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

Author

Valérie Biancalana, John Rendu, Annabelle Chaussenot, Helen Mecili, Eric Bieth, Mélanie Fradin, Sandra Mercier, Maud Michaud, Marie-Christine Nougues, Laurent Pasquier, Sabrina Sacconi, Norma B. Romero, Pascale Marcorelles, François Jérôme Authier, Antoinette Gelot Bernabe, Emmanuelle Uro-Coste, Claude Cances, Bertrand Isidor, Armelle Magot, Marie-Christine Minot-Myhie, Yann Péréon, Julie Perrier-Boeswillwald, Gilles Bretaudeau, Nicolas Dondaine, Alison Bouzenard, Mégane Pizzimenti, Bruno Eymard, Ana Ferreiro, Jocelyn Laporte, Julien Fauré, and Johann Böhm

Subjects
Neuromuscular disorder, Congenital myopathy, Calcium, Muscle weakness, Excitation–contraction coupling, Triad, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract 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.

Published
2021
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2. A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course

Author

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, 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), and Laporte, Jocelyn

Subjects
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
Abstract

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.

Published
2021
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3. Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort

Author

Aleksandra Nadaj-Pakleza, Lucas Corti, Hélène Puccio, Mathieu Anheim, Jamel Chelly, Cecilia Marelli, Julien Tarabeux, Nicolas Dondaine, Nadège Diedhiou, Odile Gebus, Marilyne Almeras, Pauline Fahrer, Cécile Cauquil, Jean-Baptiste Chanson, Béatrice Lannes, Laura Robelin, Marie Claire Vincent, Mehdi Benkirane, Guillaume Taieb, Christine Tranchant, Gabrielle Rudolf, Matthieu Canuet, Andoni Echaniz-Laguna, Lise Larrieu, Solveig Montaut, and Benoit Lhermitte

Subjects
Vestibular areflexia, Pathology, medicine.medical_specialty, Cerebellum, Ataxia, Cerebellar ataxia, business.industry, Genetic heterogeneity, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Atrophy, medicine.anatomical_structure, Peripheral neuropathy, Neurology, medicine, 030212 general & internal medicine, Neurology (clinical), medicine.symptom, business, Trinucleotide repeat expansion, 030217 neurology & neurosurgery
Abstract

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C). 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C. A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found. Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.

Published
2021
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4. Biallelic RFC1-expansion in a French multicentric sporadic ataxia cohort

Author

Solveig, Montaut, Nadège, Diedhiou, Pauline, Fahrer, Cécilia, Marelli, Benoit, Lhermitte, Laura, Robelin, Marie Claire, Vincent, Lucas, Corti, Guillaume, Taieb, Odile, Gebus, Gabrielle, Rudolf, Julien, Tarabeux, Nicolas, Dondaine, Matthieu, Canuet, Marilyne, Almeras, Mehdi, Benkirane, Lise, Larrieu, Jean-Baptiste, Chanson, Aleksandra, Nadaj-Pakleza, Andoni, Echaniz-Laguna, Cécile, Cauquil, Béatrice, Lannes, Jamel, Chelly, Mathieu, Anheim, Hélène, Puccio, and Christine, Tranchant

Subjects
Cohort Studies, Cerebellar Ataxia, Humans, Ataxia, Replication Protein C, Spinocerebellar Degenerations
Abstract

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.

Published
2020

5. Dominant Centronuclear Myopathy with Early Childhood Onset due to a Novel Mutation in BIN1

Author

Irene M. F. van Balken, Valérie Biancalana, Nicol C. Voermans, Benno Küsters, Catherine Koch, Nicolas Dondaine, Johann Böhm, Erik-Jan Kamsteeg, Jocelyn Laporte, Carlyn V Kouwenberg, Corrie E. Erasmus, and Sandra H. Vos

Subjects
Male, 0301 basic medicine, myalgia, medicine.medical_specialty, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Exercise intolerance, medicine.disease_cause, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Early childhood onset, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Family, Age of Onset, Centronuclear myopathy, Child, Autosomal dominant centronuclear myopathy, Adaptor Proteins, Signal Transducing, Aged, Genes, Dominant, Mutation, Membrane tubulation, business.industry, Tumor Suppressor Proteins, Nuclear Proteins, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Phenotype, 030104 developmental biology, Endocrinology, Neurology, Female, Neurology (clinical), medicine.symptom, business, Novel mutation, 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract

Contains fulltext : 182290.pdf (Publisher’s version ) (Closed access) Autosomal dominant centronuclear myopathy (CNM) caused by mutations in the gene coding for amphiphysin-2 (BIN1) typically presents in adulthood with progressive muscle weakness. We report a Dutch family with AD CNM due to a novel BIN1 mutation (c.53T>A (p.Val18Glu)), strongly impairing the membrane tubulation activity of amphiphysin-2. The main features were mild proximal weakness with pronounced myalgia, exercise intolerance and large muscle mass, with a childhood onset in the youngest generation and mild cognitive features. This suggests BIN1 mutations should be considered in patients with isolated exercise intolerance and myalgia, even in childhood. 7 p.

Published
2017
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6. HSPB8 haploinsufficiency causes dominant adult-onset axial and distal myopathy

Author

Anne Boland, Nicolas Dondaine, Jocelyn Laporte, Guillaume Bierry, Jean-François Deleuze, Xavière Lornage, Béatrice Lannes, Valérie Biancalana, Raphaël Schneider, Johann Böhm, Andoni Echaniz-Laguna, Julie D. Thompson, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, Haploinsufficiency, Protein Serine-Threonine Kinases, Bioinformatics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Text mining, Muscular Diseases, medicine, Humans, Family, Myopathy, Heat-Shock Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Disease progression, Middle Aged, Phenotype, 030104 developmental biology, Disease Progression, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Molecular Chaperones
Published
2017
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7. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues

Author

Anne Boland, Marguerite Miguet, Jocelyn Laporte, Julie Dawn Thompson, Robert-Yves Carlier, Nicol C. Voermans, Pierre G. Carlier, Nicolas Dondaine, Nasim Vasli, Sophie Scheidecker, Xavière Lornage, Edmar Zanoteli, Nadège Calmels, Shay Ben-Shachar, Raphaël Schneider, Pascal Laforêt, Curtis Rogers, Annie Laquerrière, Benno Küsters, Laurent Pasquier, Michel Fardeau, Valérie Kremer, Tanya Stojkovic, Erik-Jan Kamsteeg, Celia Boutte, Laura Tanner, Valérie Biancalana, Claire Gasnier, Elise Schaefer, Alexandre Moerman, Norma B. Romero, Armelle Magot, Julie Perrier, Pascale Marcorelle, Bruno Eymard, Jean Pouget, Jean-François Deleuze, Elisabeth Ollagnon-Roman, Christine Tranchant, Osorio Abath Neto, Nathalie Streichenberger, Sandra Mercier, Karine Nguyen, Helen Roper, Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Université Toulouse - Jean Jaurès (UT2J), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital de la Timone [CHU - APHM] (TIMONE), Service de génétique clinique, hôpital Sud, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut NeuroMyoGène (INMG), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), Université du Québec à Rimouski (UQAR), Physiopathologie du système nerveux., Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Sciences Moléculaires de Marseille (ISM2), Aix Marseille Université (AMU)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), AFM-16992, AFM-Téléthon, ANR-10-IDEX-0002-02, Agence Nationale de la Recherche, DBI20131228569, Fondation pour la Recherche Médicale, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Strasbourg, ANR-10-INBS-09, Agence Nationale pour la Recherche, Fondation Maladies Rares, CREGEMES, Université de Toulouse (UT), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Marseille (ECM)-Institut de Chimie du CNRS (INC)

Subjects
0301 basic medicine, Pathology, Severity of Illness Index, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Cohort Studies, 0302 clinical medicine, Respiratory function, Child, ComputingMilieux_MISCELLANEOUS, Congenital myopathy, Facial weakness, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Protein Tyrosine Phosphatases, Non-Receptor, X-linked myotubular myopathy, 3. Good health, X inactivation, Phenotype, Child, Preschool, Female, medicine.symptom, Myopathies, Structural, Congenital, Adult, Weakness, medicine.medical_specialty, Heterozygote, MTM1, Adolescent, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Pathology and Forensic Medicine, Diagnosis, Differential, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Humans, Centronuclear myopathy, Myopathy, Skewed X-inactivation, Aged, medicine.disease, 030104 developmental biology, Mutation, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), 030217 neurology & neurosurgery
Abstract

Contains fulltext : 182328.pdf (Publisher’s version ) (Closed access) X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.

Published
2017
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8. Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

Author

Emma Matthews, Edoardo Malfatti, Osorio Abath Neto, Sandra Donkervoort, Aleksandra Nadaj Pakleza, Bruno Eymard, Hernan Gonorazky, F Zorzato, Lucy Feng, Mai Thao Bui, Pinki Munot, Johann Böhm, Nicolas Dondaine, Guy Brochier, Anne Boland, Valérie Biancalana, Clémence Labasse, Ana Lia Taratuto, Susan Treves, Leigh Ramos-Platt, Emmanuelle Lacène, Xavière Lornage, Charlotte J. Sumner, Caroline Sewry, Vanessa Schartner, Julie D. Thompson, Jocelyn Laporte, Tyler Mark Pierson, Michel Fardeau, Irina Zaharieva, Susana Quijano-Roy, Rahul Phadke, Norma B. Romero, Diana Bharucha-Goebel, Maud Beuvin, Francesco Muntoni, Jean-François Deleuze, Carsten G. Bönnemann, Raphaël Schneider, Ivana Dabaj, 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), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, and Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, Triad, Sequence Homology, Core myopathy, Muscle Cells/metabolism/pathology, Cohort Studies, 0302 clinical medicine, Child, Myotonia Congenita/diagnostic imaging/*genetics/*metabolism/pathology, Cells, Cultured, Congenital myopathy, Cultured, Ryanodine receptor, Malignant hyperthermia, Middle Aged, musculoskeletal system, Amino Acid, Myotubular myopathy, medicine.anatomical_structure, Phenotype, Muscle, Female, medicine.symptom, Muscle contraction, Adult, medicine.medical_specialty, Calcium/metabolism, Adolescent, Calcium Channels, L-Type, Myotonia Congenita, Cells, Biology, Skeletal/diagnostic imaging/metabolism/pathology, NO, Pathology and Forensic Medicine, Excitation–contraction coupling, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Hypokalemic periodic paralysis, Internal medicine, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Family, Calcium Channels/*genetics/*metabolism, Centronuclear myopathy, Muscle, Skeletal, RYR1, Muscle Cells, Sequence Homology, Amino Acid, DHPR, Skeletal muscle, medicine.disease, Excitation-contraction coupling, 030104 developmental biology, Endocrinology, Mutation, Calcium, Neurology (clinical), Calcium Channels, 030217 neurology & neurosurgery
Abstract

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.

Published
2016
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9. Novel molecular diagnostic approaches for X-linked centronuclear (myotubular) myopathy reveal intronic mutations

Author

Denis Oriot, Christine Kretz, Carsten G. Bönnemann, Nicolas Dondaine, Valérie Tosch, Nasim Vasli, Norma B. Romero, Anne-Sophie Nicot, Jocelyn Laporte, Gilles Duval, Valérie Biancalana, Claire Gasnier, Magalie Barth, Hugues Puissant, and Betty Heller

Subjects
Myotubularin, Blotting, Western, Molecular Sequence Data, Biology, Exon, Genes, X-Linked, Complementary DNA, medicine, Humans, Missense mutation, splice, RNA, Messenger, Centronuclear myopathy, Gene, Cells, Cultured, Genetics (clinical), Genetics, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, DNA, Exons, Protein Tyrosine Phosphatases, Non-Receptor, medicine.disease, Congenital myopathy, Molecular biology, Introns, Neurology, Mutation, Pediatrics, Perinatology and Child Health, Neurology (clinical), Myopathies, Structural, Congenital
Abstract

X-linked centronuclear myopathy (XLMTM), also called myotubular myopathy, is a severe congenital myopathy characterized by generalized hypotonia and weakness at birth and the typical histological finding of centralization of myo-nuclei. It is caused by mutations in the MTM1 gene encoding the 3-phosphoinositides phosphatase myotubularin. Mutations in dynamin 2 and amphiphysin 2 genes lead to autosomal forms of centronuclear myopathy (CNM). While XLMTM is the most frequent and severe form of CNM, no mutations are found in about 30% of patients by sequencing all MTM1 exons. Moreover, the impact of MTM1 sequence variants is sometimes difficult to assess. It is thus important to devise a complete molecular diagnostic strategy that includes analysis of the myotubularin transcript and protein expression. We therefore developed novel antibodies against human myotubularin and showed that they are able to detect the endogenous protein by direct Western blot from muscle samples and from cultured cells. In conjunction with RT-PCR analysis we validated the consequences of missense and splice mutations on transcript integrity and protein level. We also detected and characterized a novel deep intronic mutation consisting of a single nucleotide change that induces exonisation of a conserved intronic sequence. Patients with centronuclear myopathy and no molecular diagnosis should be investigated for MTM1 defects at the cDNA and protein level.

Published
2010
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10. A novel mutation in HSPB8 causes dominant adult-onset axial and distal myopathy

Author

G. Bierry, Nicolas Dondaine, Jean-François Deleuze, Xavière Lornage, Jocelyn Laporte, Valérie Biancalana, Johann Böhm, Andoni Echaniz-Laguna, Béatrice Lannes, Julie Dawn Thompson, and Raphaël Schneider

Subjects
Pathology, medicine.medical_specialty, Neurology, business.industry, Pediatrics, Perinatology and Child Health, medicine, Neurology (clinical), medicine.symptom, business, Myopathy, Novel mutation, Genetics (clinical)
Published
2017
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11. Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations

Author

Julien Fauré, John Rendu, Montse Olivé, Pascal Laforêt, Hernan Gonorazky, Edoardo Malfatti, Nasim Vasli, Laura Gonzalez-Mera, Nicolas Dondaine, Pierre Clavelou, Joachim Weis, Thierry Maisonobe, Michel Fardeau, Jocelyn Laporte, Bruno Eymard, Norma B. Romero, Jean-Louis Mandel, Catherine Koch, Valérie Biancalana, Matthias Strittmatter, Ana Lia Taratuto, Marc Bitoun, Nathalie Carrière, Johann Böhm, and Wolfram Kress

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Muscle disorder, Biology, medicine.disease_cause, Dynamin II, medicine, Humans, Centronuclear myopathy, Age of Onset, Muscle, Skeletal, Autosomal dominant centronuclear myopathy, Dynamin, Adaptor Proteins, Signal Transducing, Genetics, Mutation, Tumor Suppressor Proteins, Facial weakness, Nuclear Proteins, Heterozygote advantage, Middle Aged, medicine.disease, DNM2, Female, Neurology (clinical), medicine.symptom, Myopathies, Structural, Congenital
Abstract

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms.

Published
2014

12. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy

Author

Christine Kretz, Nicolas Dondaine, Jean-Louis Mandel, Bernard Payrastre, Valérie Tosch, Jocelyn Laporte, Nancy Monroy, Edmar Zanoteli, Holger Maria Rohde, Hélène Tronchère, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Chaire Génétique Humaine, Collège de France (CdF (institution)), and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Myotubularin, MESH: Catalytic Domain, Protein tyrosine phosphatase, MESH: Amino Acid Sequence, MESH: Variation (Genetics), MESH: Protein Structure, Tertiary, 0302 clinical medicine, Phosphatidylinositol Phosphates, Catalytic Domain, Chlorocebus aethiops, MESH: Animals, Genetics (clinical), Genetics, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Protein-Tyrosine-Phosphatase, MESH: Arginine, General Medicine, Protein Tyrosine Phosphatases, Non-Receptor, MESH: Phosphatidylinositol Phosphates, Pedigree, Cell biology, MESH: COS Cells, COS Cells, MESH: Phosphoric Monoester Hydrolases, Female, Chromosomes, Human, Pair 3, medicine.symptom, Myopathies, Structural, Congenital, MESH: Myopathies, Structural, Congenital, MESH: Pedigree, Molecular Sequence Data, Phosphatase, MESH: Chromosomes, Human, Pair 3, Mutation, Missense, MESH: Sequence Alignment, Biology, Arginine, Transfection, Cell Line, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Centronuclear myopathy, Muscle, Skeletal, Myopathy, Molecular Biology, 030304 developmental biology, Dynamin, MESH: Mutation, Missense, MESH: Humans, MESH: Molecular Sequence Data, MESH: Transfection, Genetic Variation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Congenital myopathy, MESH: Cercopithecus aethiops, Phosphoric Monoester Hydrolases, MESH: Male, Protein Structure, Tertiary, MESH: Cell Line, DNM2, Protein Tyrosine Phosphatases, Sequence Alignment, MESH: Female, 030217 neurology & neurosurgery
Abstract

International audience; In eukaryotic cells, phosphoinositides are lipid second messengers important for many cellular processes and have been found dysregulated in several human diseases. X-linked myotubular (centronuclear) myopathy is a severe congenital myopathy caused by mutations in a phosphatidylinositol 3-phosphate (PtdIns3P) phosphatase called myotubularin, and mutations in dominant centronuclear myopathy (CNM) cases were identified in the dynamin 2 gene. The genes mutated in autosomal recessive cases of CNMs have not been found. We have identified a novel phosphoinositide phosphatase (hJUMPY) conserved through evolution, which dephosphorylates the same substrates as myotubularin, PtdIns3P and PtdIns(3,5)P(2), in vitro and ex vivo. We found, in sporadic cases of CNMs, two missense variants that affect the enzymatic function. One of these appeared de novo in a patient also carrying a de novo mutation in the dynamin 2 gene. The other missense (R336Q) found in another patient changes the catalytic arginine residue of the core phosphatase signature present in protein tyrosine/dual-specificity phosphatases and in phosphoinositide phosphatases and drastically reduces the enzymatic activity both in vitro and in transfected cells. The inheritance of the phenotype with regard to this variant is still unclear and could be either recessive with an undetected second allele or digenic. We propose that impairment of hJUMPY function is implicated in some cases of autosomal CNM and that hJUMPY cooperates with myotubularin to regulate the level of phosphoinositides in skeletal muscle.

Published
2006
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13. C.P.4.10 Mutation spectrum of the large GTPase dynamin 2 in autosomal centronuclear myopathy

Author

Amanda Krause, Edmar Zanoteli, L. Merlini, Nicolas Dondaine, Anne-Sophie Nicot, Carina Wallgren-Pettersson, C. Poirson, Anne Toussaint, Jocelyn Laporte, Jean-Louis Mandel, C. Jern, Acary Sousa Bulle Oliveira, L. Bomme Ousager, Andoni Echaniz-Laguna, Valérie Biancalana, and Christine Kretz

Subjects
Genetics, 0303 health sciences, GTPase, Biology, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Neurology, Pediatrics, Perinatology and Child Health, Mutation (genetic algorithm), medicine, Neurology (clinical), Centronuclear myopathy, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology, Dynamin
Published
2007
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