| AĆIMOVIĆ, Ivana, Marwan M. REFAAT, Adrien MOREAU, Anton SALYKIN, Steve REIKEN, Yvonne SLEIMAN, Monia SOUIDI, Jan PŘIBYL, Andrey V. KAJAVA, Sylvian RICHARD, Jonathan T. LU, Philippe CHEVALIER, Petr SKLÁDAL, Petr DVOŘÁK, Vladimír ROTREKL, Andrew R. MARKS, Melvin M. SCHEINMAN, Alain LACAMPAGNE and Albano C. MELI. Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes. JOURNAL OF CLINICAL MEDICINE. BASEL: MDPI, 2018, vol. 7, No 11, p. 1-22. ISSN 2077-0383. Available from: https://dx.doi.org/10.3390/jcm7110423. |
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@article{1490185,
author = {Aćimović, Ivana and Refaat, Marwan M. and Moreau, Adrien and Salykin, Anton and Reiken, Steve and Sleiman, Yvonne and Souidi, Monia and Přibyl, Jan and Kajava, Andrey V. and Richard, Sylvian and Lu, Jonathan T. and Chevalier, Philippe and Skládal, Petr and Dvořák, Petr and Rotrekl, Vladimír and Marks, Andrew R. and Scheinman, Melvin M. and Lacampagne, Alain and Meli, Albano C.},
article_location = {BASEL},
article_number = {11},
doi = {http://dx.doi.org/10.3390/jcm7110423},
keywords = {ryanodine receptor; CPVT; hiPSC-derived cardiomyocytes; calcium; beta-adrenergic receptor blockade; flecainide; post-translational modifications},
language = {eng},
issn = {2077-0383},
journal = {JOURNAL OF CLINICAL MEDICINE},
title = {Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes},
volume = {7},
year = {2018}
}
TY - JOUR
ID - 1490185
AU - Aćimović, Ivana - Refaat, Marwan M. - Moreau, Adrien - Salykin, Anton - Reiken, Steve - Sleiman, Yvonne - Souidi, Monia - Přibyl, Jan - Kajava, Andrey V. - Richard, Sylvian - Lu, Jonathan T. - Chevalier, Philippe - Skládal, Petr - Dvořák, Petr - Rotrekl, Vladimír - Marks, Andrew R. - Scheinman, Melvin M. - Lacampagne, Alain - Meli, Albano C.
PY - 2018
TI - Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes
JF - JOURNAL OF CLINICAL MEDICINE
VL - 7
IS - 11
SP - 1-22
EP - 1-22
PB - MDPI
SN - 20770383
KW - ryanodine receptor
KW - CPVT
KW - hiPSC-derived cardiomyocytes
KW - calcium
KW - beta-adrenergic receptor blockade
KW - flecainide
KW - post-translational modifications
N2 - 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.
ER -
A$\backslash$'CIMOVI$\backslash$'C, Ivana, Marwan M. REFAAT, Adrien MOREAU, Anton SALYKIN, Steve REIKEN, Yvonne SLEIMAN, Monia SOUIDI, Jan PŘIBYL, Andrey V. KAJAVA, Sylvian RICHARD, Jonathan T. LU, Philippe CHEVALIER, Petr SKLÁDAL, Petr DVOŘÁK, Vladimír ROTREKL, Andrew R. MARKS, Melvin M. SCHEINMAN, Alain LACAMPAGNE and Albano C. MELI. Post-Translational Modifications and Diastolic Calcium Leak Associated to the Novel RyR2-D3638A Mutation Lead to CPVT in Patient-Specific hiPSC-Derived Cardiomyocytes. \textit{JOURNAL OF CLINICAL MEDICINE}. BASEL: MDPI, 2018, vol.~7, No~11, p.~1-22. ISSN~2077-0383. Available from: https://dx.doi.org/10.3390/jcm7110423.
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