A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course

Autor: Julie Perrier-Boeswillwald, Johann Böhm, Eric Bieth, Marie-Christine Minot-Myhie, Marie-Christine Nougues, Annabelle Chaussenot, Helen Mecili, François-Jérôme Authier, Maud Michaud, Sandra Mercier, Norma B. Romero, Claude Cances, Julien Fauré, Mégane Pizzimenti, Nicolas Dondaine, Valérie Biancalana, Sabrina Sacconi, Antoinette Gelot Bernabe, John Rendu, Alison Bouzenard, Armelle Magot, Bertrand Isidor, Yann Péréon, Mélanie Fradin, Emmanuelle Uro-Coste, Jocelyn Laporte, Pascale Marcorelles, Gilles Bretaudeau, Laurent Pasquier, Ana Ferreiro, Bruno Eymard
Přispěvatelé: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Hôpital l'Archet, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique [Purpan], CHU Toulouse [Toulouse], Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), Reference Centre for Neuromuscular Disorders ( FILNEMUS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), Université de Brest (UBO), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Dynamique et Structure du Cytosquelette Neuronal, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laporte, Jocelyn
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Male
Pathology
Triad
Neuromuscular disorder
Case Report
[SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
0302 clinical medicine
Age of Onset
0303 health sciences
Congenital myopathy
medicine.diagnostic_test
Muscle weakness
Middle Aged
musculoskeletal system
Hypotonia
3. Good health
Pedigree
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Child
Preschool
Disease Progression
[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
Muscle Hypotonia
Female
medicine.symptom
Adult
medicine.medical_specialty
Adolescent
[SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics
Muscle disorder
[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics
Pathology and Forensic Medicine
03 medical and health sciences
Cellular and Molecular Neuroscience
Young Adult
Excitation–contraction coupling
[SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Genomics [q-bio.GN]
medicine
[SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC]
Humans
Centronuclear myopathy
RC346-429
030304 developmental biology
Aged
RYR1
[SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics
Muscle biopsy
business.industry
Ryanodine Receptor Calcium Release Channel
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
medicine.disease
[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Calcium
Neurology (clinical)
Neurology. Diseases of the nervous system
business
030217 neurology & neurosurgery
Central core disease
Zdroj: Acta Neuropathologica Communications
Acta Neuropathologica Communications, BioMed Central part of Springer Science, 2021, 9 (1), pp.155. ⟨10.1186/s40478-021-01254-y⟩
Acta Neuropathologica Communications, Vol 9, Iss 1, Pp 1-10 (2021)
Acta Neuropathologica Communications, 2021, 9 (1), pp.155. ⟨10.1186/s40478-021-01254-y⟩
ISSN: 2051-5960
Popis: The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
Databáze: OpenAIRE
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