A recessive ryanodine receptor 1 mutation in a CCD patient increases channel activity |
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| Authors: | Farshid Ghassemi Mirko Vukcevic Le Xu Haiyan Zhou Gerhard Meissner Francesco Muntoni Heinz Jungbluth Francesco Zorzato Susan Treves |
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| Institution: | 1. Genetics Research Centre, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran;2. Kariminejad-Najmabadi Pathology & Genetics Center, Tehran, Iran;3. Department of Neurology, Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran;4. Shiraz University of Medical Science, Shiraz, Iran;5. Women''s College Research Institute, Women''s College Hospital, University of Toronto, Toronto, ON, Canada;6. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada;7. Dr. Goodarzi Medical Genetics Center, Shiraz, Iran;1. Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesu'' Children''s Research Hospital, Rome, Italy;2. Institute of Neurology, Catholic University School of Medicine, Rome, Italy;3. Centre de Référence des Maladies Neuromusculaires, Neurology Department, Centre Hospitalier Universitaire d''Angers, Angers, France;4. Scanner et IRM de la Roseraie, Angers, France;5. Copenhagen Neuromuscular Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark;1. Department of Biomedical Sciences for Health, IRCCS Policlinico San Donato, University of Milan, Italy;2. Department of Health Science, University of Milan Bicocca, Italy;3. Department of Neurology, Penn State Hershey Medical Center, Hershey, PA, USA;4. Laboratory of Stem Cells for Tissue Engineering, IRCCS Policlinico San Donato, Italy;5. Department of Translational Surgeon and Medicine, University of Milan Bicocca, Italy;6. Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy;7. Laboratory of Muscle Histopathology and Molecular Biology, IRCCS Policlinico San Donato, Italy;1. Unit of Muscular and Neurodegenerative Disorders, Department of Neurosciences and Neurorehabilitation, Bambino Gesù Children''s Hospital, Piazza S. Onofrio 4, 00165 Rome, Italy;2. Paediatric Neurology and Neuromuscular Disorders Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Istituto Giannina Gaslini, Genoa, Italy;3. Respiratory Unit, Academic Department of Pediatrics, Bambino Gesù Children''s Hospital, IRCCS, Piazza di Sant'' Onofrio 4, 00165 Rome, Italy;4. Center of Translational and Experimental Myology, Istituto Giannina Gaslini, Genova, Italy |
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| Abstract: | Ryanodine receptors plays a crucial role in skeletal muscle excitation–contraction coupling by releasing calcium ions required for muscle contraction from the sarcoplasmic reticulum. At least three phenotypes associated with more than 100 RYR1 mutations have been identified; in order to elucidate possible pathophysiological mechanisms of RYR1 mutations linked to neuromuscular disorders, it is essential to define the mutation class by studying the functional properties of channels harbouring clinically relevant amino acid substitutions. In the present report we investigated the functional effects of the c.7304G > T RYR1 substitution (p.Arg2435Leu) found in a patient affected by central core disease. Both parents were heterozygous for the substitution while the proband was homozygous. We characterized Ca2+ homeostasis in myoD transduced myotubes from controls, the heterozygous parents and the homozygous proband expressing the endogenous mutation. We also expressed the recombinant mutant channels in heterologous cells and characterized their 3H]ryanodine binding and single channel properties. Our results show that the p.Arg2435Leu substitution affects neither the resting Ca2+], nor the sensitivity of the ryanodine receptor to pharmacological activators, but rather reduces the release of Ca2+ from intracellular stores induced by pharmacological activators as well as by KCl via the voltage sensing dihydropyridine receptor. |
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