affiliation":[{"name":"NeuroMyoG\u00e8ne Institute, University of Claude Bernard Lyon 1, 69100 Villeurbanne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Skl\u00e1dal","sequence":"additional","affiliation":[{"name":"CEITEC, Masaryk University, Brno 62500, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petr","family":"Dvo\u0159ak","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1298-0849","authenticated-orcid":false,"given":"Vladimir","family":"Rotrekl","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Medicine, Masaryk University, Brno 62500, Czech Republic"},{"name":"International Clinical Research Center, St. Anne\u2019s University Hospital, Brno 60200, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Marks","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melvin","family":"Scheinman","sequence":"additional","affiliation":[{"name":"San Francisco Medical Center, University of California, San Francisco, CA 94115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Lacampagne","sequence":"additional","affiliation":[{"name":"PhyMedExp, INSERM, University of Montpellier, CNRS, 371 Avenue du Doyen G. 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