Functional characterization of a Central Core Disease RyR1 mutation (p.Y4864H) associated with quantitative defect in RyR1 protein
| العنوان: | Functional characterization of a Central Core Disease RyR1 mutation (p.Y4864H) associated with quantitative defect in RyR1 protein |
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| المؤلفون: | Vincent Mouly, Isabelle Marty, Julien Fauré, Renée Krivosic, Nathalie Roux-Buisson, Joël Lunardi, Arnaud Lacour, Julie Brocard, Nicole Monnier, Paul D. Allen, Anne-Sophie Wozny, Marine Cacheux, Muriel Sébastien, Kamel Mamchaoui, John Rendu, Ariane Blum |
| المساهمون: | INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, Département Anesthésie-Réanimation, Hôpital Roger Salengro, CHRU de Lille, Hôpital Roger Salengro, CHRU de Lille, Lille, France, Department of Molecular Biosciences, Department of Molecular Biosciences [Oslo], Faculty of Mathematics and Natural Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Mathematics and Natural Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Département de neurologie [Lille], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Roux-Buisson, Nathalie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie, Hôpital Roger Salengro |
| المصدر: | Journal of Neuromuscular Diseases Journal of Neuromuscular Diseases, 2015, 202 (4), pp.421-432. ⟨10.3233/JND-150073⟩ Journal of Neuromuscular Diseases, IOS Press, 2015, 202 (4), pp.421-432. ⟨10.3233/JND-150073⟩ |
| بيانات النشر: | HAL CCSD, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Research Report, medicine.medical_specialty, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Biology, Calcium, medicine.disease_cause, Malignant hyperthermia, Calcium imaging, Central Core Disease, Internal medicine, medicine, RYR1, Mutation, Ryanodine receptor, Calcium channel, Muscle weakness, medicine.disease, musculoskeletal system, [SDV] Life Sciences [q-bio], Endocrinology, Neurology, Biochemistry, chemistry, Neurology (clinical), medicine.symptom, tissues, calcium release |
| الوصف: | International audience; BACKGROUND: Central Core Disease (CCD) is a congenital myopathy often resulting from a mutation in RYR1 gene. Mutations in RyR1 can increase or decrease channel activity, or induce a reduction in the amount of protein. The consequences of a single mutation are sometimes multiple and the analysis of the functional effects is complex.OBJECTIVE: The consequences of the p.Y4864H mutation identified in a CCD patient have been studied regarding both RyR1 function and amount.METHODS: The amount of RyR1 in human and mouse muscles was evaluated using qRT-PCR and quantitative Western blot, and calcium release was studied using calcium imaging on primary cultures. The results were compared between human and mouse.RESULTS: The p.Y4864H mutation induced an alteration of calcium release, and in addition was associated to a reduction in the amount of RyR1 in the patient’s muscle. This suggests two possible pathophysiological mechanisms: the alteration of calcium release could result from a modification of the channel properties of RyR1 or from a RyR1 reduction. In order to discriminate between the two hypotheses, we used the heterozygous RyR1 knockout (RyR1+/-) mouse model showing a comparable RyR1 protein reduction. No reduction in calcium release was observed in primary muscle culture from these mice, and no muscle weakness was measured.CONCLUSIONS: Because the reduction in the amount of RyR1 protein has no functional consequences in the murine model, the muscle weakness observed in the patient is most likely the result of a modification of the calcium channel function of RyR1 due to the p.Y4864H mutation. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2214-3599 2214-3602 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9c81e70ca60002847a7b4f2e57ddcaa9Test https://www.hal.inserm.fr/inserm-01216714Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9c81e70ca60002847a7b4f2e57ddcaa9 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22143599 22143602 |
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