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Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes
- Source :
- Journal of Clinical Medicine Research, Journal of Clinical Medicine Research, Elmer Press, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine Research, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Journal of Clinical Medicine, MDPI, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Vol 7, Iss 11, p 423 (2018), Journal of clinical medicine, vol 7, iss 11, Journal of Clinical Medicine; Volume 7; Issue 11; Pages: 423
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
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.
- Subjects :
- 0301 basic medicine
[SDV]Life Sciences [q-bio]
CPVT
ryanodine receptor
hiPSC-derived cardiomyocytes
calcium
β-adrenergic receptor blockade
flecainide
post-translational modifications
Clinical Sciences
lcsh:Medicine
030204 cardiovascular system & hematology
Cardiovascular
medicine.disease_cause
Catecholaminergic polymorphic ventricular tachycardia
Ventricular tachycardia
Ryanodine receptor 2
Article
03 medical and health sciences
0302 clinical medicine
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
medicine
[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology
2.1 Biological and endogenous factors
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Aetiology
beta-adrenergic receptor blockade
Flecainide
ComputingMilieux_MISCELLANEOUS
Metoprolol
Mutation
Stem Cell Research - Induced Pluripotent Stem Cell
Stem Cell Research - Induced Pluripotent Stem Cell - Human
Ryanodine receptor
business.industry
Endoplasmic reticulum
lcsh:R
General Medicine
Stem Cell Research
medicine.disease
3. Good health
Cell biology
[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Heart Disease
030104 developmental biology
cardiovascular system
business
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 19183003, 19183011, and 20770383
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Medicine Research, Journal of Clinical Medicine Research, Elmer Press, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine Research, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Journal of Clinical Medicine, MDPI, 2018, 7 (11), pp.423. ⟨10.3390/jcm7110423⟩, Journal of Clinical Medicine, Vol 7, Iss 11, p 423 (2018), Journal of clinical medicine, vol 7, iss 11, Journal of Clinical Medicine; Volume 7; Issue 11; Pages: 423
- Accession number :
- edsair.doi.dedup.....2745d8a809abd3269f2570e77b1e9281
- Full Text :
- https://doi.org/10.3390/jcm7110423⟩