Author: "Norma B Romero" / Topic: biology - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Norma B Romero"' showing total 204 results

Start Over Author "Norma B Romero" Topic biology

204 results on '"Norma B Romero"'

1. A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

Author: Robert Carlier, Mireille Cossée, Corinne Metay, Edoardo Malfatti, Pascale Richard, Norma B. Romero, Henk Granzier, Isabelle Richard, Michel Koenig, Elena Pegoraro, Aurélien Perrin, Tanya Stojkovic, Raul Juntas Morales, Marcello Villanova, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universita degli Studi di Padova, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, University of Arizona, Gestionnaire, Hal Sorbonne Université, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de recherche en Myologie – U974 SU-INSERM, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Università degli Studi di Padova = University of Padua (Unipd), and Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Gene isoform, Male, Fast myosin, Adolescent, [SDV]Life Sciences [q-bio], Child, Connectin, Deltoid Muscle, Female, Humans, Myosin Heavy Chains, Pedigree, Siblings, Muscular Diseases, Neurosciences. Biological psychiatry. Neuropsychiatry, macromolecular substances, Brief Communication, 03 medical and health sciences, 0302 clinical medicine, Myosin, Medicine, RC346-429, Messenger RNA, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, General Neuroscience, Phenotype, Cell biology, [SDV] Life Sciences [q-bio], Blot, 030104 developmental biology, biology.protein, Immunohistochemistry, Titin, Neurology. Diseases of the nervous system, Neurology (clinical), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, RC321-571
Abstract: International audience; Congenital titinopathies are myopathies with variable phenotypes and inheritance modes. Here, we fully characterized, using an integrated approach (deep phenotyping, muscle morphology, mRNA and protein evaluation in muscle biopsies), two siblings with congenital multicore myopathy harboring three TTN variants predicted to affect titin stability and titin-myosin interactions. Muscle biopsies showed multicores, type 1 fiber uniformity and sarcomeric structure disruption with some thick filament loss. Immunohistochemistry and Western blotting revealed a marked reduction of fast myosin heavy chain iso-forms. This is the first observation of a titinopathy suggesting that titin defect leads to secondary loss of fast myosin heavy chain isoforms.
Published: 2020
Full Text: View/download PDF

2. Generation of two isogenic induced pluripotent stem cell lines from a 10-year-old typical nemaline myopathy patient with a heterozygous dominant c.541G>A (p.Asp179Asn) pathogenic variant in the ACTA1 gene

Author: Kristen J. Nowak, Thierry Larmonier, Safaa Saker, Rhonda L. Taylor, Gianina Ravenscroft, Carolin K. Scriba, Norma B. Romero, Nigel G. Laing, Edoardo Malfatti, Joshua S. Clayton, The University of Western Australia (UWA), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Généthon, 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and HAL-SU, Gestionnaire
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, QH301-705.5, Induced Pluripotent Stem Cells, Germ layer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Myopathies, Nemaline, 03 medical and health sciences, 0302 clinical medicine, Nemaline myopathy, Gene duplication, medicine, Humans, Biology (General), Child, Muscle, Skeletal, Nemaline bodies, Induced pluripotent stem cell, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, 030304 developmental biology, 0303 health sciences, Lymphoblast, Cell Biology, General Medicine, medicine.disease, Congenital myopathy, Molecular biology, Actins, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, Mutation, Female, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Nemaline myopathy (NM) is a congenital myopathy typically characterized by skeletal muscle weakness and the presence of nemaline bodies in myofibres. Approximately 25% of NM cases are caused by variants in ACTA1. We generated two induced pluripotent stem cell lines from lymphoblastoid cells of a 10-year-old female with typical NM harbouring a dominant pathogenic variant in ACTA1 (c.541C>A). The isogenic lines displayed typical iPSC morphology, expressed pluripotency markers, and could differentiate into each of the three germ layers. Although the lines have partial or complete X chromosome duplication, they may still prove useful as models of human ACTA1 disease.
Published: 2021
Full Text: View/download PDF

3. Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort

Author: Ivana Dabaj, Corinne Metay, Tanya Stojkovic, Nicolas Leboucq, Susana Quijano-Roy, Jana Haberlová, François Rivier, John Rendu, Giorgio Tasca, David Gómez-Andrés, Audrey Benezit, Ximena Ortega, Fabiana Fattori, Helge Amthor, Edoardo Malfatti, Jana Zídková, Angel Sanchez-Montanez, Norma B. Romero, John Vissing, Clara Gontijo Camelo, Claudia Castiglioni, Marta Gómez García de la Banda, Laura Costa Comellas, Robert Carlier, Pascal Laforêt, Nicoline Løkken, Francina Munell, Christophe Béroud, Martin Kyncl, Eliana Cavassa, AP-HP. Université Paris Saclay, Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Motol [Prague], University of Copenhagen = Københavns Universitet (UCPH), Vall d'Hebron University Hospital [Barcelona], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Cancer and Brain Genomics (CBG), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique et Structure du Cytosquelette Neuronal, [GIN] Grenoble Institut des Neurosciences (GIN), 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), Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Sorbonne Université (SU), Bambino Gesù Children’s Hospital [Rome, Italy], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Brno, CHU Montpellier, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'Imagerie Médicale [Raymond-Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], We thank ISCIII for the fnancial support for studying LAMA2-RD in Spain., CHU Henri Mondor, Unité clinique de pathologie neuromusculaire [CHU Pitié-Salpêtrière], 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)-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), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), MORNET, Dominique, Clinica Las Condes, University of Copenhagen = Københavns Universitet (KU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Faculdade de Medicina da Universidade de São Paulo [São Paulo, Brésil], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche en myologie, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, medicine.medical_specialty, Congenital muscular dystrophy, Myopathy, [SDV]Life Sciences [q-bio], Muscle MRI, Biceps, Muscular Dystrophies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Whole Body Imaging, Heatmap, Muscular dystrophy, Muscle, Skeletal, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Muscle biopsy, biology, medicine.diagnostic_test, business.industry, Gluteus minimus, 030305 genetics & heredity, Posterior compartment of thigh, medicine.disease, biology.organism_classification, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Medius, Neurology, Neurology (clinical), Laminin, medicine.symptom, Merosin, business, 030217 neurology & neurosurgery
Abstract: Background: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. Objective: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). Results: 27 patients (2–62 years, 21–80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A “COL6-like sandwich sign” was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. Conclusion: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.
Published: 2021
Full Text: View/download PDF

4. Generation of two isogenic induced pluripotent stem cell lines from a 4-month-old severe nemaline myopathy patient with a heterozygous dominant c.553C > A (p.Arg183Ser) variant in the ACTA1 gene

Author: Kristen J. Nowak, Edoardo Malfatti, Thierry Larmonier, Gianina Ravenscroft, Carolin K. Scriba, Safaa Saker, Norma B. Romero, Rhonda L. Taylor, Joshua S. Clayton, Nigel G. Laing, The University of Western Australia (UWA), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Généthon, This work was supported by funding from an AFM Telethon Trampoline Grant (REF-21816) to Kristen Nowak, and A Foundation Building Strength Research Grant (ID-A3TR22, PI Nigel Laing). We also gratefully acknowledge funding from the Australian National Health and Medical Research Council, including a Principal Research Fellowship (APP1117510) to Nigel Laing and a Career Development Fellowship (APP1122952) to Gianina Ravenscroft., Gestionnaire, Hal Sorbonne Université, 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), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and Centre de Recherche en Myologie
Subjects: 0301 basic medicine, MESH: Mutation, QH301-705.5, MESH: Female, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Biology, medicine.disease_cause, Myopathies, Nemaline, MESH: Infant, 03 medical and health sciences, 0302 clinical medicine, Nemaline myopathy, medicine, Humans, Biology (General), Induced pluripotent stem cell, Nemaline bodies, Muscle, Skeletal, Gene, Mutation, Lymphoblast, MESH: Actins / genetics, MESH: Induced Pluripotent Stem Cells, Skeletal muscle, Infant, Cell Biology, General Medicine, medicine.disease, Congenital myopathy, Molecular biology, Actins, 3. Good health, [SDV] Life Sciences [q-bio], MESH: Humans, 030104 developmental biology, medicine.anatomical_structure, MESH: Muscle, Skeletal, MESH: Myopathies, Nemaline* / genetics, Female, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; AbstractNemaline myopathy (NM) is a congenital myopathy typically characterized by skeletal muscle weakness and the presence of abnormal thread- or rod-like structures (nemaline bodies) in myofibres. Pathogenic variants in the skeletal muscle alpha actin gene, ACTA1, cause approximately 25% of all NM cases. We generated two induced pluripotent stem cell lines from lymphoblastoid cells of a 4-month-old female with severe NM harbouring a dominant variant in ACTA1 (c.553C > A). The isogenic lines displayed characteristic iPSC morphology, expressed pluripotency markers, differentiated into cells of all three germ layers, and possessed normal karyotypes. These lines could be useful models of human ACTA1 disease.
Published: 2021
Full Text: View/download PDF

5. Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions

Author: Päivi Lahermo, Marco Savarese, Jaakko Sarparanta, Anna Vihola, Kati Donner, Norbert Vella, Cornelia Kornblum, Per Harald Jonson, Mridul Johari, Bjarne Udd, Edith Said, Francesca Magri, Giulio Piluso, Jens Reimann, Giacomo P. Comi, Sanna Huovinen, M Cauchi, H. Luque, Tanya Stojkovic, Manu Jokela, Annalaura Torella, Norma B. Romero, Peter Hackman, Eleonora Mauri, Vincenzo Nigro, Armelle Magot, Johari, Mridul, Sarparanta, Jaakko, Vihola, Anna, Jonson, Per Harald, Savarese, Marco, Jokela, Manu, Torella, Annalaura, Piluso, Giulio, Said, Edith, Vella, Norbert, Cauchi, Marija, Magot, Armelle, Magri, Francesca, Mauri, Eleonora, Kornblum, Cornelia, Reimann, Jen, Stojkovic, Tanya, Romero, Norma B, Luque, Helena, Huovinen, Sanna, Lahermo, Päivi, Donner, Kati, Comi, Giacomo Pietro, Nigro, Vincenzo, Hackman, Peter, Udd, Bjarne, Tampere University, Clinical Medicine, Department of Clinical Chemistry, Department of Neurosciences and Rehabilitation, Department of Pathology, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Genetics, Institute for Molecular Medicine Finland, and Biosciences
Subjects: Adult, Pathology, medicine.medical_specialty, Mutation, Missense, Distal myopathy, Muscle Proteins, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, AGE, 0302 clinical medicine, Stress granule, medicine, Humans, Missense mutation, Proteinopathy, Muscle, Skeletal, Myopathy, Gene, 030304 developmental biology, Inclusion Bodies, X-linked, Original Paper, 0303 health sciences, Muscle Weakness, HEARING-LOSS, Haplotype, Rimmed vacuoles, 3112 Neurosciences, Middle Aged, Pedigree, Amyloidogenesis, 3. Good health, Multisystem proteinopathy, Amyloidogenesi, Distal Myopathies, MULTISYSTEM PROTEINOPATHY, Stress granules, Cell culture, RARE FORM, Neurology (clinical), 3111 Biomedicine, medicine.symptom, 030217 neurology & neurosurgery, PHASE-SEPARATION
Abstract: Using deep phenotyping and high-throughput sequencing, we have identified a novel type of distal myopathy caused by mutations in the Small muscle protein X-linked (SMPX) gene. Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well. Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher. In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking. Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration. Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics. In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein. In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-021-02319-x.
Published: 2021

6. NEM6, KBTBD13-Related Congenital Myopathy: Myopathological Analysis in 18 Dutch Patients Reveals Ring Rods Fibers, Cores, Nuclear Clumps, and Granulo-Filamentous Protein Material

Author: Nicol C. Voermans, Claire Boulogne, Benno Küsters, Clémence Labasse, Baziel G.M. van Engelen, Coen A.C. Ottenheijm, Josine M. de Winter, Guy Brochier, Karlijn Bouman, Lilian Eshuis, Esmee S.B. Van Kleef, Norma B. Romero, A. Madelaine, Cynthia Gillet, Edoardo Malfatti, Physiology, and ACS - Pulmonary hypertension & thrombosis
Subjects: Adult, Male, Pathology, medicine.medical_specialty, genetic structures, Muscle Fibers, Skeletal, Muscle Proteins, Myopathies, Nemaline, Sarcomere, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Nemaline myopathy, law, medicine, Myotilin, Humans, Myopathy, Actin, 030304 developmental biology, Aged, Netherlands, 0303 health sciences, biology, Chemistry, General Medicine, Middle Aged, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Congenital myopathy, Neurology, biology.protein, Titin, Female, Neurology (clinical), sense organs, medicine.symptom, Electron microscope, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 232919.pdf (Publisher’s version ) (Closed access) Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.
Published: 2021
Full Text: View/download PDF

7. rAAV-related therapy fully rescues myonuclear and myofilament function in X-linked myotubular myopathy

Author: Belinda S. Cowling, Julien Ochala, Jocelyn Laporte, Edmar Zanoteli, David L. Mack, Jennifer E. Morgan, Yotam Levy, Hichem Tasfaout, Heinz Jungbluth, Michael W. Lawlor, Jacob A. Ross, Dawn A. Lowe, Norma B. Romero, King‘s College London, 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), University College of London [London] (UCL), Universidade de São Paulo Medical School (FMUSP), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Guy's and St Thomas' Hospital [London], Institute of Psychiatry, Psychology & Neuroscience, King's College London, Medical College of Wisconsin [Milwaukee] (MCW), University of Washington [Seattle], IT University of Copenhagen, 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), IT University of Copenhagen (ITU), and Gestionnaire, Hal Sorbonne Université
Subjects: Male, Myofilament, Myotubularin, Genetic enhancement, Muscle Fibers, Skeletal, Skeletal muscle, lcsh:RC346-429, Mice, 0302 clinical medicine, Myofibrils, Congenital myopathy, 0303 health sciences, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dependovirus, Protein Tyrosine Phosphatases, Non-Receptor, X-linked myotubular myopathy, Cell biology, Phenotype, medicine.anatomical_structure, Child, Preschool, Female, medicine.symptom, Muscle Contraction, Myopathies, Structural, Congenital, Adult, Adolescent, Force production, Genetic Vectors, Population, Biology, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Dogs, medicine, Animals, Humans, Myonuclear domain, education, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, Research, Infant, Muscle weakness, Genetic Therapy, medicine.disease, Disease Models, Animal, Microscopy, Electron, Neurology (clinical), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: X-linked myotubular myopathy (XLMTM) is a life-threatening skeletal muscle disease caused by mutations in the MTM1 gene. XLMTM fibres display a population of nuclei mispositioned in the centre. In the present study, we aimed to explore whether positioning and overall distribution of nuclei affects cellular organization and contractile function, thereby contributing to muscle weakness in this disease. We also assessed whether gene therapy alters nuclear arrangement and function. We used tissue from human patients and animal models, including XLMTM dogs that had received increasing doses of recombinant AAV8 vector restoring MTM1 expression (rAAV8-cMTM1). We then used single isolated muscle fibres to analyze nuclear organization and contractile function. In addition to the expected mislocalization of nuclei in the centre of muscle fibres, a novel form of nuclear mispositioning was observed: irregular spacing between those located at the fibre periphery, and an overall increased number of nuclei, leading to dramatically smaller and inconsistent myonuclear domains. Nuclear mislocalization was associated with decreases in global nuclear synthetic activity, contractile protein content and intrinsic myofilament force production. A contractile deficit originating at the myofilaments, rather than mechanical interference by centrally positioned nuclei, was supported by experiments in regenerated mouse muscle. Systemic administration of rAAV8-cMTM1 at doses higher than 2.5 × 1013 vg kg−1 allowed a full rescue of all these cellular defects in XLMTM dogs. Altogether, these findings identify previously unrecognized pathological mechanisms in human and animal XLMTM, associated with myonuclear defects and contractile filament function. These defects can be reversed by gene therapy restoring MTM1 expression in dogs with XLMTM.
Published: 2020
Full Text: View/download PDF

8. Physiological impact and disease reversion for the severe form of centronuclear myopathy linked to dynamin

Author: Roberto Silva-Rojas, Xènia Massana Muñoz, Christine Kretz, Julien Ochala, Norma B. Romero, Belinda S. Cowling, Jocelyn Laporte, and Alexia Menuet
Subjects: Male, 0301 basic medicine, GTPase, macromolecular substances, Therapeutics, Mitochondrion, Biology, medicine.disease_cause, Muscle biology, Dynamin II, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Myocyte, Centronuclear myopathy, Muscle, Skeletal, Autosomal dominant centronuclear myopathy, Dynamin, Mice, Knockout, Mice, Inbred BALB C, Mutation, General Medicine, Neuromuscular disease, Oligonucleotides, Antisense, medicine.disease, Mitochondria, 3. Good health, Cell biology, Mice, Inbred C57BL, DNM2, 030104 developmental biology, 030220 oncology & carcinogenesis, Muscle, Medicine, Female, Research Article, Genetic diseases, Myopathies, Structural, Congenital
Abstract: Classical dynamins are large GTPases regulating membrane and cytoskeleton dynamics, and they are linked to different pathological conditions ranging from neuromuscular diseases to encephalopathy and cancer. Dominant dynamin 2 (DNM2) mutations lead to either mild adult onset or severe autosomal dominant centronuclear myopathy (ADCNM). Our objectives were to better understand the pathomechanism of severe ADCNM and test a potential therapy. Here, we created the Dnm2SL/+ mouse line harboring the common S619L mutation found in patients with severe ADCNM and impairing the conformational switch regulating dynamin self-assembly and membrane remodeling. The Dnm2SL/+ mouse faithfully reproduces severe ADCNM hallmarks with early impaired muscle function and force, together with myofiber hypotrophy. It revealed swollen mitochondria lacking cristae as the main ultrastructural defect and potential cause of the disease. Patient analysis confirmed this structural hallmark. In addition, DNM2 reduction with antisense oligonucleotides after disease onset efficiently reverted locomotor and force defects after only 3 weeks of treatment. Most histological defects including mitochondria alteration were partially or fully rescued. Overall, this study highlights an efficient approach to revert the severe form of dynamin-related centronuclear myopathy. These data also reveal that the dynamin conformational switch is key for muscle function and should be targeted for future therapeutic developments., The dynamin 2 S619L mouse model displays defects in skeletal muscle that are rescued by reducing dynamin 2 protein levels with antisense oligonucleotide treatment.
Published: 2020

9. Lamin-related congenital muscular dystrophy alters mechanical signaling and skeletal muscle growth

Author: Gillian Butler-Browne, Julien Messéant, Norma B. Romero, Emmanuelle Lacène, Sophie Moog, Catherine Coirault, Arnaud Ferry, Gisèle Bonne, Astrid Brull, Kamel Mamchaoui, Daniel J. Owens, and Mark Viggars
Subjects: Myogenesis, Skeletal muscle, Biology, medicine.disease, Muscle atrophy, Muscle hypertrophy, Cell biology, LMNA, medicine.anatomical_structure, medicine, Congenital muscular dystrophy, medicine.symptom, Muscular dystrophy, Lamin
Abstract: BackgroundLaminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that impair skeletal muscle growth may contribute to the disease severity.MethodsWe used human muscle stem cells (MuSCs) carrying 4 different LMNA mutations and two mouse models of muscle laminopathies, representing a spectrum of disease severity, to investigate the ability of skeletal muscle to differentiate and to hypertrophy in response to mechanical challenges. We extended these finding to individuals with LMNA-related muscular dystrophy using muscle biopsies.ResultsIn vitro, we observe impaired myogenic differentiation with disorganized cadherin/β catenin adhesion complexes in MuSCs carrying LMNA-CMD. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective accretion of activated MuSCs, defective protein synthesis and defective remodeling of the neuro-muscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the Yes-Associated Protein (YAP), a key sensor and mediator of mechanical cues. We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely-related EDMD models.ConclusionsCombining studies in vitro, in vivo and patient samples, we find that LMNA-CMD mutations interfere with mechano-signaling pathways in skeletal muscle, implicating defective skeletal muscle growth as a pathogenic contributor for the severity of LMNA-related muscular dystrophy.
Published: 2020
Full Text: View/download PDF

10. ACTN2 mutations cause 'Multiple structured Core Disease' (MsCD)

Author: Edoardo Malfatti, Livija Medne, Xavière Lornage, A. Reghan Foley, Katherine R. Chao, Jocelyn Laporte, Michael M Marchetti, Jean-François Deleuze, David Orlikowski, Michel Fardeau, Johann Böhm, Carsten G. Bönnemann, Sandra Donkervoort, Robert Carlier, S. Neuhaus, Norma B. Romero, Vandana Gupta, Clémence Labasse, Raphaël Schneider, Claire A Grosgogeat, 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), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Harvard Medical School [Boston] (HMS), Hôpital Raymond Poincaré [AP-HP], National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Children’s Hospital of Philadelphia (CHOP ), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), and univOAK, Archive ouverte
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Myotonia Congenita, Z-line, Core myopathy, ACTN2, Alpha-actinin-2, Article, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Nemaline myopathy, medicine, Animals, Humans, Missense mutation, Actinin, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Muscle, Skeletal, Zebrafish, Exome sequencing, Congenital myopathy, Muscle biopsy, medicine.diagnostic_test, biology, Myogenesis, Muscle weakness, medicine.disease, biology.organism_classification, 030104 developmental biology, Mutation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery
Abstract: The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.
Published: 2019
Full Text: View/download PDF

11. Clathrin plaques and associated actin anchor intermediate filaments in skeletal muscle

Author: Jeanne Lainé, Pascale Guicheney, Guy Brochier, Stéphane Vassilopoulos, Mai Thao Bui, Agathe Franck, E. Lacène, Eline Lemerle, Norma B. Romero, Marc Bitoun, Gilles Moulay, Sofia Benkhelifa-Ziyyat, Michael Trichet, Christel Gentil, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-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), Neurobiologie et diversité cellulaire (NDC), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Centre de recherche en myologie, 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), Microscopie Electronique [IBPS] (IBPS-ME), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Morphologie Neuromusculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Coeur, Muscle et Vaisseaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gestionnaire, Hal Sorbonne Université, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), 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), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Intermediate Filaments, macromolecular substances, Clathrin, Desmin, 03 medical and health sciences, Dynamin II, 0302 clinical medicine, medicine, Animals, Humans, Intermediate filament, Muscle, Skeletal, Molecular Biology, Actin, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Dynamin, Mice, Knockout, 0303 health sciences, Costameres, Sarcolemma, biology, Skeletal muscle, Cell Biology, Articles, Actins, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cell Biology of Disease, Mutation, biology.protein, 030217 neurology & neurosurgery, Wiskott-Aldrich Syndrome Protein, Myopathies, Structural, Congenital
Abstract: International audience; Clathrin plaques are stable features of the plasma membrane observed in several cell types. They are abundant in muscle, where they localize at costameres that link the contractile apparatus to the sarcolemma and connect the sarcolemma to the basal lamina. Here, we show that clathrin plaques and surrounding branched actin filaments form microdomains that anchor a three-dimensional desmin intermediate filament (IF) web. Depletion of clathrin plaque and branched actin components causes accumulation of desmin tangles in the cytoplasm. We show that dynamin 2, whose mutations cause centronuclear myopathy (CNM), regulates both clathrin plaques and surrounding branched actin filaments, while CNM-causing mutations lead to desmin disorganization in a CNM mouse model and patient biopsies. Our results suggest a novel paradigm in cell biology, wherein clathrin plaques act as platforms capable of recruiting branched cortical actin, which in turn anchors IFs, both essential for striated muscle formation and function.
Published: 2019
Full Text: View/download PDF

12. Mild clinical presentation in KLHL40-related nemaline myopathy (NEM 8)

Author: John Rendu, Julien Fauré, Laurent Pelletier, Pierre G. Carlier, Laurent Servais, Norma B. Romero, Andreea Mihaela Seferian, Véronique Forin, Edoardo Malfatti, Teresa Gidaro, Jessica Taytard, E. Gargaun, C Bosson, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de réhabilitation pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), NMR Laboratory, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie (U153 Inserm - IM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], and HAL-UPMC, Gestionnaire
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Muscle Proteins, KLHL40, Biology, medicine.disease_cause, Myopathies, Nemaline, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Nemaline myopathy, medicine, Humans, Nemaline bodies, Child, Muscle, Skeletal, Genetics (clinical), Sanger sequencing, Mutation, Muscle biopsy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Genetic heterogeneity, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Phenotype, Neurology, Pediatrics, Perinatology and Child Health, symbols, Female, Neurology (clinical), Presentation (obstetrics), medicine.symptom, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy.
Published: 2020
Full Text: View/download PDF

13. Anti-HMGCR Antibody–Related Necrotizing Autoimmune Myopathy Mimicking Muscular Dystrophy

Author: Claude-Alain Maurage, Norma B. Romero, Vincent Tiffreau, Louis Vallée, Isabelle Nelson, Rabah Ben Yaou, Emmanuelle Jaillette, Céline Tard, Fabienne Jouen, Jean-Marie Cuisset, Gisèle Bonne, Sylvie Nguyen, Patrick Vermersch, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'excellence Inflamex, Sorbonne Paris Cité, Unité de Recherche Pluridisciplinaire Sport, Santé, Société (URePSSS) - ULR 7369 - ULR 4488 (URePSSS), Université d'Artois (UA)-Université du Littoral Côte d'Opale (ULCO)-Université de Lille, Département Anesthésie-Réanimation, Hôpital Roger Salengro, CHRU de Lille, Hôpital Roger Salengro, CHRU de Lille, Lille, France, Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Service de Neuropédiatrie, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Service de neuropédiatrie [CHU Lille]
Subjects: Pathology, medicine.medical_specialty, Delayed Diagnosis, Necrosis, [SDV]Life Sciences [q-bio], Inflammation, Autoimmune Diseases, Diagnosis, Differential, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Muscular Diseases, Fibrosis, Biopsy, medicine, Humans, Muscular dystrophy, Muscle, Skeletal, Autoantibodies, 030203 arthritis & rheumatology, Muscle biopsy, medicine.diagnostic_test, biology, business.industry, General Medicine, medicine.disease, Pediatrics, Perinatology and Child Health, Disease Progression, biology.protein, Immunohistochemistry, Female, Hydroxymethylglutaryl CoA Reductases, Creatine kinase, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Introduction Necrotizing autoimmune myopathies (NAMs) are acquired myopathies with myofibrillar necrosis and weak or absent inflammatory component, sometimes associated with anti-signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies. Observation The patient, a girl now aged 20 years, was first assessed at the age of 5 years for abnormal gait revealing frank pelvic deficit. Creatine kinase (CK) levels were as high as 7,500 IU/L. Subsequent muscle biopsy showed some necrosis, fiber regeneration, and fibrosis consistent with muscular dystrophy (MD). Protein immunohistochemistry was normal. The disease course was progressive until wheelchair use at the age of 9 years. At 12 years of age, a second muscle biopsy found an advanced MD with some perivascular inflammatory mononuclear cells. All molecular analyses done through 14 years of follow-up were negative till anti-HMGCR antibodies were detected at a significant amount when she was 19 years old. Discussion NAMs begin at a pediatric age and may have a chronic course mimicking MDs. Muscular biopsy can be misleading with a predominantly dystrophic pattern without inflammation. Conclusion This observation should prompt the assessment of NAMs in all MDs, even pediatric, without molecular solutions.
Published: 2017
Full Text: View/download PDF

14. Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy

Author: Claire-Sophie Davoine, Michel Fardeau, Damien Sternberg, Emmanuel Fournier, Marie-Joséphine Fontenille, Arnaud Lacour, Norma B. Romero, Elodie De Bruyckere, D. Hantai, Julien Messéant, Geoffroy Vellieux, Sophie Nicole, Tanya Stojkovic, Sylvie Sukno, Françoise Bouhour, Jeanine Koenig, S. Bauche, E. Lacène, Pascal Laforêt, Lucie Wolf, Laure Strochlic, Guy Brochier, Bruno Eymard, Aleksandra Nadaj-Pakleza, Frédéric Chevessier, Véronique Manel, Nathalie Streichenberger, Bertrand Fontaine, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Universitätsklinikum Erlangen, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de reference des maladies neuromusculaires Nantes-Angers, CHU d'Angers et Nantes, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Hôpital Roger Salengro [Lille], Centre de référence des maladies rares neuromusculaires, Centre hospitalier de Béthune, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
Subjects: Adult, 0301 basic medicine, medicine.medical_specialty, Weakness, Glycosylation, Neurology, Adolescent, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], Sarcoplasm, Neuromuscular Junction, 030105 genetics & heredity, Biology, Neuromuscular junction, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Muscle, Skeletal, Myopathy, Aged, Retrospective Studies, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Myasthenic Syndromes, Congenital, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Middle Aged, Congenital myasthenic syndrome, medicine.disease, Transmembrane protein, 3. Good health, Endocrinology, medicine.anatomical_structure, Female, Synaptopathy, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Follow-Up Studies, Myopathies, Structural, Congenital
Abstract: International audience; Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients’ muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation–reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a “tubular aggregates myopathy with synaptopathy”.
Published: 2017
Full Text: View/download PDF

15. RecessiveMYPNmutations cause cap myopathy with occasional nemaline rods

Author: Jean-Marie Cuisset, Anne Boland, Edoardo Malfatti, Matteo Garibaldi, Jean-François Deleuze, Johann Böhm, Michel Fardeau, Jocelyn Laporte, Xavière Lornage, Norma B. Romero, Raphaël Schneider, Robert-Yves Carlier, Bruno Eymard, Valérie Biancalana, Chrystel Cheraud, and Julie D. Thompson
Subjects: 0301 basic medicine, Genetics, Messenger RNA, Mutation, Genetic heterogeneity, MYPN, Consanguinity, Biology, medicine.disease_cause, Sarcomere, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Neurology, medicine, Neurology (clinical), Cap myopathy, Exome, 030217 neurology & neurosurgery
Abstract: Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.
Published: 2017
Full Text: View/download PDF

16. ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy

Author: Monica Bulla, Anastazja Szlauer, Nicolas Demaurex, Maurizio Moggio, Jill E. Urquhart, Anne Boland, Edoardo Malfatti, James O'Sullivan, Christian G. DeGoede, Jocelyn Laporte, Helen Kingston, Marina Mora, Norma B. Romero, Michela Ripolone, Jean-François Deleuze, Catherine Koch, Johann Böhm, Raffaella Violano, William G. Newman, Giovanni Baranello, Timothy Dawson, Simon G. Williams, and John Nixon
Subjects: 0301 basic medicine, medicine.medical_specialty, ORAI1, Mutant, Skeletal muscle, chemistry.chemical_element, STIM1, Calcium, Biology, Cell biology, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, medicine.anatomical_structure, chemistry, Internal medicine, Genotype, Genetics, medicine, medicine.symptom, Myopathy, 030217 neurology & neurosurgery, Genetics (clinical), Homeostasis
Abstract: Calcium (Ca(2+) ) is a physiological key factor, and the precise modulation of free cytosolic Ca(2+) levels regulates multiple cellular functions. Store-operated Ca(2+) entry (SOCE) is a major mechanism controlling Ca(2+) homeostasis, and is mediated by the concerted activity of the Ca(2+) sensor STIM1 and the Ca(2+) channel ORAI1. Dominant gain-of-function mutations in STIM1 or ORAI1 cause tubular aggregate myopathy (TAM) or Stormorken syndrome, while recessive loss-of-function mutations are associated with immunodeficiency. Here we report the identification and functional characterization of novel ORAI1 mutations in TAM patients. We assess basal activity and SOCE of the mutant ORAI1 channels, and we demonstrate that the G98S and V107M mutations generate constitutively permeable ORAI channels, while T184M alters the channel permeability only in the presence of STIM1. These data indicate a mutation-dependent pathomechanism and a genotype/phenotype correlation, as the ORAI1 mutations associated with the most severe symptoms induce the strongest functional cellular effect. Examination of the non-muscle features of our patients strongly suggest that TAM and Stormorken syndrome are spectra of the same disease. Overall, our results emphasize the importance of SOCE in skeletal muscle physiology, and provide new insights in the pathomechanisms involving aberrant Ca(2+) homeostasis and leading to muscle dysfunction. This article is protected by copyright. All rights reserved.
Published: 2017
Full Text: View/download PDF

17. MUSCLE FUNCTION & HOMEOSTASIS / MOLECULAR THERAPEUTIC APPROACHES

Author: B. Cadot, E. Lacène, Norma B. Romero, Teresinha Evangelista, and Maud Beuvin
Subjects: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Biology, Genetics (clinical), Homeostasis, Function (biology), Cell biology
Published: 2020
Full Text: View/download PDF

18. A Heterozygous Mutation in the Filamin C Gene Causes an Unusual Nemaline Myopathy With Ring Fibers

Author: Johann Böhm, Mai-Thao Bui, Guy Brochier, Corinne Metay, Anais Chanut, Jocelyn Laporte, Xavière Lornage, Ursula Oppermann, Teresinha Evangelista, Guillaume Bassez, Pierre G. Carlier, E. Lacène, Norma B. Romero, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and univOAK, Archive ouverte
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, Filamins, Biology, Filamin, Myopathies, Nemaline, Muscle MRI, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Nemaline myopathy, medicine, Humans, FLNC, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Nemaline bodies, Myopathy, Actin, 030304 developmental biology, 0303 health sciences, Muscle biopsy, Filamin C-related myopathies, medicine.diagnostic_test, Filamin C (FLNC), General Medicine, Middle Aged, medicine.disease, Pedigree, Phenotype, Neurology, Mutation, Distal Myopathies, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), medicine.symptom, Sarcomere disorganization, 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract: Autosomal dominant pathogenic variants in the filamin C gene (FLNC) have been associated with myofibrillar myopathies, distal myopathies, and isolated cardiomyopathies. Mutations in different functional domains of FLNC can cause various clinical phenotypes. A novel heterozygous missense variant c.608G>A, p.(Cys203Tyr) in the actin binding domain of FLCN was found to cause an upper limb distal myopathy (MIM #614065). The muscle MRI findings are similar to those observed in FLNC-myofibrillar myopathy (MIM #609524). However, the muscle biopsy revealed >20% of muscle fibers with nemaline bodies, in addition to numerous ring fibers and a predominance of type 1 fibers. Overall, this case shows some unique and rare aspects of FLNC-myopathy constituting a new morphologic phenotype of FLNC-related myopathies.
Published: 2020
Full Text: View/download PDF

19. A New Glycogen Storage Disease Caused by a Dominant PYGM Mutation

Author: Pascal Laforêt, Roberto Silva-Rojas, Béatrice Lannes, Guy Brochier, Mai Thao Bui, Jocelyn Laporte, Andoni Echaniz-Laguna, Norma B. Romero, John Vissing, Johann Böhm, Evelina Edelweiss, Xavière Lornage, Mette Cathrine Ørngreen, Catherine Birck, Service de neurologie [Le Kremlin Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, National Reference Center for FAP (NNERF)/ APHP/ INSERM U 1191, Hôpital de Bicêtre, Petites Molécules de neuroprotection, neurorégénération et remyélinisation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), 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), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Les Hôpitaux Universitaires de Strasbourg (HUS), Fondation pour la Recherche MÃ©dicale, FRM: PLP20170939073 Institut National de la SantÃ© et de la Recherche MÃ©dicale, Inserm Fondation Maladies Rares, FMR: IPM05201114 Institut National des Sciences de l'Univers, Centre National de la Recherche Scientifique, INSU,CNRS Institut National de la SantÃ© et de la Recherche MÃ©dicale, Inserm Centre National de la Recherche Scientifique, CNRS, This work was supported by Institut National de Santé et de Recherche Médicale (Inserm), Centre National de Recherche Scientifique (CNRS), Strasbourg University, and the Fondation Maladies Rares (IPM05201114). R.S.R. was funded by Fondation Recherche Médicale doctoral fellowship (PLP20170939073)., Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), and 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)
Subjects: 0301 basic medicine, Adult, Male, Mutant, Biology, medicine.disease_cause, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Glycogen storage disease, Missense mutation, Humans, Exome sequencing, Genetics, Mutation, Glycogen, Middle Aged, medicine.disease, Glycogen Storage Disease, 3. Good health, Pedigree, 030104 developmental biology, Neurology, chemistry, Myophosphorylase, Glycogen Phosphorylase, Muscle Form, Desmin, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), 030217 neurology & neurosurgery
Abstract: International audience; Objective: Glycogen storage diseases (GSDs) are severe human disorders resulting from abnormal glucose metabolism, and all previously described GSDs segregate as autosomal recessive or X-linked traits. In this study, we aimed to molecularly characterize the first family with a dominant GSD. Methods: We describe a dominant GSD family with 13 affected members presenting with adult-onset muscle weakness, and we provide clinical, metabolic, histological, and ultrastructural data. We performed exome sequencing to uncover the causative gene, and functional experiments in the cell model and on recombinant proteins to investigate the pathogenic effect of the identified mutation. Results: We identified a heterozygous missense mutation in PYGM segregating with the disease in the family. PYGM codes for myophosphorylase, the enzyme catalyzing the initial step of glycogen breakdown. Enzymatic tests revealed that the PYGM mutation impairs the AMP-independent myophosphorylase activity, whereas the AMP-dependent activity was preserved. Further functional investigations demonstrated an altered conformation and aggregation of mutant myophosphorylase, and the concurrent accumulation of the intermediate filament desmin in the myofibers of the patients. Interpretation: Overall, this study describes the first example of a dominant glycogen storage disease in humans, and elucidates the underlying pathomechanisms by deciphering the sequence of events from the PYGM mutation to the accumulation of glycogen in the muscle fibers. ANN NEUROL 2020;88:274–282.
Published: 2020
Full Text: View/download PDF

20. Homoplasmic deleterious MT-ATP6/8 mutations in adult patients

Author: Claude Jardel, Norma B. Romero, Sandrine Filaut, Isabelle Serre, Benoit Rucheton, Francis Haraux, Maria del Mar Amador, Anne Lombès, Sarah Leonard-Louis, T. Maisonobe, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Protéines et Systèmes Membranaires (LPSM), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Adult, Male, Mitochondrial DNA, Mitochondrial Diseases, Mitochondrial disease, [SDV]Life Sciences [q-bio], oxidative phosphorylation, Oxidative phosphorylation, Biology, Hybrid Cells, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Glycolysis, Muscle, Skeletal, Molecular Biology, Gene, Cells, Cultured, Homoplasmy, ATP synthase, homoplasmy, cybrids, High-Throughput Nucleotide Sequencing, Cell Biology, Sequence Analysis, DNA, Fibroblasts, Mitochondrial Proton-Translocating ATPases, medicine.disease, Molecular biology, mitochondrial disease, 030104 developmental biology, MT-ATP6, Mutation, biology.protein, Molecular Medicine, Female, 030217 neurology & neurosurgery
Abstract: To address the frequency of complex V defects, we systematically sequenced MT-ATP6/8 genes in 512 consecutive patients. We performed functional analysis in muscle or fibroblasts for 12 out of 27 putative homoplasmic mutations and in cybrids for four. Fibroblasts, muscle and cybrids with known deleterious mutations underwent parallel analysis. It included oxidative phosphorylation spectrophotometric assays, western blots, structural analysis, ATP production, glycolysis and cell proliferation evaluation. We demonstrated the deleterious nature of three original mutations. Striking gradation in severity of the mutations consequences and differences between muscle, fibroblasts and cybrids implied a likely under-diagnosis of human complex V defects.
Published: 2020
Full Text: View/download PDF

21. Pathogenic variants in the myosin chaperone UNC-45B cause progressive myopathy with eccentric cores

Author: Serena Governali, Jonathan Baets, Sarah Djeddi, Willem De Ridder, Reza Maroofian, Ying Hu, Stephanie Efthymiou, Xavière Lornage, Stefan Conijn, Vincenzo Salpietro, Aritoshi Iida, Satoru Noguchi, Norma B. Romero, Magdalena Mroczek, Carola Hedberg-Oldfors, Tumtip Sangruchi, Julien Fauré, S. Neuhaus, Wojciech Pokrzywa, Ichizo Nishino, Ana Töpf, Kanokwan Boonyapisit, Fabiana Lubieniecki, Edoardo Malfatti, Jantima Tanboon, Chiara Fiorillo, Johann Böhm, Thorsten Hoppe, Véronique Bolduc, Soledad Monges, Niklas Darin, Coen A.C. Ottenheijm, Riley M. McCarty, Volker Straub, Anders Oldfors, Gabriella Di Rosa, A. Reghan Foley, Henry Houlden, John Rendu, Nancy L. Kuntz, Jocelyn Laporte, Carsten G. Bönnemann, Carl Elias Kutzner, Tanya Stojkovic, Katherine R. Chao, Iren Horkayne-Szakaly, Sandra Donkervoort, National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), University of Cologne, 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), 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Antwerp (UA), Mahidol University [Bangkok], University College of London [London] (UCL), Newcastle University [Newcastle], Amsterdam UMC - Amsterdam University Medical Center, Northwestern University Feinberg School of Medicine, Hospital Nacional de Pediatría J.P. Garrahan, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Hôpital Raymond Poincaré [AP-HP], National Center of Neurology and Psychiatry, University of Gothenburg (GU), National Center of Neurology and Psychiatry [Tokyo, Japan], University of Messina, Università degli studi di Genova = University of Genoa (UniGe), International Institute of Molecular and Cell Biology [Warsaw] (IIMCB), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University of Arizona, univOAK, Archive ouverte, Physiology, and ACS - Pulmonary hypertension & thrombosis
Subjects: 0301 basic medicine, Male, muscle, myosin, Sarcomere, Whole Exome Sequencing, 0302 clinical medicine, Myofibrils, Loss of Function Mutation, Myosin, Missense mutation, chaperone, Transgenes, Genetics (clinical), Caenorhabditis elegans, C. elegans, core myopathy, myofibrillar, sarcomere, UNC-45, UNC45B, Adolescent, Adult, Alleles, Animals, Caenorhabditis elegans Proteins, Female, Genetic Variation, Humans, Molecular Chaperones, Muscle, Skeletal, Muscular Diseases, Myosins, Sarcomeres, Sequence Analysis, RNA, Young Adult, Mutation, Missense, biology, Skeletal, Cell biology, Myosin binding, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Sequence Analysis, macromolecular substances, Article, 03 medical and health sciences, Exome Sequencing, Genetics, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Myopathy, fungi, biology.organism_classification, 030104 developmental biology, Chaperone (protein), Mutation, biology.protein, RNA, Human medicine, Missense, Myofibril, 030217 neurology & neurosurgery
Abstract: The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.
Published: 2020
Full Text: View/download PDF

22. KBTBD13 is an actin-binding protein that modulates muscle kinetics

Author: Leonardo Nogara, Saskia Lassche, Jonne Doorduin, Norma B. Romero, Benno Küsters, Tamar E. Sztal, Baziel G.M. van Engelen, Balázs Kiss, Stefan Conijn, Josine M. de Winter, Coen A.C. Ottenheijm, Weikang Ma, Georg Ramm, Viola Oorschot, Joery P. Molenaar, Shengyi Shen, Christopher N. Johnson, Richard J. Rodenburg, Bert Blaauw, Robbert van der Pijl, Henk Granzier, Thomas E. Hall, Ken Campbell, Frank Li, Thomas C. Irving, Alan H. Beggs, Michaela Yuen, Reinier A. Boon, Manuela Marabita, Menne van Willigenburg, Esmee S.B. Van Kleef, Noelia Lozano-Vidal, Sylvia J. P. Bogaards, Robert J. Bryson-Richardson, Avnika A. Ruparelia, Dilson E. Rassier, Martijn van de Locht, Edoardo Malfatti, Malin Persson, Zherui Xiong, Nicol C. Voermans, Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), VIDI 016.126.319 645648, H2020-MSCA-RISE-2014 W.OR17-08 National Institutes of Health, NIH: R01 HD075802 U.S. Department of Energy, USDOE National Institute of General Medical Sciences, NIGMS: 1S10OD018090-01 National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIAMS: HL133359, R01 AR053897 National Institute of Child Health and Human Development, NICHD Muscular Dystrophy Association, MDA: MDA602235 Office of Science, SC Argonne National Laboratory, ANL: 9 P41 GM103622 Advanced Photon Sciences, APS: DE-AC02-06CH11357 National Health and Medical Research Council, NHMRC: APP1121651 Vetenskapsrådet, VR: 2015-00385, This work was supported by the Dutch Foundation for Scientific Research (VIDI 016.126.319 to CACO), the Princess Beatrix Muscle Foundation (W.OR17-08 to CACO, NCV, and BGMVE), H2020-MSCA-RISE-2014 (645648 Muscle Stress Relief to CACO), the Advanced Photon Source (DE-AC02-06CH11357), A Foundation Building Strength for Nemaline Myopathy (to CACO), the National Health and Medical Research Council (NHMRC) Early Career Fellowship (APP1121651 to MY), the National Institute of Child Health and Human Development (NIH R01 HD075802 to AHB), the Muscular Dystrophy Association (USA) (MDA602235 to AHB), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH R01 AR053897 to HG), the NIH (HL133359 to KC). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. This project was supported by grant 9 P41 GM103622 from the National Institute of General Medical Sciences of the NIH. Use of the Pilatus 3 1M detector was provided by grant 1S10OD018090-01 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institute of General Medical Sciences or the NIH. MP was funded by a postdoctoral grant from the Swedish Research Council (2015-00385)., Physiology, ACS - Pulmonary hypertension & thrombosis, ACS - Microcirculation, ACS - Atherosclerosis & ischemic syndromes, ACS - Heart failure & arrhythmias, and Academic Medical Center
Subjects: 0301 basic medicine, Sarcomeres, Muscle Relaxation, [SDV]Life Sciences [q-bio], Kinetics, Muscle Proteins, Skeletal muscle, Myopathies, Nemaline, Contractility, 03 medical and health sciences, Mice, 0302 clinical medicine, Nemaline myopathy, All institutes and research themes of the Radboud University Medical Center, medicine, Animals, Humans, Actin-binding protein, Actin, Zebrafish, Mice, Knockout, biology, Relaxation (psychology), Chemistry, Other Research Radboud Institute for Health Sciences [Radboudumc 0], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], General Medicine, Zebrafish Proteins, Neuromuscular disease, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 030104 developmental biology, medicine.anatomical_structure, Muscle relaxation, 030220 oncology & carcinogenesis, Biophysics, biology.protein, Commentary, Genetic diseases, Muscle Biology
Abstract: International audience; The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFPlabeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.
Published: 2020
Full Text: View/download PDF

23. HNRNPDL-related muscular dystrophy: expanding the clinical, morphological and MRI phenotypes

Author: Fabio Barroso, Claudia Cejas, Teresinha Evangelista, Mai Thao Bui, Ana Lia Taratuto, Norma B. Romero, Maria Saccoliti, Johann Böhm, Bjarne Udd, Guy Brochier, Alberto Dubrovsky, Xavière Lornage, Andrés Berardo, Jocelyn Laporte, Mridul Johari, 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), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Folkhälsan Research Center, Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 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], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituto de Investigaciones Neurologicas (FLENI), Instituto de Investigaciones Neurologicas, Hospital Universitario Fundacion Favaloro, University of Tampere [Finland], Department of Medical and Clinical Genetics, University of Helsinki, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pathology, medicine.medical_specialty, Argentina, Limb girdle, Thigh, Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, medicine, Autophagy, Humans, Heterogeneous Nuclear Ribonucleoprotein D0, 030212 general & internal medicine, Muscular dystrophy, Heterogeneous-Nuclear Ribonucleoprotein D, Myopathy, Rimmed vacuolar myopathy, Aged, Muscle biopsy, medicine.diagnostic_test, LGMDD3 HNRNPDL-related, 3112 Neurosciences, Rimmed vacuoles, HNRNPDL gene, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Pedigree, medicine.anatomical_structure, Phenotype, Neurology, Muscular Dystrophies, Limb-Girdle, Mutation, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Distal lower limb muscle weakness, Limb-girdle muscular dystrophy
Abstract: Autosomal dominant limb girdle muscular dystrophy D3 HNRNPDL-related is a rare dominant myopathy caused by mutations in HNRNPDL. Only three unrelated families have been described worldwide, a Brazilian and a Chinese carrying the mutation c.1132G>A p.(Asp378Asn), and one Uruguayan with the mutation c.1132G>C p. (Asp378His), both mutations occurring in the same codon. The present study enlarges the clinical, morphological and muscle MRI spectrum of AD-HNRNPDL-related myopathies demonstrating the significant particularities of the disease. We describe two new unrelated Argentinean families, carrying the previously reported c.1132G>C p.(Asp378His) HNRNPDL mutation. There was a wide phenotypic spectrum including oligo-symptomatic cases, pure limb girdle muscle involvement or distal lower limb muscle weakness. Scapular winging was the most common finding, observed in all patients. Muscle MRIs of the thigh, at different stages of the disease, showed particular involvement of adductor magnus and vastus besides a constant preservation of the rectus femoris and the adductor longus muscles, defining a novel MRI pattern. Muscle biopsy findings were characterized by the presence of numerous rimmed vacuoles, cytoplasmic bodies, and abundant autophagic material at the histochemistry and ultrastructural levels. HNRNPDL-related LGMD D3 results in a wide range of clinical phenotypes from the classic proximal form of LGMD to a more distal phenotype. Thigh MRI suggests a specific pattern. Codon 378 of HNRNPDL gene can be considered a mutation hotspot for HNRNPDL-related myopathy. Pathologically, the disease can be classified among the autophagic rimmed vacuolar myopathies as with the other multisystem proteinopathies.
Published: 2019
Full Text: View/download PDF

24. Amphiphysin 2 modulation rescues myotubular myopathy and prevents focal adhesion defects in mice

Author: Maxime Sartori, Valentina M. Lionello, Christine Kretz, Nadia Messaddeq, Jocelyn Laporte, Yann Herault, Pascale Koebel, Sarah Djerroud, Belinda S. Cowling, Suzie Buono, Anne-Sophie Nicot, Pascal Kessler, Ivana Prokic, Norma B. Romero, 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 de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), 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 Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), IGBMC-Médecine translationnelle et neurogénétique, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Male, Myotubularin, Integrin, Longevity, Mice, Transgenic, Nerve Tissue Proteins, Focal adhesion, 03 medical and health sciences, 0302 clinical medicine, Laminin, medicine, Myocyte, Animals, Humans, Muscle Strength, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Adaptor Proteins, Signal Transducing, 0303 health sciences, Focal Adhesions, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, Integrin beta1, Muscles, Tumor Suppressor Proteins, Skeletal muscle, Muscle weakness, Nuclear Proteins, General Medicine, Protein Tyrosine Phosphatases, Non-Receptor, 3. Good health, Cell biology, medicine.anatomical_structure, Animals, Newborn, Amphiphysin, biology.protein, medicine.symptom, 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract: Centronuclear myopathies (CNMs) are severe diseases characterized by muscle weakness and myofiber atrophy. Currently, there are no approved treatments for these disorders. Mutations in the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for X-linked CNM (XLCNM), also called myotubular myopathy, whereas mutations in the membrane remodeling Bin/amphiphysin/Rvs protein amphiphysin 2 [bridging integrator 1 (BIN1)] are responsible for an autosomal form of the disease. Here, we investigated the functional relationship between MTM1 and BIN1 in healthy skeletal muscle and in the physiopathology of CNM. Genetic overexpression of human BIN1 efficiently rescued the muscle weakness and life span in a mouse model of XLCNM. Exogenous human BIN1 expression with adeno-associated virus after birth also prevented the progression of the disease, suggesting that human BIN1 overexpression can compensate for the lack of MTM1 expression in this mouse model. Our results showed that MTM1 controls cell adhesion and integrin localization in mammalian muscle. Alterations in this pathway in Mtm1 −/y mice were associated with defects in myofiber shape and size. BIN1 expression rescued integrin and laminin alterations and restored myofiber integrity, supporting the idea that MTM1 and BIN1 are functionally linked and necessary for focal adhesions in skeletal muscle. The results suggest that BIN1 modulation might be an effective strategy for treating XLCNM.
Published: 2019
Full Text: View/download PDF

25. A novel gain-of-function mutation inORAI1causes late-onset tubular aggregate myopathy and congenital miosis

Author: Sabrina Sacconi, Pierfrancesco Ottaviani, Francesco Laschena, Beatrice Riva, Giovanni Antonini, Guy Brochier, Enrico Bertini, Elisa Vizzaccaro, Armando A. Genazzani, Matteo Garibaldi, Clémence Labasse, Norma B. Romero, and Fabiana Fattori
Subjects: 0301 basic medicine, medicine.medical_specialty, biology, Myogenesis, Late onset, Asymptomatic, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Internal medicine, Thrombocytopathy, Genetics, medicine, biology.protein, Missense mutation, Creatine kinase, Congenital miosis, medicine.symptom, Myopathy, 030217 neurology & neurosurgery, Genetics (clinical)
Abstract: We present three members of an Italian family affected by tubular aggregate myopathy (TAM) and congenital miosis harboring a novel missense mutation in ORAI1. All patients had a mild, late onset TAM revealed by asymptomatic creatine kinase (CK) elevation and congenital miosis consistent with a Stormorken-like Syndrome, in the absence of thrombocytopathy. Muscle biopsies showed classical histological findings but ultrastructural analysis revealed atypical tubular aggregates (TAs). The whole body muscle magnetic resonance imaging (MRI) showed a similar pattern of muscle involvement that correlated with clinical severity. The lower limbs were more severely affected than the scapular girdle, and thighs were more affected than legs. Molecular analysis revealed a novel c.290C>G (p.S97C) mutation in ORAI1 in all affected patients. Functional assays in both human embryonic kidney (HEK) cells and myotubes showed an increased rate of Ca2+ entry due to a constitutive activation of the CRAC channel, consistent with a 'gain-of-function' mutation. In conclusion, we describe an Italian family harboring a novel heterozygous c.290C>G (p.S97C) mutation in ORAI1 causing a mild- and late-onset TAM and congenital miosis via constitutive activation of the CRAC channel. Our findings extend the clinical and genetic spectrum of the ORAI1-related TAM.
Published: 2016
Full Text: View/download PDF

26. Mutation-specific effects on thin filament length in thin filament myopathy

Author: Nicol C. Voermans, Balázs Kiss, Eun Jeong Lee, Alan H. Beggs, Christopher T. Pappas, Carina Wallgren-Pettersson, Michaela Yuen, Sandra Donkervoort, Vandana Gupta, Nigel F. Clarke, Edoardo Malfatti, Ger J.M. Stienen, Barbara Joureau, Katarina Pelin, Norma B. Romero, Henk Granzier, Josine M. de Winter, Carol C. Gregorio, Carsten G. Bönnemann, Baziel G.M. van Engelen, Simon Edvardson, Vilma Lotta Lehtokari, and Coen A.C. Ottenheijm
Subjects: 0301 basic medicine, biology, Chemistry, Skeletal muscle, macromolecular substances, Anatomy, Sarcomere, TPM2, 03 medical and health sciences, Nebulin, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Neurology, Myosin, biology.protein, medicine, Biophysics, Neurology (clinical), medicine.symptom, Myopathy, 030217 neurology & neurosurgery, Actin, Muscle contraction
Abstract: Nemaline myopathy and congenital fiber type disproportion are among the most common nondystrophic congenital muscular disorders.1 Genes that are implicated in these myopathies encode proteins that are either components of the skeletal muscle thin filament, including nebulin (NEB), skeletal muscle alpha-actin1 (ACTA1), beta-tropomyosin 2 (TPM2), alpha-tropomyosin 3 (TPM3), troponin T type 1 (TNNT1), cofilin-2 (CFL2), and leiomodin-3 (LMOD3), or are thought to contribute to stability or turnover of thin filament proteins, such as kelch repeat and BTB (POZ) domain containing 13 (KBTBD13), and kelchlike family members 40 (KLHL40) and 41 (KLHL41).2–6 Hence, muscle diseases caused by mutations in these genes are here referred to as thin filament myopathies. For a schematic of the thin filament and its associated proteins, see Figure 1. Patients with thin filament myopathy suffer from muscle weakness, but the underlying mechanisms are poorly understood. FIGURE 1 Schematic of the skeletal muscle thin filament. The thin filament is an essential structure in the sarcomere, the smallest contractile unit in skeletal muscle. The actin-based backbone of the thin filament is decorated with proteins that are involved ... The thin filament is a major constituent of the sarcomere, the smallest contractile unit in muscle, and is essential for force generation; its length determines the overlap between the thin and thick filament, and thereby the number of force-generating interactions that can be formed between actin and myosin. In healthy human muscle, the length of the thick filament is 1.6μm and that of the thin filament is regulated at 1.1 to 1.3μm.7 Accordingly, force depends on sarcomere length, with increasing force as the overlap between thick and thin filaments increases (up to a sarcomere length of ~2.6μm; ie, the ascending limb of the force–sarcomere length relation), and decreasing force at longer sarcomere lengths as the overlap between thick and thin filaments decreases (ie, the descending limb; Fig 2A8,9). Hence, appropriate length of the thin filament is important for muscle fiber strength; a shorter length causes lower force generation by shifting the descending limb of the force–sarcomere length relation downward. FIGURE 2 The force–sarcomere length relation in muscle fibers from thin filament myopathy patients and control (CTRL) subjects. (A) The shape of the force–sarcomere length relation is determined by the amount of overlap between the thick and thin ... Whether mutations in genes implicated in thin filament myopathy contribute to force loss by affecting thin filament length is unclear. Mouse models with mutations in Neb exhibit a shorter thin filament length associated with lower force generation that becomes more prominent as sarcomere length increases.10–12 Preliminary studies on a small number of human biopsies were largely in agreement with this observation.13,14 Whether these findings translate to a large group of patients, and whether shorter thin filament length is a general mechanism underlying force loss in thin filament myopathies with a variety of different gene defects, is unknown. Therefore, we studied muscle fibers from 51 patients with thin filament myopathy caused by mutations in NEB, ACTA1, TPM2, TPM3, TNNT1, KBTBD13, KLHL40, and KLHL41. In these fibers, we determined the sarcomere length-dependence of force, a functional assay that provides insight into the contractile strength of muscle fibers as well as the length of the thin filaments. In a novel, conditional Neb knockout mouse model that recapitulates thin filament myopathy—including shorter thin filament length—we studied whether muscle possesses mechanisms that compensate for shorter thin filament length, and we specifically focused on the addition of sarcomeres in series.
Published: 2016
Full Text: View/download PDF

27. Dermatomyositis With or Without Anti-Melanoma Differentiation-Associated Gene 5 Antibodies

Author: Aurélie Grados, Aurélien Delluc, Alain Meyer, Laurent Drouot, Nathalie Costedoat-Chalumeau, Nathalie Streichenberger, Odile Dubourg, C. Preusse, Jean Sibilia, Olivier Boyer, Laurent Servais, Elizabeth Diot, Antoine Dossier, David Saadoun, Divy Cornec, Eduard Gallardo, Serge Herson, Aude Rigolet, Dominique Menard, Jeremy Martinet, Xavier Ferrer, Marielle Roux, Norma B. Romero, Hans-Hilmar Goebel, David Launay, Xavier Suárez-Calvet, Laurent Arnaud, Claire Larroche, Baptiste Hervier, Yurdagul Uzunhan, Sophie Besnard, Patrice Cacoub, Sarah Leonard-Louis, Vincent Langlois, Jean-Luc Charuel, Jessie Aouizerate, Mohamed Hamidou, Arnaud Hot, T. Stojkovic, Emmanuelle Campana-Salort, Fabienne Jouen, Nicolas Schleinitz, Raphael De Paz, H. Lévesque, Benjamin Terrier, Hervé Devilliers, Bernard Grosbois, Anthony Behin, Thierry Maisonobe, Isabelle Koné-Paut, Miguel Hie, Brigitte Bader-Meunier, Rémi Bellance, Pascal Laforêt, Laure Gallet, Nicolas Limal, Debora Pehl, Lucile Musset, Anne Tournadre, Gaëlle Leroux, Peter Hufnagl, Bruno Eymard, Olivier Benveniste, Norman Zerbe, Werner Stenzel, Boris Bienvenu, Chafika Morati, Olivier Fain, Yves Allenbach, Philippe Petiot, and Eric Hachulla
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, Autoantibody, Skeletal muscle, Inflammation, Dermatomyositis, Biology, medicine.disease, Pathophysiology, Pathology and Forensic Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Atrophy, medicine.anatomical_structure, Immunology, medicine, medicine.symptom, Myopathy, 030217 neurology & neurosurgery
Abstract: The anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody is specifically associated with dermatomyositis (DM). Nevertheless, anti–MDA5 + -patients experience characteristic symptoms distinct from classic DM, including severe signs of extramuscular involvement; however, the clinical signs of myopathy are mild or even absent. The morphological and immunological features are not yet described in adulthood. Data concerning the pathophysiology of anti-MDA5 DM are sparse; however, the importance of the interferon (IFN) type I pathway involved in DM has been shown. Our aim was to define morphological alterations of the skeletal muscle and the intrinsic immune response of anti–MDA5-positive DM patients. Immunohistological and RT-PCR analysis of muscle biopsy specimens from anti-MDA5 and classic DM were compared. Those with anti-MDA5 DM did not present the classic features of perifascicular fiber atrophy and major histocompatibility complex class I expression. They did not show significant signs of capillary loss; tubuloreticular formations were observed less frequently. Inflammation was focal, clustering around single vessels but significantly less intense. Expression of IFN-stimulated genes was up-regulated in anti-MDA5 DM; however, the IFN score was significantly lower. Characteristic features were observed in anti-MDA5 DM and not in classic DM patients. Only anti-MDA5 DM showed numerous nitric oxide synthase 2–positive muscle fibers with sarcoplasmic colocalization of markers of regeneration and cell stress. Anti–MDA5-positive patients demonstrate a morphological pattern distinct from classic DM.
Published: 2016
Full Text: View/download PDF

28. Pediatric laminopathies: Whole-body magnetic resonance imaging fingerprint and comparison with Sepn1 myopathy

Author: Susana Quijano-Roy, Viviane Azzi, Pascale Richard, Dominique Mompoint, Gisèle Bonne, Jean Bergounioux, Brigitte Estournet, Robert Yves-Carlier, Ivana Dabaj, Karolina Hankiewicz, David Gómez-Andrés, Christine Ioos, Rabah Ben Yaou, and Norma B. Romero
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Physiology, Whole body imaging, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Atrophy, Physiology (medical), medicine, Myopathy, integumentary system, biology, medicine.diagnostic_test, business.industry, Dystrophy, Magnetic resonance imaging, Anatomy, musculoskeletal system, biology.organism_classification, medicine.disease, Medius, 030104 developmental biology, Flexor Digitorum Longus, Neurology (clinical), medicine.symptom, Abnormality, business, 030217 neurology & neurosurgery
Abstract: Introduction We sought to define the whole-body MRI (WB-MRI) fingerprint of muscle involvement in pediatric LMNA-related dystrophy (LMNA-RD) and to compare it with SEPN1-related myopathy (SEPN1-RM). Methods Signal abnormality and atrophy in 109 muscles were scored by semiquantitative scales in 8 children with LMNA-RD and represented by heatmaps. These features were compared with those from 9 SEPN1-RM patients by random forests. Results LMNA-RD showed predominant signal abnormalities in erector spinae, serratus anterior, subscapularis, gluteus medius and minimus, vastii, adductor magnus and longus, semimembranosus, medial gastrocnemius, and soleus muscles. Psoas, sternocleidomastoid, gracilis, and sartorius muscles often had normal signal but showed atrophy. Cranial, flexor digitorum longus, and tibialis posterior muscles were spared. According to random forests, atrophied semimembranosus in SEPN1-RM was the most relevant feature to distinguish these patients from LMNA-RD. Conclusions A selective pattern in WB-MRI for pediatric LMNA-RD exists and can be differentiated from SEPN1-RM by machine learning. Muscle Nerve 54: 192-202, 2016.
Published: 2016
Full Text: View/download PDF

29. Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment

Author: Philippe Labrune, José C. Milisenda, Sarah Leonard-Louis, Thomas Krag, Benedikt Schoser, Louisa Jauze, Aleksandra Nadaj-Pakleza, Giuseppe Ronzitti, Claire Lefeuvre, Guy Brochier, Sabrina Sacconi, Ichizo Nishino, Federico Mingozzi, Carola Hedberg-Oldfors, Michio Inoue, Edoardo Malfatti, François Petit, Evelyne Goillot, Umut Cagin, Nathalie Streichenberger, Clémence Labasse, A. Madelaine, Julien Fabregue, John Vissing, Pascal Laforêt, Anders Oldfors, Norma B. Romero, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AGROCAMPUS OUEST, 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Rigshospitalet [Copenhagen], Copenhagen University Hospital, Nutrition, diabète et cerveau (NUDICE), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CIBER de Enfermedades Raras (CIBERER), Centre de référence des maladies rares neuromusculaires, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, Université de Bordeaux (UB), University of Copenhagen = Københavns Universitet (UCPH), ANR-17-CE18-0014,TRACeGSDIII,Optimisation translationnelle d'un vecteur AAV pour le traitement de GSDIII(2017), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Nutrition, diabète et cerveau, Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), and University of Copenhagen = Københavns Universitet (KU)
Subjects: Male, Pathology, Biopsy, [SDV]Life Sciences [q-bio], Sarcoplasm, Glycogen storage disease type III, lcsh:RC346-429, Glycogen Storage Disease Type III, Mice, chemistry.chemical_compound, 0302 clinical medicine, Metabolic myopathies, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, Glycogen, medicine.diagnostic_test, Middle Aged, 3. Good health, medicine.anatomical_structure, Glycogenesis, Female, Adult, medicine.medical_specialty, Biology, Pathology and Forensic Medicine, Glycogen debranching enzyme, 03 medical and health sciences, Cellular and Molecular Neuroscience, Autophagy, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, Glycogen storage disease III, Muscle, Skeletal, lcsh:Neurology. Diseases of the nervous system, Aged, 030304 developmental biology, Muscle biopsy, Research, Autophagic impairment, Skeletal muscle, Myopathology, medicine.disease, Disease Models, Animal, Muscle glycogenosis, chemistry, Vacuoles, Neurology (clinical), 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
Published: 2019
Full Text: View/download PDF

30. Dusty core disease (DuCD): expanding morphological spectrum of RYR1 recessive myopathies

Author: Guy Brochier, Julien Fauré, Jocelyn Laporte, Clémence Labasse, Isabelle Marty, Jorge A. Bevilacqua, Ana Lia Taratuto, Emmanuelle Lacène, Julie Brocard, Edoardo Malfatti, Maud Beuvin, Giovanni Antonini, John Rendu, Soledad Monges, A. Madelaine, Matteo Garibaldi, Fabiana Lubieniecki, Norma B. Romero, 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), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad de Chile = University of Chile [Santiago] (UCHILE), Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia [Buenos Aires] (FLENI), FLENI, 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), Université de Strasbourg (UNISTRA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de recherche en Myologie – U974 SU-INSERM, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Pathology, muscle, [SDV]Life Sciences [q-bio], lcsh:RC346-429, centronuclear myopathy, 0302 clinical medicine, cohort studies, newborn, congenital myopathy, middle aged, genes, humans, child, medicine.diagnostic_test, adult, ryanodine receptor calcium release channel, musculoskeletal system, skeletal, muscular diseases, aged, female, entral core disease, dusty core disease, ryanodine receptor, RYR1 recessive, adolescent, biopsy, child, preschool, genes, recessive, infant, infant, newborn, male, muscle, skeletal, young adult, Child, Preschool, Immunohistochemistry, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, medicine.medical_specialty, Genes, Recessive, Biology, preschool, Pathology and Forensic Medicine, Lesion, 03 medical and health sciences, Cellular and Molecular Neuroscience, Central Core Disease, medicine, Centronuclear myopathy, Muscle, Skeletal, lcsh:Neurology. Diseases of the nervous system, RYR1, Muscle biopsy, Research, Infant, Newborn, recessive, medicine.disease, Congenital myopathy, 030104 developmental biology, Neurology (clinical), Myofibril, 030217 neurology & neurosurgery, Central core disease
Abstract: Several morphological phenotypes have been associated to RYR1-recessive myopathies. We recharacterized the RYR1-recessive morphological spectrum by a large monocentric study performed on 54 muscle biopsies from a large cohort of 48 genetically confirmed patients, using histoenzymology, immunohistochemistry, and ultrastructural studies. We also analysed the level of RyR1 expression in patients’ muscle biopsies. We defined “dusty cores” the irregular areas of myofibrillar disorganisation characterised by a reddish-purple granular material deposition with uneven oxidative stain and devoid of ATPase activity, which represent the characteristic lesion in muscle biopsy in 54% of patients. We named Dusty Core Disease (DuCD) the corresponding entity of congenital myopathy. Dusty cores had peculiar histological and ultrastructural characteristics compared to the other core diseases. DuCD muscle biopsies also showed nuclear centralization and type1 fibre predominance. Dusty cores were not observed in other core myopathies and centronuclear myopathies. The other morphological groups in our cohort of patients were: Central Core (CCD: 21%), Core-Rod (C&R:15%) and Type1 predominance “plus” (T1P+:10%). DuCD group was associated to an earlier disease onset, a more severe clinical phenotype and a lowest level of RyR1 expression in muscle, compared to the other groups. Variants located in the bridge solenoid and the pore domains were more frequent in DuCD patients. In conclusion, DuCD is the most frequent histopathological presentation of RYR1-recessive myopathies. Dusty cores represent the unifying morphological lesion among the DuCD pathology spectrum and are the morphological hallmark for the recessive form of disease. Electronic supplementary material The online version of this article (10.1186/s40478-018-0655-5) contains supplementary material, which is available to authorized users.
Published: 2019
Full Text: View/download PDF

31. Core-rod myopathy due to a novel mutation in BTB/POZ domain of KBTBD13 manifesting as late onset LGMD

Author: Guy Brochier, Enrico Bertini, Giovanni Antonini, Margherita Verardo, Carmen Paradas, Marcello Pinti, Norma B. Romero, Salvatore Raffa, Emilia Servián-Morilla, Giulia Di Rocco, Matteo Garibaldi, Lara Gibellini, Fabiana Fattori, Carlo Augusto Bortolotti, Clémence Labasse, and Elena Maria Pennisi
Subjects: Male, Models, Molecular, 0301 basic medicine, Central core myopathy, Congenital myopathies, Core-rod myopathy, KBTBD13, LGMD, Nemaline myopathy, Pathology, medicine.medical_specialty, Tomography Scanners, X-Ray Computed, Green Fluorescent Proteins, Muscle Proteins, Late onset, Biology, lcsh:RC346-429, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, Humans, Progressive proximal muscle weakness, Muscle, Skeletal, Myopathy, BTB/POZ domain, Letter to the Editor, Creatine Kinase, lcsh:Neurology. Diseases of the nervous system, Aged, RYR1, Muscle biopsy, medicine.diagnostic_test, NAD, medicine.disease, Magnetic Resonance Imaging, Microscopy, Electron, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, BTB-POZ Domain, Mutation, Neurology (clinical), medicine.symptom, Novel mutation, 030217 neurology & neurosurgery
Abstract: Few genes (RYR1, NEB, ACTA1, CFL2, KBTBD13) have been associated with core-rod congenital myopathies [7]. KBTBD13 belongs to the Kelch-repeat super-family of proteins and is implicated in the ubiquitination pathway. Dominant mutations in KBTBD13 have been associated with a peculiar form of core-rod myopathy (NEM6) so far [10]. Childhood onset, slowly progressive proximal muscle weakness with characteristic slowness of movements and combination of nemaline rods, irregular shaped cores and unusual type2 fibres hypotrophy at muscle biopsy, were the main characteristics shared in all the affected members of the four KBTBD13 families reported in the literature [12]. We report on a 65 years old patient, of Sardinian origin, with atypical clinical and morphological presentation of NEM6 due to a novel mutation in KBTBD13 gene.
Published: 2018
Full Text: View/download PDF

32. Genetic Mutations and Demographic, Clinical, and Morphological Aspects of Myofibrillar Myopathy in a French Cohort

Author: T. Stojkovic, Michel Fardeau, Roseli Corazzini, Pascal Laforêt, A. Madelaine, Alzira Alves de Siqueira Carvalho, Vinicius Gomes da Silva, Emmanuele Lacene, Guy Brochier, Anthony Behin, Konstantinos Papadopoulos, Bruno Eymard, Norma B. Romero, and Clémance Labasse
Subjects: 0301 basic medicine, Adult, Male, Adolescent, Protein aggregation, Biology, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Myofibrillar myopathy, Humans, Age of Onset, Muscle, Skeletal, Genetics (clinical), Aged, Demography, Genes, Dominant, Retrospective Studies, Genetics, Genetic heterogeneity, General Medicine, Middle Aged, Genetic association analysis, 030104 developmental biology, Cohort, Mutation, Female, France, 030217 neurology & neurosurgery, Myopathies, Structural, Congenital
Abstract: Protein aggregate myopathies (PAM) represent a group of familial or sporadic neuromuscular conditions with marked clinical and genetic heterogeneity that occur in children and adults. Familial PAM includes myofibrillar myopathies defined by the presence of desmin-positive protein aggregates and degenerative intermyofibrillar network changes. PAM is often caused by dysfunctional genes, such as DES, PLEC 1, CRYAB, FLNC, MYOT, ZASP, BAG3, FHL1, and DNAJB6.To retrospectively analyze genetic mutations and demographic, clinical, and morphological aspects of PAM in a French population.Forty-eight PAM patients (29 men, 19 women) were divided into two groups, those with genetically (GIM) and nongenetically identified (NGIM) mutations associated with myofibrillar myopathy.Age of myopathy onset ranged from 13 to 68 years. GIM group mutations (81.25%) included DES (14), ZASP (8), FLNC (4), MYOT (4), BAG3 (1), CRYAB (2), and DNAJB6 (6). The MYOT subgroup displayed a significantly older onset age (p = 0.029). Autosomal dominant inheritance was found in 74.3% of GIM and 44.4% of NGIM subjects. Overall, 22.9% had Maghrebian heritage, 72.9% Caucasian, and 4.2% Asian. The most common clinical sign was distal muscle weakness (66%) followed by simultaneous distal and proximal weakness in 49%. Eleven patients had contractures, one had a rigid spine, and five had respiratory dysfunction. GIM subjects had greater cardiac involvement (51.7%) versus the NGIM group (33.3%). The average serum creatine kinase level was 393 U/L in GIM and 382 U/L in NGIM subjects. Morphological analysis showed significant differences among GIM subgroups, including the number of vacuoles and regenerated fibers (ZASP), group atrophy (ZASP), and rubbed out fibers (MYOT). Ultrastructural findings showed significant differences in intranuclear rods, Z-disc thickness, and intranuclear inclusions between gene mutation subgroups. Paracrystalline inclusions were present in three patients (DNAJB6). The most frequent mutation in was in DES, followed by ZASP.GIM and NGIM PAM subjects showed similar results, suggesting that any unknown genes, which cause this disease have characteristics similar to those already described. Considering the complexity of clinical, morphological, and genetic data related to PAM, particularly myofibrillar myopathies, physicians should be careful when diagnosing patients with sporadic PAM.
Published: 2018

33. Mechanosensitive clathrin platforms anchor desmin intermediate filaments in skeletal muscle

Author: Marc Bitoun, Agathe Franck, Gilles Moulay, Jeanne Lainé, Pascale Guicheney, Thao Bui M, Norma B. Romero, Michaël Trichet, Guy Brochier, E. Lacène, Stéphane Vassilopoulos, Sabrina Sacconi, Anais Fongy, Anne Bigot, Mouly, Sofia Benkhelifa-Ziyyat, Christel Gentil, and Catherine Coirault
Subjects: 0303 health sciences, biology, Myogenesis, Chemistry, macromolecular substances, Clathrin, Cell biology, 03 medical and health sciences, 0302 clinical medicine, biology.protein, Mechanosensitive channels, Desmin, Cytoskeleton, Intermediate filament, 030217 neurology & neurosurgery, Actin, 030304 developmental biology, Dynamin
Abstract: Large flat clathrin plaques are stable features of the plasma membrane associated with sites of strong adhesion suggesting that they could also play a role in force transduction. Here, we analyzed how clathrin plaques interact with the cytoskeleton and how they respond to mechanical cues in skeletal muscle myotubes. We show that branched actin networks surrounding clathrin plaques are directly regulated by dynamin 2, anchor intermediate filaments and sequester YAP at the plasma membrane. Dynamin 2, clathrin and desmin intermediate filaments are all required for basal YAP nucleocytoplasmic distribution and efficient nuclear translocation in response to mechanical stimuli. Dynamin 2 mutations that are responsible for centronuclear myopathy in humans disorganize the desmin network and deregulate YAP signaling both in vitro and in vivo. Thus, clathrin plaques and associated dynamin 2 are defined here as a new sensor conveying mechanical cues and integrate cell signaling with cytoskeletal regulation.
Published: 2018
Full Text: View/download PDF

34. Myofibrillar myopathies: State of the art, present and future challenges

Author: Dominique Figarella-Branger, Norma B. Romero, Emmanuelle Salort-Campana, Bjarne Udd, Jérôme Franques, Isabelle Nelson, Thierry Maisonobe, Gisèle Bonne, Pascal Laforêt, Bruno Eymard, Anthony Behin, Karim Wahbi, A. Maues de Paula, H.M. Bécane, Shahram Attarian, Denis Duboc, Robert-Yves Carlier, Pierre G. Carlier, Annie Verschueren, T. Stojkovic, Jean Pouget, Pascale Richard, and Patrick Vicart
Subjects: Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Cardiomyopathy, Muscle Proteins, Young Adult, Myofibrils, medicine, Humans, FLNC, Muscular dystrophy, Child, Muscle, Skeletal, Myopathy, Muscle biopsy, biology, medicine.diagnostic_test, business.industry, LDB3, Middle Aged, medicine.disease, Neurology, biology.protein, Female, Titin, Desmin, Neurology (clinical), medicine.symptom, business, Myopathies, Structural, Congenital
Abstract: Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.
Published: 2015
Full Text: View/download PDF

35. A Premature Stop Codon in MYO18B is Associated with Severe Nemaline Myopathy with Cardiomyopathy

Author: Norma B. Romero, Edoardo Malfatti, E. Lacène, Maud Beuvin, Johann Böhm, Guy Brochier, and Jocelyn Laporte
Subjects: Research Report, Congenital myopathy, Pathology, medicine.medical_specialty, MYO18B, Nonsense mutation, Cardiomyopathy, myosin, Biology, medicine.disease, Exon, Nemaline myopathy, Neurology, Myosin, medicine, Neurology (clinical), nemaline myopathy, Nemaline bodies, cardiomyopathy, Exome sequencing
Abstract: Background: Nemaline myopathies (NM) are rare and severe muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Although ten genes have been implicated in the etiology of NM, an important number of patients remain without a molecular diagnosis. Objective: Here we describe the clinical and histopathological features of a sporadic case presenting with severe NM and cardiomyopathy. Using exome sequencing, we aimed to identify the causative gene. Results: We identified a homozygous nonsense mutation in the last exon of MYO18B, leading to a truncated protein lacking the most C-terminal part. MYO18B codes for an unconventional myosin protein and it is mainly expressed in skeletal and cardiac muscles, two tissues severely affected in the patient. We showed that the mutation does not impact on mRNA stability. Immunostaining and Western blot confirmed the absence of the full-length protein. Conclusion: We propose MYO18B as a novel gene associated with nemaline myopathy and cardiomyopathy.
Published: 2015
Full Text: View/download PDF

36. Acute rhabdomyolysis and inflammation

Author: Asmaa Mamoune, Norma B. Romero, Chris Ottolenghi, François-Xavier Mauvais, Pascale de Lonlay, Laetitia Lallement, Florence Habarou, and Yamina Hamel
Subjects: Inflammation, RYR1, medicine.medical_specialty, Sarcolemma, Phosphatidate Phosphatase, Gene mutation, Biology, medicine.disease, Rhabdomyolysis, Endocrinology, Mitochondrial respiratory chain, Internal medicine, Acute Disease, Genetics, medicine, Cytokines, Humans, Aldolase A deficiency, medicine.symptom, Acute rhabdomyolysis, Genetics (clinical)
Abstract: Rhabdomyolysis results from the rapid breakdown of skeletal muscle fibers, which leads to leakage of potentially toxic cellular content into the systemic circulation. Acquired causes by direct injury to the sarcolemma are most frequent. The inherited causes are: i) metabolic with failure of energy production, including mitochondrial fatty acid ß-oxidation defects, LPIN1 mutations, inborn errors of glycogenolysis and glycolysis, more rarely mitochondrial respiratory chain deficiency, purine defects and peroxysomal α-methyl-acyl-CoA-racemase defect (AMACR), ii) structural causes with muscle dystrophies and myopathies, iii) calcium pump disorder with RYR1 gene mutations, iv) inflammatory causes with myositis. Irrespective of the cause of rhabdomyolysis, the pathology follows a common pathway, either by the direct injury to sarcolemma by increased intracellular calcium concentration (acquired causes) or by the failure of energy production (inherited causes), which leads to fiber necrosis. Rhabdomyolysis are frequently precipitated by febrile illness or exercise. These conditions are associated with two events, elevated temperature and high circulating levels of pro-inflammatory mediators such as cytokines and chemokines. To illustrate these points in the context of energy metabolism, protein thermolability and the potential benefits of arginine therapy, we focus on a rare cause of rhabdomyolysis, aldolase A deficiency. In addition, our studies on lipin-1 (LPIN1) deficiency raise the possibility that several diseases involved in rhabdomyolysis implicate pro-inflammatory cytokines and may even represent primarily pro-inflammatory diseases. Thus, not only thermolability of mutant proteins critical for muscle function, but also pro-inflammatory cytokines per se, may lead to metabolic decompensation and rhabdomyolysis.
Published: 2015
Full Text: View/download PDF

37. Phenotype and genotype of muscle ryanodine receptor rhabdomyolysis-myalgia syndrome

Author: Nicol C. Voermans, Nanna Witting, Norma B. Romero, John Rendu, Erik-Jan Kamsteeg, F. Bompaire, Nathalie Roux-Buisson, Morten Duno, Pascal Laforêt, Nanna S. Poulsen, John Vissing, F. Feillet, Anthony Behin, Julia R. Dahlqvist, and Julien Fauré
Subjects: 0301 basic medicine, myalgia, Adult, Male, medicine.medical_specialty, Adolescent, Genotype, Denmark, Population, Gastroenterology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Rhabdomyolysis, Muscle hypertrophy, 03 medical and health sciences, Young Adult, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Internal medicine, Medicine, Humans, education, Child, Myositis, Netherlands, RYR1, education.field_of_study, biology, business.industry, Malignant hyperthermia, Ryanodine Receptor Calcium Release Channel, General Medicine, Myalgia, Syndrome, Middle Aged, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 030104 developmental biology, Phenotype, Neurology, Mutation, biology.protein, Creatine kinase, Female, Neurology (clinical), France, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Objectives Rhabdomyolysis and myalgia are common conditions, and mutation in the ryanodine receptor 1 gene (RYR1) is suggested to be a common cause. Due to the large size of RYR1, however, sequencing has not been widely accessible before the recent advent of next-generation sequencing technology and limited phenotypic descriptions are therefore available. Material & methods We present the medical history, clinical and ancillary findings of patients with RYR1 mutations and rhabdomyolysis and myalgia identified in Denmark, France and The Netherlands. Results Twenty-two patients with recurrent rhabdomyolysis (CK > 10 000) or myalgia with hyperCKemia (>1.5 × ULN) and a RYR1 mutation were identified. One had mild wasting of the quadriceps muscle, but none had fixed weakness. Symptoms varied from being restricted to intense exercise to limiting ADL function. One patient developed transient kidney failure during rhabdomyolysis. Two received immunosuppressants on suspicion of myositis. None had episodes of malignant hyperthermia. Muscle biopsies were normal, but CT/MRI showed muscle hypertrophy in most. Delay from first symptom to diagnosis was 12 years on average. Fifteen different dominantly inherited mutations were identified. Ten were previously described as pathogenic and 5 were novel, but rare/absent from the background population, and predicted to be pathogenic by in silico analyses. Ten of the mutations were reported to give malignant hyperthermia susceptibility. Conclusion Mutations in RYR1 should be considered as a significant cause of rhabdomyolysis and myalgia syndrome in patients with the characteristic combination of rhabdomyolysis, myalgia and cramps, creatine kinase elevation, no weakness and often muscle hypertrophy.
Published: 2018
Full Text: View/download PDF

38. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

Author: Mark R. Davis, Glyn Williams, Irina Zaharieva, Lucy Feng, Helge Amthor, Adnan Y. Manzur, Muriel Holder, Gina L. O'Grady, Caroline Sewry, Gemma Poke, Julien Fauré, Carsten G. Bönnemann, Pinki Munot, Sandra Donkervoort, Susan Treves, Sabrina W. Yum, A. Reghan Foley, Edmar Zanoteli, Joanne Dixon, Livija Medne, Juliet Taylor, Anna Sarkozy, E. Malfatti, John Rendu, Christoph Bachmann, J. Andoni Urtizberea, Susana Quijano-Roy, Francesco Muntoni, Christopher John Holmes, Laurent Servais, Rahul Phadke, Norma B. Romero, Laila Bastaki, Osorio Abath Neto, and Heinz Jungbluth
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, STAC3, Adolescent, Myotonia Congenita, malignant hyperthermia, Biology, Compound heterozygosity, Severity of Illness Index, NO, Young Adult, 03 medical and health sciences, Exome Sequencing, Severity of illness, congenital myopathy, Genetics, medicine, Humans, Genetic Predisposition to Disease, Child, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Excitation Contraction Coupling, Genetics (clinical), Exome sequencing, Adaptor Proteins, Signal Transducing, Sarcolemma, Malignant hyperthermia, Infant, Skeletal muscle, excitation–contraction coupling, medicine.disease, Phenotype, Congenital myopathy, Pedigree, 3. Good health, Protein Transport, Sarcoplasmic Reticulum, 030104 developmental biology, medicine.anatomical_structure, Amino Acid Substitution, Child, Preschool, Calcium, Female, Protein Binding
Abstract: SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.
Published: 2018

39. Diseases of the skeletal muscle

Author: Edoardo Malfatti and Norma B. Romero
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, Skeletal muscle, The Renaissance, Biology, Pathogenicity, Muscle histology, Protein expression, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, medicine, Histopathology, Identification (biology), 030217 neurology & neurosurgery
Abstract: After the advances created by the use of cryostat sections and histochemistry 60 years ago, muscle histopathology is now living a real renaissance. In the field of genetic neuromuscular disorders, muscle biopsy analysis is fundamental to address questions about pathogenicity and protein expression when new genes are discovered through next-generation sequencing approaches. Moreover, the identification of the same gene mutated in previously considered distinct histopathologic entities imposes a constant reassessment of morphologic boundaries in several groups of disorders. In other fields like the acquired inflammatory myopathies, histologic analysis nowadays helps to affirm a diagnosis, set up therapeutic strategies, and verify the success of immunosuppressive treatment. In this exciting scenario morphologists are definitely key figures in the neuromuscular field. The objective of this chapter is to give an overview on morphology of the most frequent and recently identified muscle conditions, stressing the importance that only a combined analysis of clinical findings, muscle histology, and specific ancillary investigations is effective in reaching a precise diagnosis and orienting therapy.
Published: 2018
Full Text: View/download PDF

40. Clinical heterogeneity and phenotype/genotype findings in 5 families with &ITGYG1&IT deficiency

Author: Rabah Ben Yaou, David Gaist, Marc Bartoli, John Vissing, Julia R. Dahlqvist, Gisèle Bonne, Pascal Laforêt, Frédéric Parisot, Philippe Labrune, Philippe Petiot, Isabelle Nelson, Aurélie Hubert, Bruno Eymard, Morten Duno, Robert Carlier, Thomas O. Krag, Martin Krahn, Fabrice Michel, Maud Beuvin, François Petit, Norma B. Romero, Nathalie Streichenberger, Edoardo Malfatti, Mathieu Cerino, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Ben Yaou, Rabah
Subjects: 0301 basic medicine, Weakness, Pathology, medicine.medical_specialty, Vacuole, Disease, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Compound heterozygosity, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, medicine, Journal Article, Gene, Genetics (clinical), Exome sequencing, chemistry.chemical_classification, Glycogen, 030104 developmental biology, Enzyme, chemistry, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery
Abstract: Objective:To describe the variability of muscle symptoms in patients carrying mutations in the GYG1 gene, encoding glycogenin-1, an enzyme involved in the biosynthesis of glycogen, and to discuss genotype-phenotype relations.Methods:We describe 9 patients from 5 families in whom muscle biopsies showed vacuoles with an abnormal accumulation of glycogen in muscle fibers, partially α-amylase resistant suggesting polyglucosan bodies. The patients had either progressive early-onset limb-girdle weakness or late-onset distal or scapuloperoneal muscle affection as shown by muscle imaging. No clear definite cardiac disease was found. Histologic and protein analysis investigations were performed on muscle.Results:Genetic analyses by direct or exome sequencing of the GYG1 gene revealed 6 different GYG1 mutations. Four of the mutations were novel. They were compound heterozygous in 3 families and homozygous in 2. Protein analysis revealed either the absence of glycogenin-1 or reduced glycogenin-1 expression with impaired glucosylation.Conclusions:Our report extends the genetic and clinical spectrum of glycogenin-1–related myopathies to include scapuloperoneal and distal affection with glycogen accumulation.
Published: 2017
Full Text: View/download PDF

41. Common and variable clinical, histological, and imaging findings of recessive RYR1-related centronuclear myopathy patients

Author: Cristiane de Araújo Martins Moreno, Valérie Biancalana, Julien Fauré, Jahannaz Dastgir, Lilia Mesrob, Soledad Monges, L. Medne, Edoardo Malfatti, Diana Bharucha-Goebel, Mariarita Santi, Emmanuelle Salort-Campana, James J. Collins, Raphaël Schneider, Chrystel Cheraud, A. Reghan Foley, Fabiana Lubieniecki, Norma B. Romero, Acary Souza Bulle Oliveira, Sandra Donkervoort, Julie Dawn Thompson, Osorio Abath Neto, Sabrina W. Yum, Carsten G. Bönnemann, John Rendu, Brenda Banwell, Johann Böhm, Anne Boland, Julio Brandao Guimaraes, Jocelyn Laporte, Xavière Lornage, Edmar Zanoteli, Bruno Eymard, Uluç Yiş, Payam Mohassel, Jean-François Deleuze, Umbertina Conti Reed, Doris Lechner, Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies neuromusculaires et de la SLA, and Hôpital de la Timone [CHU - APHM] (TIMONE)
Subjects: 0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Adolescent, Biology, Compound heterozygosity, Ophthalmoparesis, Cohort Studies, Congenital myopathies, 03 medical and health sciences, 0302 clinical medicine, RYR1, medicine, Humans, Centronuclear myopathy, Child, Muscle, Skeletal, Genetics (clinical), Muscle biopsy, medicine.diagnostic_test, MUTAÇÃO GENÉTICA, Facial weakness, Infant, Ryanodine Receptor Calcium Release Channel, Middle Aged, musculoskeletal system, medicine.disease, Hypotonia, 030104 developmental biology, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurology, Child, Preschool, Pediatrics, Perinatology and Child Health, Mutation, Female, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Central core disease, Myopathies, Structural, Congenital
Abstract: International audience; Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including centronuclear myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related centronuclear myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in Comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related centronuclear myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients. (C) 2017 Elsevier B.V. All rights reserved.
Published: 2017
Full Text: View/download PDF

42. Corrigendum to '22nd International Congress of the World Muscle Society, Saint Malo, France, 3rd-7th October 2017' [Neuromuscular Disorders 27S2 (2017) S51-S270]

Author: A. Chatagnon, T. Stojkovic, Julien Fauré, Nathalie Roux-Buisson, Norma B. Romero, C Bosson, J. Durigneux, François Rivier, Soledad Monges, B. Bankole, Isabelle Marty, John Rendu, CHU Grenoble, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)
Subjects: 0303 health sciences, biology, business.industry, [SDV]Life Sciences [q-bio], Physiology, SAINT, Ancient history, biology.organism_classification, 03 medical and health sciences, 0302 clinical medicine, Neurology, International congress, Pediatrics, Perinatology and Child Health, Medicine, Neurology (clinical), business, Malo, 030217 neurology & neurosurgery, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience
Published: 2017
Full Text: View/download PDF

43. Morphological spectrum of RYR1 recessive myopathies: Clinical and genetic correlation

Author: Guy Brochier, E. Lacène, Gisèle Bonne, Fabiana Lubieniecki, F. Levy Borsato, Soledad Monges, Sabrina Sacconi, Clémence Labasse, A. Madelaine, Stéphane Vassilopoulos, Norma B. Romero, Giovanni Antonini, Maud Beuvin, Marc Bitoun, John Rendu, Ana Lia Taratuto, Jorge A. Bevilacqua, Matteo Garibaldi, CHU Grenoble, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Institut de Myologie, and 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)
Subjects: Genetics, RYR1, Neurology, [SDV]Life Sciences [q-bio], Pediatrics, Perinatology and Child Health, Neurology (clinical), Biology, Genetic correlation, Spectrum (topology), Myopathie, Genetics (clinical)
Published: 2017
Full Text: View/download PDF

44. Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C

Author: Michel Fardeau, Shari Fallet, Silvia Torelli, Norma B. Romero, C Pollitt, Gillian Storey, Caroline Sewry, Paola Prandini, Rumaisa Bashir, Thomas Voit, Derek J. Blake, Louise V.B. Anderson, Kate Bushby, Susan C. Brown, Volker Straub, Y Yuva, Isabelle Richard, Francesco Muntoni, Ralf Herrmann, Matthew A. Benson, Jean-Marc Burgunder, and Martin Brockington
Subjects: Adult, Male, Adolescent, Genotype, Genetic Linkage, Blotting, Western, 610 Medicine & health, Polymerase Chain Reaction, Muscular Dystrophies, Muscle hypertrophy, Immunoenzyme Techniques, Fukuyama congenital muscular dystrophy, Genetics, medicine, Humans, Pentosyltransferases, Age of Onset, Muscular dystrophy, Child, Dystroglycans, Walker–Warburg syndrome, Molecular Biology, Genetics (clinical), DNA Primers, Membrane Glycoproteins, Fukutin-related protein, biology, Calpain, Infant, Proteins, General Medicine, Middle Aged, medicine.disease, Fukutin, Pedigree, Cytoskeletal Proteins, Phenotype, Haplotypes, Child, Preschool, Mutation, biology.protein, Congenital muscular dystrophy, Female, Laminin, Chromosomes, Human, Pair 19, Microsatellite Repeats, Limb-girdle muscular dystrophy
Abstract: The limb girdle and congenital muscular dystrophies (LGMD and CMD) are characterized by skeletal muscle weakness and dystrophic muscle changes. The onset of symptoms in CMD is within the first few months of life, whereas in LGMD they can occur in late childhood, adolescence or adult life. We have recently demonstrated that the fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C), characterized by the inability to walk, leg muscle hypertrophy and a secondary deficiency of laminin alpha2 and alpha-dystroglycan. Both MDC1C and LGMD2I map to an identical region on chromosome 19q13.3. To investigate whether these are allelic disorders, we undertook mutation analysis of FKRP in 25 potential LGMD2I families, including some with a severe and early onset phenotype. Mutations were identified in individuals from 17 families. A variable reduction of alpha-dystroglycan expression was observed in the skeletal muscle biopsy of all individuals studied. In addition, several cases showed a deficiency of laminin alpha2 either by immunocytochemistry or western blotting. Unexpectedly, affected individuals from 15 families had an identical C826A (Leu276Ileu) mutation, including five that were homozygous for this change. Linkage analysis identified at least two possible haplotypes in linkage disequilibrium with this mutation. Patients with the C826A change had the clinically less severe LGMD2I phenotype, suggesting that this is a less disruptive FKRP mutation than those found in MDC1C. The spectrum of LGMD2I phenotypes ranged from infants with an early presentation and a Duchenne-like disease course including cardiomyopathy, to milder phenotypes compatible with a favourable long-term outcome.
Published: 2017
Full Text: View/download PDF

45. Dynamin-2 mutations linked to Centronuclear Myopathy impair actin-dependent trafficking in muscle cells

Author: Pascale Guicheney, Mai Thao Bui, Arlek M. González-Jamett, Ximena Báez-Matus, Fernando Hinostroza, Jacqueline Vásquez-Navarrete, María José Olivares, Pablo Caviedes, Maria José Guerra-Fernández, Norma B. Romero, Jorge A. Bevilacqua, Marc Bitoun, Ana M. Cárdenas, Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaiso [Chile], Programa de Farmacología Molecular y Clínica, Instituto de Ciencias Biomedicas, 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), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Centre de Recherche en Myologie
Subjects: 0301 basic medicine, Science, Gene Expression, macromolecular substances, medicine.disease_cause, Article, Myoblasts, Dynamin II, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Myocyte, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Centronuclear myopathy, Genetic Association Studies, Actin, Dynamin, Genetics, Muscle Cells, Mutation, Glucose Transporter Type 4, Multidisciplinary, Sarcolemma, biology, medicine.disease, Congenital myopathy, Actins, Cell biology, Enzyme Activation, Disease Models, Animal, Protein Transport, 030104 developmental biology, biology.protein, Medicine, Protein Multimerization, 030217 neurology & neurosurgery, GLUT4, Myopathies, Structural, Congenital, Protein Binding
Abstract: Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM-linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM.
Published: 2017
Full Text: View/download PDF

46. Mutation Update: The Spectra of Nebulin Variants and Associated Myopathies

Author: Thomas L. Winder, Vilma-Lotta Lehtokari, Nigel F. Clarke, Kathryn N. North, K. Kiiski, Nigel G. Laing, Pauliina Repo, Alan H. Beggs, Kati Donner, Sarah A. Sandaradura, Carol J Saunders, Jennifer A. Frey, Jocelyn Laporte, Norma B. Romero, Carina Wallgren-Pettersson, Peter G. Barth, M. Marttila, Katarina Pelin, Johan T. den Dunnen, and Paediatric Neurology
Subjects: Genotype, Muscle Proteins, Biology, medicine.disease_cause, Article, 03 medical and health sciences, Exon, Nebulin, 0302 clinical medicine, Nemaline myopathy, Muscular Diseases, Databases, Genetic, actin-myosin, Genetics, medicine, Animals, Humans, Myopathy, Exome, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, nemaline (rod) myopathy, NEB, Exons, nebulin, medicine.disease, 3. Good health, Alternative Splicing, Phenotype, Chromosomes, Human, Pair 2, Models, Animal, Distal Myopathies, biology.protein, sarcomere, medicine.symptom, 030217 neurology & neurosurgery
Abstract: A mutation update on the nebulin gene (NEB) is necessary because of recent developments in analysis methodology, the identification of increasing numbers and novel types of variants, and a widening in the spectrum of clinical and histological phenotypes associated with this gigantic, 183 exons containing gene. Recessive pathogenic variants in NEB are the major cause of nemaline myopathy (NM), one of the most common congenital myopathies. Moreover, pathogenic NEB variants have been identified in core-rod myopathy and in distal myopathies. In this update, we present the disease-causing variants in NEB in 159 families, 143 families with NM, and 16 families with NM-related myopathies. Eighty-eight families are presented here for the first time. We summarize 86 previously published and 126 unpublished variants identified in NEB. Furthermore, we have analyzed the NEB variants deposited in the Exome Variant Server (http://evs.gs.washington.edu/EVS/), identifying that pathogenic variants are a minor fraction of all coding variants (~7%). This indicates that nebulin tolerates substantial changes in its amino acid sequence, providing an explanation as to why variants in such a large gene result in relatively rare disorders. Lastly, we discuss the difficulties of drawing reliable genotype–phenotype correlations in NEB-associated disease.
Published: 2014
Full Text: View/download PDF

47. A new muscle glycogen storage disease associated with glycogenin-1 deficiency

Author: Fabrice Michel, Cristina Domínguez-González, Gabriel Viennet, H. Orhan Akman, Johanna Nilsson, Carola Hedberg-Oldfors, Cornelia Kornblum, Aurelio Hernández-Laín, Salvatore DiMauro, Norma B. Romero, Peter Van den Bergh, Anders Oldfors, Andrew G. Engel, and Edoardo Malfatti
Subjects: 0303 health sciences, medicine.medical_specialty, Glycogenin, Skeletal muscle, Biology, Compound heterozygosity, medicine.disease, 3. Good health, Glycogen debranching enzyme, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, medicine.anatomical_structure, Neurology, Internal medicine, medicine, biology.protein, Glycogen storage disease, Neurology (clinical), medicine.symptom, Myopathy, Glycogen synthase, GSK3B, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: We describe a slowly progressive myopathy in 7 unrelated adult patients with storage of polyglucosan in muscle fibers. Genetic investigation revealed homozygous or compound heterozygous deleterious variants in the glycogenin-1 gene (GYG1). Most patients showed depletion of glycogenin-1 in skeletal muscle, whereas 1 showed presence of glycogenin-1 lacking the C-terminal that normally binds glycogen synthase. Our results indicate that either depletion of glycogenin-1 or impaired interaction with glycogen synthase underlies this new form of glycogen storage disease that differs from a previously reported patient with GYG1 mutations who showed profound glycogen depletion in skeletal muscle and accumulation of glycogenin-1.
Published: 2014
Full Text: View/download PDF

48. Muscle magnetic resonance imaging and histopathology inACTA1-related congenital nemaline myopathy

Author: Adele D'Amico, Roger Gejman, Fabiana Fattori, Filippo M. Santorelli, Enrico Bertini, Jorge A. Bevilacqua, Karin Alvarez, Jorge Díaz, Claudia Castiglioni, Norma B. Romero, Emanuele Bellacchio, and Denis Cassandrini
Subjects: Pathology, medicine.medical_specialty, Muscle biopsy, medicine.diagnostic_test, Physiology, Neurogenetics, Magnetic resonance imaging, Anatomy, Biology, medicine.disease, Cellular and Molecular Neuroscience, Nemaline myopathy, medicine.anatomical_structure, Tongue, Physiology (medical), Biopsy, medicine, Histopathology, Neurology (clinical), Nemaline bodies
Abstract: Introduction: Muscle biopsy is usually diagnostic in nemaline myopathy (NM), but some patients may show nonspecific findings, leading to pitfalls in diagnosis. Muscle MRI is a helpful complementary tool. Methods: We assessed the clinical, histopathological, MRI, and molecular findings in a 19-year-old patient with NM in whom 2 muscle biopsies with ultrastructural examination showed no nemaline bodies. We analyzed the degree and pattern of muscle MRI involvement of the entire body, including the tongue and pectoral muscles. Results: Muscle MRI abnormalities in sartorius, adductor magnus, and anterior compartment muscles of the leg suggested NM. A previously unreported fatty infiltration of the tongue was found. A third biopsy after the muscle MRI showed scant nemaline bodies. A novel heterozygous de novo ACTA1 c.611C>T/p.Thr204Ile mutation was detected. Conclusions: We highlight the contribution of muscle imaging in addressing the genetic diagnosis of ACTA1-related NM. Muscle Nerve 50: 1011–1016, 2014
Published: 2014
Full Text: View/download PDF

49. Anti-HMGCR Autoantibodies in European Patients With Autoimmune Necrotizing Myopathies

Author: Norma B. Romero, Anne Tournadre, Chafika Morati, T. Stojkovic, Rémi Bellance, Dominique Menard, Sophie Besnard, Nathalie Costedoat-Chalumeau, Emmanuelle Campana-Salort, Lucile Musset, Fabienne Jouen, Bruno Eymard, Patrice Cacoub, Bernard Grosbois, Olivier Boyer, Laurent Drouot, Jean Sibilia, Laurent Servais, Jean Luc Charuel, Olivier Fain, Yves Allenbach, Antoine Dossier, Claire Larroche, Serge Herson, Marielle Roux, Aude Rigolet, Jérémie Martinet, Benjamin Terrier, Anthony Behin, Thierry Maisonobe, Brigitte Bader-Meunier, Olivier Benveniste, Isabelle Koné-Paut, Raphael De Paz, Odile Dubourg, Pascal Laforêt, Laurent Arnaud, Elisabeth Diot, and Xavier Ferrer
Subjects: medicine.medical_specialty, Pathology, Statin, Necrosis, biology, business.industry, medicine.drug_class, Autoantibody, General Medicine, Hydroxymethylglutaryl-CoA reductase, Gastroenterology, Titer, Weight loss, Internal medicine, Cohort, biology.protein, Medicine, Creatine kinase, medicine.symptom, business
Abstract: Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (
Published: 2014
Full Text: View/download PDF

50. CONGENITAL MYOPATHIES: RYR1 AND TITIN

Author: J. Pastor, Guy Brochier, Clémence Labasse, A. Madelaine, Norma B. Romero, Teresinha Evangelista, and Maud Beuvin
Subjects: RYR1, Pathology, medicine.medical_specialty, Neurology, biology, business.industry, Pediatrics, Perinatology and Child Health, biology.protein, Medicine, Titin, Neurology (clinical), business, Genetics (clinical)
Published: 2019
Full Text: View/download PDF

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

204 results on '"Norma B Romero"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources