Descriptor: "Muscular Dystrophies, Limb-Girdle" / Publisher: hal ccsd - Searchworks@Jio Institute Digital Library Search Results

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29 results on '"Muscular Dystrophies, Limb-Girdle"'

1. Deep phenotyping of an international series of patients with late‐onset dysferlinopathy

Author: Fernández-Eulate, Gorka, Querin, Giorgia, Moore, Ursula, Behin, Anthony, Masingue, Marion, Bassez, Guillaume, Leonard-Louis, Sarah, Laforêt, Pascal, Maisonobe, Thierry, Merle, Philippe-Edouard, Spinazzi, Marco, Solé, Guilhem, Kuntzer, Thierry, Bedat-Millet, Anne-Laure, Salort-Campana, Emmanuelle, Attarian, Shahram, Péréon, Yann, Feasson, Leonard, Graveleau, Julie, Nadaj-Pakleza, Aleksandra, Leturcq, France, Gorokhova, Svetlana, Krahn, Martin, Eymard, Bruno, Straub, Volker, Evangelista, Teresinha, Stojkovic, Tanya, 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), Newcastle University [Newcastle], Hôpital Raymond Poincaré [AP-HP], Université Paris-Saclay, Service de Neurophysiologie [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), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), CHU Amiens-Picardie, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), CHU Rouen, Normandie Université (NU), Hôpital de la Timone [CHU - APHM] (TIMONE), 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), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Centre hospitalier de Saint-Nazaire, CHU Strasbourg, Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), Gestionnaire, Hal Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)
Subjects: Adult, Dysferlinopathy, Pathology, medicine.medical_specialty, Necrosis, muscle pathology, [SDV]Life Sciences [q-bio], Muscle Proteins, Late onset, Inflammation, Dysferlin, 03 medical and health sciences, Camptocormia, 0302 clinical medicine, medicine, Humans, 030212 general & internal medicine, Myopathy, late onset, Retrospective Studies, Muscle biopsy, medicine.diagnostic_test, biology, business.industry, Membrane Proteins, Middle Aged, medicine.disease, 3. Good health, LGMDR2, dysferlin, [SDV] Life Sciences [q-bio], Neurology, Muscular Dystrophies, Limb-Girdle, biology.protein, Female, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, myopathy
Abstract: International audience; Background: To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients.Methods: Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (
Published: 2021
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2. Late-onset camptocormia caused by a heterozygous in-frame CAPN3 deletion

Author: Marco Spinazzi, Jerome Poupiot, Julien Cassereau, France Leturcq, Laurent Brunereau, Edoardo Malfatti, Isabelle Richard, Franck Letournel, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Généthon, 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, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Henri Mondor, and Richard, Isabelle
Subjects: 0301 basic medicine, Pathology, Supine position, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Muscle Proteins, Electromyography, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Camptocormia, 0302 clinical medicine, Age of Onset, Genetics (clinical), Sequence Deletion, medicine.diagnostic_test, biology, Calpain, Magnetic Resonance Imaging, Calpainopathy, Neurology, Calpain-3, Female, medicine.medical_specialty, Heterozygote, Paravertebral myopathy, Late onset, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Spinal Curvatures, Muscular Atrophy, Spinal, 03 medical and health sciences, medicine, Humans, Muscle, Skeletal, Pathological, Aged, Muscle biopsy, business.industry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Pediatrics, Perinatology and Child Health, biology.protein, Creatine kinase, Bent‑spine, Neurology (clinical), Differential diagnosis, business, 030217 neurology & neurosurgery
Abstract: International audience; Camptocormia is defined by a pathological involuntary flexion of the thoracic and lumbar spine that is fully reducible in the supine position. Although originally described as a manifestation of conversion disorder, it is more commonly caused by a wide range of neurological diseases, in particular movement and neuromuscular disorders. We describe here a rare case of late onset camptocormia caused by autosomal dominant calpainopathy due to a heterozygous in-frame deletion in CAPN3 leading to loss of a single lysin amino acid in the catalytic domain of calpain-3. Creatine kinase levels, electromyography, and thigh muscle MRI were normal. Muscle biopsy did not show lobulated fibers and calpain-3 protein expression was not decreased, but in vitro functional assays showed impaired proteolytic function of. Lys254del CAPN3. Autosomal dominant calpainopathy should be considered in the differential diagnosis of late onset camptocormia and unexplained paravertebral myopathies even in presence of normal creatine kinase levels, and in absence of lobulated fibers, of decreased calpain-3 protein expression, and of muscle limb involvement.
Published: 2021
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3. Retrospective analysis and reclassification of DYSF variants in a large French series of dysferlinopathy patients

Author: Svetlana Gorokhova, Théo Charnay, Karine Nguyen, Nathalie Bonello-Palot, Véronique Blanck, Mathieu Cerino, Nicolas Lévy, Christophe Pécheux, Marc Bartoli, Florence Riccardi, Martin Krahn, Hôpital de la Timone [CHU - APHM] (TIMONE), 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), and Bartoli, Marc
Subjects: 0301 basic medicine, Dysferlinopathy, medicine.medical_specialty, MEDLINE, Genomics, Computational biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, 030105 genetics & heredity, 03 medical and health sciences, medicine, Retrospective analysis, Humans, Genetic Testing, Dysferlin, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Molecular pathology, business.industry, Genetic Variation, medicine.disease, Pathogenicity, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, business
Abstract: Purpose Recent evolution of sequencing technologies and the development of international standards in variant interpretation have profoundly changed the diagnostic approaches in clinical genetics. As a consequence, many variants that were initially claimed to be disease-causing can be now reclassified as benign or uncertain in light of the new data available. Unfortunately, the misclassified variants are still present in the scientific literature and variant databases, greatly interfering with interpretation of diagnostic sequencing results. Despite the urgent need, large-scale efforts to update the classifications of these variants are still not sufficient. Methods We retrospectively analyzed 176 DYSF gene variants that were identified in dysferlinopathy patients referred to the Marseille Medical Genetics Department for diagnostic sequencing since 2001. Results We reclassified all variants into five-tier American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) pathogenicity classes, revealing changed pathogenicity for 17 variants. We then updated the information for the variants that have been previously published in the variant database and submitted 46 additional DYSF variants. Conclusion Besides direct benefit for dysferlinopathy diagnostics, our study contributes to the much needed effort to reanalyze variants from previously published cohorts and to work with curators of variant databases to update the entries for erroneously classified variants. Unlabelled Image
Published: 2021
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4. Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

Author: Owens, Daniel, Messéant, Julien, Moog, Sophie, Viggars, Mark, Ferry, Arnaud, Mamchaoui, Kamel, Lacène, Emmanuelle, Romero, Norma, Brull, Astrid, Bonne, Gisèle, Butler-Browne, Gillian, Coirault, Catherine, Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Liverpool John Moores University (LJMU), 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), Inovarion, Centre de recherche en Myologie – U974 SU-INSERM, 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), Gestionnaire, HAL Sorbonne Université 5, Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: congenital, hereditary, and neonatal diseases and abnormalities, Genotype, Biopsy, Muscle Fibers, Skeletal, Neuromuscular Junction, Fluorescent Antibody Technique, Gene Expression, Cell Cycle Proteins, Cell Communication, Article, lcsh:Chemistry, RC1200, Mice, QH301, RA0421, satellite cell, Animals, Humans, Genetic Predisposition to Disease, Muscle, Skeletal, lcsh:QH301-705.5, QH426, Genetic Association Studies, mechanotransduction, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, integumentary system, nutritional and metabolic diseases, nuclear envelope, Lamin Type A, QP, Disease Models, Animal, Phenotype, Muscular Dystrophies, Limb-Girdle, lcsh:Biology (General), lcsh:QD1-999, Mutation, embryonic structures, YAP, muscle growth, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, Transcription Factors
Abstract: Laminopathies 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&ndash, 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 mutations may impair skeletal muscle growth. Using human muscle stem cells (MuSCs) carrying LMNA-CMD mutations, we observe impaired myogenic fusion with disorganized cadherin/&beta, catenin adhesion complexes. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective fusion of activated MuSCs, defective protein synthesis and defective remodeling of the neuromuscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the yes-associated protein (YAP). 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 but less severe EDMD models. In conclusion, combining studies in vitro, in vivo, and patient samples, we find that LMNA-CMD mutations interfere with mechanosignaling pathways in skeletal muscle, implicating A-type lamins in the regulation of skeletal muscle growth.
Published: 2020
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5. Sarcoglycanopathies: state of the art and therapeutic perspectives

Author: Fernández-Eulate, Gorka, Leturcq, France, Laforêt, Pascal, Richard, Isabelle, Stojkovic, Tanya, Centre de référence des maladies neuromusculaires Nord/Est/Ile-de-France [Paris], 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)-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), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Raymond Poincaré [AP-HP], 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, and Richard, Isabelle
Subjects: musculoskeletal diseases, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Therapies, Investigational, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, musculoskeletal system, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, Muscular Dystrophies, Limb-Girdle, Neurology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Disease Progression, Sarcoglycanopathies, Humans
Abstract: Sarcoglycanopathies are the third most common cause of autosomal recessive limb girdle muscular dystrophies (LGMD). They are the result of a deficiency in one of the sarcoglycans a, b, g, or d. The usual clinical presentation is that of a symmetrical involvement of the muscles of the pelvic and scapular girdles as well as of the trunk, associated with more or less severe cardio-respiratory impairment and a marked increase of serum CK levels. The first symptoms appear during the first decade, the loss of ambulation occurring often during the second decade. Lesions observed on the muscle biopsy are dystrophic. This is associated with a decrease or an absence of immunostaining of the sarcoglycan corresponding to the mutated gene and, to a lesser degree, of the other three sarcoglycans. Many mutations have been reported in the four incriminated genes and some of them are prevalent in certain populations. To date, there is no curative treatment, which does not prevent the development of many clinical trials, especially in gene therapy.Les sarcoglycanopathies - État des lieux et perspectives thérapeutiques.Les sarcoglycanopathies font partie des dystrophies musculaires des ceintures (LGMD) autosomiques récessives et représentent la troisième cause la plus fréquente d’entre elles. Elles sont consécutives à un déficit d’un des sarcoglycanes α, β, γ, ou δ. La présentation clinique habituelle est celle d’une atteinte symétrique des muscles des ceintures pelvienne et scapulaire ainsi que du tronc, associée à une atteinte cardiorespiratoire plus ou moins sévère et une élévation franche des créatine-phospho-kinases (CPK). Les premiers symptômes apparaissent au cours de la première décennie, la perte de la marche survenant souvent au cours de la deuxième décennie. Les lésions sont de type dystrophique sur la biopsie musculaire. Il s’y associe une diminution ou une absence d’immunomarquage du sarcoglycane correspondant au gène muté, et dans une moindre mesure des trois autres sarcoglycanes associés. De nombreuses mutations ont été rapportées dans les quatre gènes impliqués et quelques-unes d’entre elles sont prépondérantes dans certaines populations. à ce jour, il n’existe pas de traitement curatif ce qui n’empêche pas de voir se développer de nombreux essais cliniques, notamment en thérapie génique.
Published: 2020
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6. Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

Author: Alexandra Salvi, Eugénie Dionnet, Nathalie Da Silva, Francesca Puppo, Svetlana Gorokhova, Martin Krahn, Aurelia Defour, Marc Bartoli, Nicolas Lévy, 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), and Bartoli, Marc
Subjects: medicine.medical_specialty, RNA Splicing, Mutation, Missense, Muscle Proteins, Genomics, Computational biology, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, 03 medical and health sciences, Exon, Genetics, medicine, Missense mutation, Humans, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Calpain, 030305 genetics & heredity, Intron, Exons, medicine.disease, 3. Good health, Muscular Dystrophies, Limb-Girdle, RNA splicing, Medical genetics, Limb-girdle muscular dystrophy, Minigene
Abstract: Improving the accuracy of variant interpretation during diagnostic sequencing is a major goal for genomic medicine. In order to explore an often overlooked splicing effect of missense variants, we developed the functional assay (“minigene”) for the majority of exons of CAPN3, the gene responsible for Limb Girdle Muscular Dystrophy (LGMD). By systematically screening 21 missense variants distributed along the gene, we found that eight clinically relevant missense variants located at a certain distance from the exon/intron borders (deep exonic missense variants) disrupted normal splicing of CAPN3 exons. Several recent machine learning based computational tools failed to predict splicing impact for the majority of these deep exonic missense variants, highlighting the importance of including variants of this type in the training sets during the future algorithm development. Overall, 24 variants in CAPN3 gene were explored, leading to the change in the ACMG classification of seven of them when results of the “minigene” functional assay were taken into account. Our findings reveal previously unknown splicing impact of several clinically important variants in CAPN3 and draw attention to the existence of deep exonic variants with a disruptive effect on gene splicing that could be overlooked by the current approaches in clinical genetics.
Published: 2020
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7. A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity

Author: Thomas Krag, Carinne Roudaut, John Vissing, Julia R. Dahlqvist, Morten Duno, Isabelle Richard, Jerome Poupiot, University of Copenhagen = Københavns Universitet (KU), 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 Copenhagen = Københavns Universitet (UCPH), and Richard, Isabelle
Subjects: Adult, Male, Proband, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Adolescent, Muscle Proteins, calpain 3, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease_cause, Young Adult, 03 medical and health sciences, Genetics, medicine, Humans, Missense mutation, Child, Genetics (clinical), limb girdle muscular dystrophy, Aged, 030304 developmental biology, 0303 health sciences, Mutation, Muscle biopsy, dominant inheritance, biology, medicine.diagnostic_test, Calpain, 030305 genetics & heredity, Muscle weakness, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Middle Aged, medicine.disease, Molecular biology, Pedigree, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, calpainopathy, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, Creatine kinase, medicine.symptom, Limb-girdle muscular dystrophy
Abstract: Recessively inherited limb girdle muscular dystrophy (LGMD) type 2A is the most common LGMD worldwide. Here, we report the first single missense variant in CAPN3 causing dominantly inherited calpainopathy. A 43-year-old proband, his father and two sons were heterozygous for a c.1715G>C p.(Arg572Pro) variant in CAPN3. Affected family members had at least three of the following; muscle pain, a LGMD2A pattern of muscle weakness and wasting, muscle fat replacement on MRI, myopathic muscle biopsy, and elevated creatine kinase. Total calpain 3 protein expression was 4 ± 3% of normal. In vitro analysis of c.1715G>C and the previously described c.643_663del variant indicated that the mutant proteins lack autolytic and proteolytic activity and decrease the quantity of wild-type CAPN3 protein. Our findings suggest that dominantly inherited calpainopathy is not unique to the previously reported c.643_663del mutation of CAPN3, and that dominantly inherited calpainopathy should be considered for other single variations in CAPN3. This article is protected by copyright. All rights reserved.
Published: 2020
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8. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy patients

Author: Laura Costa-Comellas, Chiara Panicucci, Ana Camacho-Salas, Ulrike Schara, Claudio Semplicini, Isabel Illa, Arturo Fraga-Bau, Leroy ten Dam, Jan De Bleecker, Lea Leonardis, Jesper Helbo Storgaard, Juan Carlos de Leon-Hernández, Vittoria Zangaro, Giacomo P. Comi, Vincenzo Nigro, Adele D'Amico, Benedikt Schoser, Pia Gallano, Manuela Santos, Edoardo Malfatti, Cristina Domínguez-González, F. Munell, De Vos Elke, Alicia Alonso-Jimenez, Matteo Garibaldi, Bjarne Udd, Nicoline Løkken, A. J. van der Kooi, Giorgio Tasca, John Vissing, Jordi Díaz-Manera, Elena Pegoraro, Andrea Gangfuß, Jorge Alonso-Pérez, Claudia Weiss, Luisa Politano, Marie Rohlenová, Cristina Garrido, David Gómez-Andrés, Jana Haberlová, Roberto Fernández-Torrón, Gabriele Dekomien, Kristl G. Claeys, Marianne de Visser, Andrés Nascimento, Michela Guglieri, Carlos Ortez, Isabelle Richard, Lidia Gonzalez-Quereda, Béla Melegh, Claudio Bruno, Omar Abdel-Mannan, Anna Sarkozy, Adolfo López de Munain, Blaz Koritnik, Nicolas Deconinck, Kinga Hadzsiev, Luca Bello, Johanna Palmio, Volker Straub, 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, Neurology, ANS - Neuroinfection & -inflammation, Graduate School, Alonso-Pérez, Jorge, González-Quereda, Lidia, Bello, Luca, Guglieri, Michela, Straub, Volker, Gallano, Pia, Semplicini, Claudio, Pegoraro, Elena, Zangaro, Vittoria, Nascimento, André, Ortez, Carlo, Comi, Giacomo Pietro, ten Dam, Leroy, De Visser, Marianne, van der Kooi, A J, Garrido, Cristina, Santos, Manuela, Schara, Ulrike, Gangfuß, Andrea, Løkken, Nicoline, Storgaard, Jesper Helbo, Vissing, John, Schoser, Benedikt, Dekomien, Gabriele, Udd, Bjarne, Palmio, Johanna, D'Amico, Adele, Politano, Luisa, Nigro, Vincenzo, Bruno, Claudio, Panicucci, Chiara, Sarkozy, Anna, Abdel-Mannan, Omar, Alonso-Jimenez, Alicia, Claeys, Kristl G, Gomez-Andrés, David, Munell, Francina, Costa-Comellas, Laura, Haberlová, Jana, Rohlenová, Marie, Elke, De Vo, De Bleecker, Jan L, Dominguez-González, Cristina, Tasca, Giorgio, Weiss, Claudia, Deconinck, Nicola, Fernández-Torrón, Roberto, López de Munain, Adolfo, Camacho-Salas, Ana, Melegh, Béla, Hadzsiev, Kinga, Leonardis, Lea, Koritnik, Blaz, Garibaldi, Matteo, de Leon-Hernández, Juan Carlo, Malfatti, Edoardo, Fraga-Bau, Arturo, Richard, Isabelle, Illa, Isabel, and Díaz-Manera, Jordi
Subjects: 0301 basic medicine, Registrie, Male, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Medizin, Limb girdle muscular dystrophie, Cohort Studies, 0302 clinical medicine, Registries, Child, sarcoglycan, ComputingMilieux_MISCELLANEOUS, treatment, Cohort, cohort, Middle Aged, limb girdle muscular dystrophies, 3. Good health, Europe, Child, Preschool, registries, Female, Cohort study, Sarcoglycanopathies, Adult, medicine.medical_specialty, Adolescent, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, Limb girdle muscular dystrophies, Sarcoglycan, Genetic Association Studies, SGCA, Aged, Retrospective Studies, business.industry, Retrospective cohort study, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Treatment, 030104 developmental biology, Sarcoglycanopathy, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurology (clinical), Human medicine, Age of onset, business, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy
Abstract: Sarcoglycanopathies comprise four subtypes of autosomal recessive limb-girdle muscular dystrophies (LGMDR3, LGMDR4, LGMDR5 and LGMDR6) that are caused, respectively, by mutations in the SGCA, SGCB, SGCG and SGCD genes. In 2016, several clinicians involved in the diagnosis, management and care of patients with LGMDR3–6 created a European Sarcoglycanopathy Consortium. The aim of the present study was to determine the clinical and genetic spectrum of a large cohort of patients with sarcoglycanopathy in Europe. This was an observational retrospective study. A total of 33 neuromuscular centres from 13 different European countries collected data of the genetically confirmed patients with sarcoglycanopathy followed-up at their centres. Demographic, genetic and clinical data were collected for this study. Data from 439 patients from 13 different countries were collected. Forty-three patients were not included in the analysis because of insufficient clinical information available. A total of 159 patients had a confirmed diagnosis of LGMDR3, 73 of LGMDR4, 157 of LGMDR5 and seven of LGMDR6. Patients with LGMDR3 had a later onset and slower progression of the disease. Cardiac involvement was most frequent in LGMDR4. Sixty per cent of LGMDR3 patients carried one of the following mutations, either in a homozygous or heterozygous state: c.229C>T, c.739G>A or c.850C>T. Similarly, the most common mutations in LMGDR5 patients were c.525delT or c.848G>A. In LGMDR4 patients the most frequent mutation was c.341C>T. We identified onset of symptoms before 10 years of age and residual protein expression lower than 30% as independent risk factors for losing ambulation before 18 years of age, in LGMDR3, LGMDR4 and LGMDR5 patients. This study reports clinical, genetic and protein data of a large European cohort of patients with sarcoglycanopathy. Improving our knowledge about these extremely rare autosomal recessive forms of LGMD was helped by a collaborative effort of neuromuscular centres across Europe. Our study provides important data on the genotype-phenotype correlation that is relevant for the design of natural history studies and upcoming interventional trials in sarcoglycanopathies.
Published: 2020
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9. Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A

Author: Zaher Elbeck, Karine Charton, William Lostal, John E. Smith, Jack Yves Deschamps, Guillaume Corre, Isabelle Richard, Marine Faivre, Henk Granzier, Nathalie Bourg, Xidan Li, Ralph Knöll, Laurence Suel, Jochen Gohlke, Carinne Roudaut, Heather Best, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), and Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon
Subjects: 0301 basic medicine, Primates, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Transgene, RNA Splicing, Muscle Proteins, Article, Dysferlin, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Species Specificity, Enzyme Stability, medicine, Animals, Connectin, Tissue Distribution, Transgenes, Muscular dystrophy, Muscle, Skeletal, Regulation of gene expression, Mice, Knockout, Binding Sites, biology, Calpain, Myocardium, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Medicine, Genetic Therapy, Dependovirus, medicine.disease, Cardiotoxicity, 3. Good health, Cell biology, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Proteolysis, biology.protein, Titin, Ectopic expression, Titin binding, 030217 neurology & neurosurgery, Biomarkers
Abstract: International audience; Limb-girdle muscular dystrophy type 2A (LGMD2A or LGMDR1) is a neuromuscular disorder caused by mutations in the calpain 3 gene ( CAPN3 ). Previous experiments using adeno-associated viral (AAV) vector–mediated calpain 3 gene transfer in mice indicated cardiac toxicity associated with the ectopic expression of the calpain 3 transgene. Here, we performed a preliminary dose study in a severe double-knockout mouse model deficient in calpain 3 and dysferlin. We evaluated safety and biodistribution of AAV9-desmin-hCAPN3 vector administration to nonhuman primates (NHPs) with a dose of 3 × 10 13 viral genomes/kg. Vector administration did not lead to observable adverse effects or to detectable toxicity in NHP. Of note, the transgene expression did not produce any abnormal changes in cardiac morphology or function of injected animals while reaching therapeutic expression in skeletal muscle. Additional investigation on the underlying causes of cardiac toxicity observed after gene transfer in mice and the role of titin in this phenomenon suggest species-specific titin splicing. Mice have a reduced capacity for buffering calpain 3 activity compared to NHPs and humans. Our studies highlight a complex interplay between calpain 3 and titin binding sites and demonstrate an effective and safe profile for systemic calpain 3 vector delivery in NHP, providing critical support for the clinical potential of calpain 3 gene therapy in humans.
Published: 2019
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10. Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation

Author: Teresinha Evangelista, Diane McKenna-Yasek, Janice A. Dominov, Babi Ramesh Reddy Nallamilli, Judith N Hudson, Hanns Lochmüller, Virginie Kergourlay, Marc Bartoli, Madhuri Hegde, Özgün Uyan, Robert H. Brown, Nicolas Lévy, Laura E. Rufibach, Martin Krahn, 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], 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), Department of Neurology, Institute of Human Genetics, and Newcastle University [Newcastle]
Subjects: 0301 basic medicine, Dysferlinopathy, RNA Splicing, Dysferlin, 03 medical and health sciences, Exon, 0302 clinical medicine, Medicine, Humans, Research Articles, ComputingMilieux_MISCELLANEOUS, Genetics, biology, business.industry, General Neuroscience, Point mutation, Intron, Membrane Proteins, Oligonucleotides, Antisense, medicine.disease, Exon skipping, Introns, 3. Good health, Distal Myopathies, Muscular Atrophy, 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, RNA splicing, Mutation, biology.protein, Neurology (clinical), business, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, Research Article
Abstract: Objective Dysferlin is a large transmembrane protein that functions in critical processes of membrane repair and vesicle fusion. Dysferlin‐deficiency due to mutations in the dysferlin gene leads to muscular dystrophy (Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD2B), distal myopathy with anterior tibial onset (DMAT)), typically with early adult onset. At least 416 pathogenic dysferlin mutations are known, but for approximately 17% of patients, one or both of their pathogenic variants remain undefined following standard exon sequencing methods that interrogate exons and nearby flanking intronic regions but not the majority of intronic regions. Methods We sequenced RNA from myogenic cells to identify a novel dysferlin pathogenic variant in two affected siblings that previously had only one disease‐causing variant identified. We designed antisense oligonucleotides (AONs) to bypass the effects of this mutation on RNA splicing. Results We identified a new pathogenic point mutation deep within dysferlin intron 50i. This intronic variant causes aberrant mRNA splicing and inclusion of an additional pseudoexon (PE, we term PE50.1) within the mature dysferlin mRNA. PE50.1 inclusion alters the protein sequence, causing premature translation termination. We identified this mutation in 23 dysferlinopathy patients (seventeen families), revealing it to be one of the more prevalent dysferlin mutations. We used AON‐mediated exon skipping to correct the aberrant PE50.1 splicing events in vitro, which increased normal mRNA production and significantly restored dysferlin protein expression. Interpretation Deep intronic mutations can be a common underlying cause of dysferlinopathy, and importantly, could be treatable with AON‐based exon‐skipping strategies.
Published: 2019
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11. Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials

Author: Tim Hodgson, Dorothy Wallace, Madoka Mori-Yoshimura, Kate Bushby, Diana Bharucha-Goebel, Carmen Paradas, John W. Day, Roberto Stramare, Jean-Yves Hogrel, Elena Bravver, Bruce Harwick, Mark Smith, Andrew M. Blamire, Claudio Semplicini, Emmanuelle Salort-Campana, Pierre G. Carlier, Marni Jacobs, Alessandro Rampado, Laura E. Rufibach, Matthew B. Harms, Olivia Schreiber-Katz, Plavi Mittal, Jerry R. Mendell, Eva Coppenrath, Fiona E. Smith, Sheryl Foster, Stanley T. Fricke, Anna Mayhew, David Bendahan, Tanya Stojkovic, Hanns Lochmüller, Anthony Peduto, Jordi Díaz-Manera, Michelle Eagle, Noriko Sato, Yann Le Fur, H. Hilsden, Suna Turk, U. Moore, Simone Spuler, Kristi J. Jones, Shin'ichi Takeda, Anne M. Sawyer, Volker Straub, Glenn Foster, Elena Pegoraro, Sabine Krause, Louise Ward, Susan Sparks, Hansel J. Otero, Carolina Tesi Rocha, M. James, Luca Bello, Takeshi Tamaru, Alan Pestronk, Jaume Llauger, Roberto Fernández-Torrón, Ulrike Grieben, Susana Rico Gala, Maggie C. Walter, CIBER de Enfermedades Raras (CIBERER), Newcastle University [Newcastle], 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), Georgetown University [Washington] (GU), Università degli Studi di Padova = University of Padua (Unipd), Ludwig Maximilian University [Munich] (LMU), Aix Marseille Université (AMU), Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), The University of Sydney, Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, National Institute of Neurological Disorders and Stroke [Bethesda] (NINDS), National Institutes of Health [Bethesda] (NIH), Neurologie, maladies neuro-musculaires [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Washington University in Saint Louis (WUSTL), 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), Universita degli Studi di Padova, Stanford University School of Medicine [Stanford], Stanford University [Stanford], Max Delbrück Center for Molecular Medicine (MDC), Helmholtz-Gemeinschaft, Washington University in St Louis, Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), United Kingdom Met Office [Exeter], 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), Department of Neurology, Solid State NMR Group, University of Warwick, University of Warwick [Coventry], Max Delbrück Center, Computer Science Department [Boston] (Boston University), Boston University [Boston] (BU), Centre de référence des maladies neuromusculaires et de la SLA, Hôpital de la Timone [CHU - APHM] (TIMONE), 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), and Hospital Universitario Virgen del Rocío [Sevilla]
Subjects: 0301 basic medicine, muscular dystrophy, Adult, Male, medicine.medical_specialty, Dysferlinopathy, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Disease, Muscle disorder, Muscle MRI, Outcome measures, 03 medical and health sciences, outcome measures, 0302 clinical medicine, medicine, Humans, In patient, Longitudinal Studies, Muscular dystrophy, Muscle, Skeletal, ComputingMilieux_MISCELLANEOUS, dysferlinopathy, muscle MRI, Surgery, Neurology (clinical), Psychiatry and Mental Health, Muscle mri, business.industry, Middle Aged, medicine.disease, Magnetic Resonance Imaging, Clinical trial, 030104 developmental biology, Cross-Sectional Studies, Muscular Dystrophies, Limb-Girdle, Neuromuscular, Pattern recognition (psychology), [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, Radiology, Function and Dysfunction of the Nervous System, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Background and objectiveDysferlinopathies are a group of muscle disorders caused by mutations in the DYSF gene. Previous muscle imaging studies describe a selective pattern of muscle involvement in smaller patient cohorts, but a large imaging study across the entire spectrum of the dysferlinopathies had not been performed and previous imaging findings were not correlated with functional tests.MethodsWe present cross-sectional T1-weighted muscle MRI data from 182 patients with genetically confirmed dysferlinopathies. We have analysed the pattern of muscles involved in the disease using hierarchical analysis and presented it as heatmaps. Results of the MRI scans have been correlated with relevant functional tests for each region of the body analysed.ResultsIn 181 of the 182 patients scanned, we observed muscle pathology on T1-weighted images, with the gastrocnemius medialis and the soleus being the most commonly affected muscles. A similar pattern of involvement was identified in most patients regardless of their clinical presentation. Increased muscle pathology on MRI correlated positively with disease duration and functional impairment.ConclusionsThe information generated by this study is of high diagnostic value and important for clinical trial development. We have been able to describe a pattern that can be considered as characteristic of dysferlinopathy. We have defined the natural history of the disease from a radiological point of view. These results enabled the identification of the most relevant regions of interest for quantitative MRI in longitudinal studies, such as clinical trials.Clinical trial registrationNCT01676077.
Published: 2018
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12. AAV-mediated transfer of FKRP shows therapeutic efficacy in a murine model but requires control of gene expression

Author: William J. Martin, Steven J. Foltz, Karine Charton, Nathalie Bourg, Aaron M. Beedle, Evelyne Gicquel, Isabelle Richard, Natacha Maizonnier, Fedor Svinartchouk, 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)-Généthon-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), University of Georgia [USA], École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), École Pratique des Hautes Études (EPHE), and 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
Subjects: 0301 basic medicine, Glycosylation, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Gene Expression, medicine.disease_cause, Muscular Dystrophies, Mice, chemistry.chemical_compound, 0302 clinical medicine, Gene expression, Muscular dystrophy, Dystroglycans, Laminin binding, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Mutation, Fukutin-related protein, Articles, General Medicine, LGMD, Cell biology, FKRP, Protein Binding, Biology, Abnormal glycosylation, 03 medical and health sciences, Muscle Dystrophy, Transferases, Genetics, medicine, Animals, Pentosyltransferases, Muscle, Skeletal, Molecular Biology, Pentosephosphates, Proteins, Genetic Therapy, medicine.disease, Fukutin, Disease Models, Animal, 030104 developmental biology, Gene Expression Regulation, Muscular Dystrophies, Limb-Girdle, chemistry, biology.protein, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Limb Girdle Muscular Dystrophies type 2I (LGMD2I), a recessive autosomal muscular dystrophy, is caused by mutations in the Fukutin Related Protein (FKRP) gene. It has been proposed that FKRP, a ribitol-5-phosphate transferase, is a participant in α-dystroglycan (αDG) glycosylation, which is important to ensure the cell/matrix anchor of muscle fibers. A LGMD2I knock-in mouse model was generated to express the most frequent mutation (L276I) encountered in patients. The expression of FKRP was not altered neither at transcriptional nor at translational levels, but its function was impacted since abnormal glycosylation of αDG was observed. Skeletal muscles were functionally impaired from 2 months of age and a moderate dystrophic pattern was evident starting from 6 months of age. Gene transfer with a rAAV2/9 vector expressing Fkrp restored biochemical defects, corrected the histological abnormalities and improved the resistance to eccentric stress in the mouse model. However, injection of high doses of the vector induced a decrease of αDG glycosylation and laminin binding, even in WT animals. Finally, intravenous injection of the rAAV-Fkrp vector into a dystroglycanopathy mouse model due to Fukutin (Fktn) knock-out indicated a dose-dependent toxicity. These data suggest requirement for a control of FKRP expression in muscles.
Published: 2017
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13. Hip region muscular dystrophy and emergence of motor deficits in dysferlin-deficient Bla/J mice

Author: Toni Ahtoniemi, Randal J. Nonneman, Natallia V. Riddick, Matthew L. Hirsch, Thomas G. Hampton, Catherine F. Dial, Hillarie P. Windish, Isabelle Richard, Nadia Nagy, Telmo Llanga, Jukka Puoliväli, Douglas E. Albrecht, Kimmo Lehtimäki, Sheryl S. Moy, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), 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, and École Pratique des Hautes Études (EPHE)
Subjects: 0301 basic medicine, Male, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Physiology, Bla/J, MESH: Mice, Knockout, Muscular Dystrophies, Dysferlin, Grip strength, Mice, 0302 clinical medicine, MESH: Animals, Muscular dystrophy, Gait, Original Research, Mice, Knockout, MESH: Muscle, Skeletal, biology, Anatomy, MESH: Hip, MESH: Motor Activity, medicine.anatomical_structure, Female, medicine.symptom, medicine.medical_specialty, Weakness, Dysferlinopathy, Skeletal Muscle, mouse model, MESH: Muscular Dystrophies, Limb-Girdle, Muscular Conditions, Disorders and Treatments, Motor Activity, Neurological Conditions, Disorders and Treatments, Psoas Muscles, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, Gluteal muscles, Muscle, Skeletal, MESH: Mice, locomotor deficits, Hip, MESH: Dysferlin, business.industry, MESH: Gait, Dystrophy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Muscular Dystrophies, MESH: Male, dysferlin, Disease Models, Animal, 030104 developmental biology, Endocrinology, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, MESH: Disease Models, Animal, business, MESH: Female, 030217 neurology & neurosurgery, Motor Control, muscular MR imaging and spectroscopy
Abstract: International audience; The identification of a dysferlin-deficient animal model that accurately displays both the physiological and behavior aspects of human dysferlinopathy is critical for the evaluation of potential therapeutics. Disease progression in dysferlin-deficient mice is relatively mild, compared to the debilitating human disease which manifests in impairment of particular motor functions. Since there are no other known models of dysferlinopathy in other species, locomotor proficiency and muscular anatomy through MRI (both lower leg and hip region) were evaluated in dysferlin-deficient B6.A-Dysf prmd /GeneJ (Bla/J) mice to define disease parameters for therapeutic assessment. Despite the early and progressive gluteal muscle dystrophy and significant fatty acid accumulation, the emergence of significant motor function deficits was apparent at approximately 1 year of age for standard motor challenges including the rotarod, a marble bury test, grip strength, and swimming speed. Earlier observations of decreased performance for Bla/J mice were evident during extended monitoring of overall exploration and rearing activity. Comprehensive treadmill gait analyses of the Bla/J model indicated significant differences in paw placement angles and stance in relation to speed and platform slope. At 18 months of age, there was no significant difference in the life expectancy of Bla/J mice compared to wild type. Consistent with progressive volume loss and fatty acid accumulation in the hip region observed by MRI, mass measurement of individual muscles confirmed gluteal and psoas muscles were the only muscles demonstrating a significant decrease in muscle mass, which is analogous to hip-girdle weakness observed in human dysferlin-deficient patients. Collectively, this longitudinal analysis identifies consistent disease parameters that can be indicators of efficacy in studies developing treatments for human dysferlin deficiency.
Published: 2017
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14. Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D

Author: Bernard Clair, Sylvie Chevret, Djillali Annane, Raquel Guimarães-Costa, Abdallah Fayssoil, Tanya Stojkovic, Cendrine Chaffaut, Olivier Nardi, David Orlikowski, Adam Ogna, Pascal Laforêt, Karim Wahbi, Anthony Behin, Hélène Prigent, Frédéric Lofaso, HAL UPMC, Gestionnaire, 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), Service de réanimation médicale[Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Centre d’Investigation Clinique 1429 [Garches] (CIC 1429), Hôpital Raymond Poincaré [AP-HP]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistique et information médicale de l’hôpital Saint Louis (Equipe ECSTRA) (SBIM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut national du cancer [Boulogne] (INCA)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Cardiologie [CHU Cochin], Service de physiologie et d'explorations fonctionnelles [CHU Raymond-Poincaré], 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), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut national du cancer [Boulogne] (INCA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpital Cochin [AP-HP]
Subjects: Male, Heredity, Pulmonology, Genetic Linkage, Physiology, Vital Capacity, Cardiomyopathy, lcsh:Medicine, Duchenne Muscular Dystrophy, Cardiovascular Physiology, Muscular Dystrophies, 0302 clinical medicine, Medicine and Health Sciences, Medicine, Respiratory function, Respiratory system, lcsh:Science, Multidisciplinary, Ejection fraction, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Heart, Prognosis, Respiratory Muscles, 3. Good health, Neurology, X-Linked Traits, Sex Linkage, Cardiology, Female, Cardiomyopathies, Respiratory Insufficiency, Research Article, Adult, medicine.medical_specialty, Death Rates, Diastole, 03 medical and health sciences, Population Metrics, Respiratory Failure, Diagnostic Medicine, Internal medicine, Respiratory muscle, Sarcoglycanopathies, Genetics, Humans, Demography, Clinical Genetics, Population Biology, business.industry, lcsh:R, Biology and Life Sciences, Arrhythmias, Cardiac, medicine.disease, Surgery, 030228 respiratory system, Respiratory failure, Muscular Dystrophies, Limb-Girdle, Heart failure, People and Places, lcsh:Q, business, Physiological Processes, Sleep, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Ejection Fraction
Abstract: BACKGROUND:Type 2C and 2D limb girdle muscular dystrophies (LGMD) are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio-respiratory events and mortality in LGMD 2C and 2D. METHODS:We reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax), cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke) and mortality as outcomes of interest for the present analysis. RESULTS:A total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24-38]. At baseline, median pulmonary vital capacity (VC) was 31% of predicted value [20-40]. Median maximal inspiratory pressure (MIP) was 31 cmH2O [IQR 20.25-39.75]. Median maximal expiratory pressure (MEP) was 30 cm H2O [20-36]. Median left ventricular ejection fraction (LVEF) was 55% [45-64] with 38% of patients with LVEF
Published: 2016
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15. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

Author: Juliette Nectoux, Rafael de Cid, Sylvain Baulande, France Leturcq, Jon Andoni Urtizberea, Isabelle Penisson-Besnier, Aleksandra Nadaj-Pakleza, Carinne Roudaut, Audrey Criqui, Lucie Orhant, Delphine Peyroulan, Raba Ben Yaou, Isabelle Nelson, Anna Maria Cobo, Marie-Christine Arné-Bes, Emmanuelle Uro-Coste, Patrick Nitschke, Mireille Claustres, Gisèle Bonne, Nicolas Lévy, Jamel Chelly, Isabelle Richard, Mireille Cossée, Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génopole [Evry], Université d'Évry-Val-d'Essonne (UEVE), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte, Nantes-Angers, Centre de Référence Maladies Neuromusculaires de l'Enfant et de l'Adulte, Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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)-Centre National de la Recherche Scientifique (CNRS), Nowak, Cécile, and Centre de Recherche en Myologie
Subjects: Adult, Male, Screening techniques, Ubiquitin-Protein Ligases, ASTN2 Gene, DNA Mutational Analysis, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, Tripartite Motif Proteins, 03 medical and health sciences, 0302 clinical medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscular dystrophy, Gene, Genetics (clinical), Loss function, 030304 developmental biology, Family Health, Comparative Genomic Hybridization, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Massive parallel sequencing, Base Sequence, Breakpoint, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, Pedigree, Muscular Dystrophies, Limb-Girdle, Female, Gene Deletion, 030217 neurology & neurosurgery, Transcription Factors
Abstract: International audience; Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but this gene is not systematically analysed because of the absence of specific signs and difficulties in protein analysis. By using high-throughput variants screening techniques, we identified variants in TRIM32 in two patients presenting nonspecific LGMD. We report the first case of total inactivation by homozygous deletion of the entire TRIM32 gene. Of interest, the deletion removes part of the ASTN2 gene, a large gene in which TRIM32 is nested. Despite the total TRIM32 gene inactivation, the patient does not present a more severe phenotype. However, he developed a mild progressive cognitive impairment that may be related to the loss of function of ASTN2 because association between ASTN2 heterozygous deletions and neurobehavioral disorders was previously reported. Regarding genomic characteristics at breakpoint of the deleted regions of TRIM32, we found a high density of repeated elements, suggesting a possible hotspot. These observations illustrate the importance of high-throughput technologies for identifying molecular defects in LGMD, confirm that total loss of function of TRIM32 is not associated with a specific phenotype and that TRIM32/ASTN2 inactivation could be associated with cognitive impairment.
Published: 2015
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16. The Phenotype of Dysferlin-Deficient Mice Is Not Rescued by Adeno-Associated Virus–Mediated Transfer of Anoctamin 5

Author: Le Roy, Florence, Suel, Laurence, Poupiot, Jérôme, Bartoli, Marc, Monjaret, François, Suel-Petat, Laurence, Bourg-Alibert, Nathalie, Vihola, Anna, Marchand, Sylvie, Roudaut, Carinne, Gicquel, Evelyne, Udd, Bjarne, Richard, Isabelle, Charton, Karine, CHU Pontchaillou [Rennes], Laboratoire Analyse, Modélisation et Matériaux pour la Biologie et l'Environnement (LAMBE - UMR 8587), Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Généthon, 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), Baculovirus et Thérapie, Centre National de la Recherche Scientifique (CNRS), Folkhälsan Research Center, Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Neurology Department, Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE - UMR 8587), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Généthon, Evry, GENETHON, Genethon, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, École Pratique des Hautes Études (EPHE), and 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
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Dependovirus, MESH: Protein Isoforms, medicine.disease_cause, MESH: Mice, Knockout, MESH: Down-Regulation, Dysferlin, Mice, 0302 clinical medicine, MESH: Genetic Vectors, Protein Isoforms, MESH: Animals, Muscular dystrophy, Adeno-associated virus, Genetics (clinical), Genetics, Mice, Knockout, 0303 health sciences, MESH: Muscle, Skeletal, Gene Transfer Techniques, Dependovirus, Phenotype, Cell biology, microRNAs, medicine.anatomical_structure, muscles, MESH: Membrane Proteins, medicine.symptom, Gene isoform, MESH: Muscular Dystrophies, Limb-Girdle, Genetic Vectors, Anoctamins, Down-Regulation, MESH: Gene Transfer Techniques, Biology, MESH: Phenotype, Cell Line, 03 medical and health sciences, Downregulation and upregulation, Chloride Channels, MESH: Mice, Inbred C57BL, death, medicine, Animals, Humans, Myopathy, Muscle, Skeletal, MESH: Mice, 030304 developmental biology, sudden, MESH: Dysferlin, MESH: Humans, MESH: Chloride Channels, Skeletal muscle, Membrane Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, MESH: Anoctamins, MESH: Cell Line, Mice, Inbred C57BL, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, 030217 neurology & neurosurgery, genetic therapy
Abstract: International audience; Mutations in dysferlin and anoctamin 5 are the cause of muscular disorders, with the main presentations as limb-girdle muscular dystrophy or Miyoshi type of distal myopathy. Both these proteins have been implicated in sarcolemmal resealing. On the basis of similarities in associated phenotypes and protein functions, we tested the hypothesis that ANO5 protein could compensate for dysferlin absence. We first defined that the main transcript of ANO5 expressed in skeletal muscle is the 22-exon full-length isoform, and we demonstrated that dysferlin-deficient (Dysf (prmd)) mice have lower Ano5 expression levels, an observation that further enhanced the rational of the tested hypothesis. We then showed that AAV-mediated transfer of human ANO5 (hANO5) did not lead to apparent toxicity in wild-type mice. Finally, we demonstrated that AAV-hANO5 injection was not able to compensate for dysferlin deficiency in the Dysf (prmd) mouse model or improve the membrane repair defect seen in the absence of dysferlin. Consequently, overexpressing hANO5 does not seem to provide a valuable therapeutic strategy for dysferlin deficiency.
Published: 2013
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17. Dual Effects of Exercise in Dysferlinopathy

Author: Fabrice Chrétien, Nathalie Bourg, Isabelle Richard, Romain K. Gherardi, Alice Marchand, François-Jérôme Authier, Olivier Biondi, Marie Villemeur, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), INSERM U955, équipe 10, 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), IMRB - 'Biologie du système neuromusculaire' [Créteil] (U955 Inserm - UPEC), École nationale vétérinaire - Alfort (ENVA)-Institut Mondor de Recherche Biomédicale (IMRB), 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, and École pratique des hautes études (EPHE)
Subjects: Aging, MESH: Swimming, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, MESH: Mice, Mutant Strains, MESH: Muscle Contraction, Muscle Fibers, Skeletal, Isometric exercise, MESH: Physical Conditioning, Animal, Quadriceps Muscle, Running, Dysferlin, Mice, 0302 clinical medicine, Eccentric, MESH: Aging, MESH: Animals, Muscular dystrophy, 0303 health sciences, MESH: Muscle, Skeletal, MESH: Muscle Fibers, Skeletal, biology, MESH: Muscle Strength, Anatomy, MESH: Membrane Proteins, MESH: Quadriceps Muscle, medicine.symptom, Locomotion, Muscle Contraction, medicine.medical_specialty, Dysferlinopathy, MESH: Muscular Dystrophies, Limb-Girdle, MESH: Locomotion, MESH: Microscopy, Electron, Pathology and Forensic Medicine, Necrosis, 03 medical and health sciences, Physical Conditioning, Animal, Internal medicine, medicine, Animals, Muscle Strength, Muscle, Skeletal, Myopathy, MESH: Mice, Swimming, 030304 developmental biology, MESH: Necrosis, Sarcolemma, MESH: Dysferlin, Cell Membrane, MESH: Running, Membrane Proteins, Plasma membrane repair, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Mice, Mutant Strains, Microscopy, Electron, Endocrinology, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, 030217 neurology & neurosurgery, MESH: Cell Membrane
Abstract: International audience; Dysferlinopathy refers to a group of autosomal recessive muscular dystrophies due to mutations in the dysferlin gene causing deficiency of a membrane-bound protein crucially involved in plasma membrane repair. The condition is characterized by marked clinical heterogeneity, the different phenotypes/modes of presentation being unrelated to the genotype. For unknown reasons, patients are often remarkably active before the onset of symptoms. Dysferlin deficiency-related persistence of mechanically induced sarcolemma disruptions causes myofiber damage and necrosis. We postulate that limited myodamage may initially remain hidden with well-preserved resistance to physical strains. By subjecting dysferlin-deficient B6.A/J-Dysf(prmd) mice to long-term swimming exercise, we observed that concentric/isometric strain improved muscle strength and alleviated muscular dystrophy by limiting the accumulation of membrane lesions. By contrast, eccentric strain induced by long-term running in a wheel worsened the dystrophic process. Myofiber damage induced by eccentric strain increased with age, reflecting the accumulation of non-necrotic membrane lesions up to a critical threshold. This phenomenon was modulated by daily spontaneous activity. Transposed to humans, our results may suggest that the past activity profile shapes the clinical phenotype of the myopathy and that patients with dysferlinopathy should likely benefit from concentric exercise-based physiotherapy.
Published: 2013
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18. Lack of Correlation between Outcomes of Membrane Repair Assay and Correction of Dystrophic Changes in Experimental Therapeutic Strategy in Dysferlinopathy

Author: Martin Krahn, Laurence Suel, Marina Pryadkina, William Lostal, Isabelle Richard, Marc Bartoli, Joseph A. Roche, Nathalie Bourg, Robert J. Bloch, Perrine Borel, Daniel Stockholm, Rumaisa Bashir, Carinne Roudaut, Nicolas Lévy, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Généthon, 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), and Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Pathology, Anatomy and Physiology, Mouse, Membrane Fusion, Muscular Dystrophies, Dysferlin, Mice, Sarcolemma, 0302 clinical medicine, Myocyte, Skeletal muscles, Muscular dystrophy, Musculoskeletal System, 0303 health sciences, Multidisciplinary, Muscles, Muscle Biochemistry, Animal Models, Dependovirus, Muscle analysis, Cell biology, Phenotype, Treatment Outcome, medicine.anatomical_structure, Muscle proteins, Neurology, Hyperexpression techniques, Muscle, Medicine, Female, Research Article, Genetically modified mouse, Cell Physiology, medicine.medical_specialty, Dysferlinopathy, Histology, Science, Mice, Transgenic, Biology, Muscle Types, 03 medical and health sciences, Model Organisms, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Lasers, Cell Membrane, Membrane Proteins, Skeletal muscle, Bystander Effect, Genetic Therapy, medicine.disease, Cell membranes, Gene Expression Regulation, Muscular Dystrophies, Limb-Girdle, Membrane protein, Muscle contraction, biology.protein, Gene Deletion, 030217 neurology & neurosurgery
Abstract: International audience; Mutations in the dysferlin gene are the cause of Limb-girdle Muscular Dystrophy type 2B and Miyoshi Myopathy. The dysferlin protein has been implicated in sarcolemmal resealing, leading to the idea that the pathophysiology of dysferlin deficiencies is due to a deficit in membrane repair. Here, we show using two different approaches that fullfiling membrane repair as asseyed by laser wounding assay is not sufficient for alleviating the dysferlin deficient pathology. First, we generated a transgenic mouse overexpressing myoferlin to test the hypothesis that myoferlin, which is homologous to dysferlin, can compensate for the absence of dysferlin. The myoferlin overexpressors show no skeletal muscle abnormalities, and crossing them with a dysferlin-deficient model rescues the membrane fusion defect present in dysferlin-deficient mice in vitro. However, myoferlin overexpression does not correct muscle histology in vivo. Second, we report that AAV-mediated transfer of a minidysferlin, previously shown to correct the membrane repair deficit in vitro, also fails to improve muscle histology. Furthermore, neither myoferlin nor the minidysferlin prevented myofiber degeneration following eccentric exercise. Our data suggest that the pathogenicity of dysferlin deficiency is not solely related to impairment in sarcolemmal repair and highlight the care needed in selecting assays to assess potential therapies for dysferlinopathies.
Published: 2012
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19. A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C

Author: Herson, France, Hentati, Faycal, Rigolet, Aude, Behin, Anthony, Romero, Norma, Leturcq, France, Laforêt, Pascal, Maisonobe, Thierry, Amouri, Rim, Haddad, Hafedh, Audit, Muriel, Montus, Marie, Masurier, Carole, Gjata, Bernard, Georger, Christophe, Cheraï, Mustapha, Carlier, Pierre, Hogrel, Yves, Herson, Ariane, Allenbach, Yves, Lemoine, François, Klatzmann, David, Sweeney, H Lee, Mulligan, Richard, Eymard, Bruno, Caizergues, Didier, Voit, Thomas, Benveniste, Olivier, Herson, Serge, Hogrel, Jean-Yves, Sweeney, H. Lee, Service de Neurologie, Institut National de Neurologie, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), 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 biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurophysiologie [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), Généthon, Immunologie moléculaire et biothérapies innovantes (IMBI), Généthon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Laboratoire RMN, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Service de médecine interne et d'immunologie clinique [CHU Pitié-Salpêtrière], Service de biothérapies [CHU Pitié-Salpétrière], 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), Department of Physiology, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], 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), 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), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Thérapie des maladies du muscle strié, 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), CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP]-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)-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), 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), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Neurophysiologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Recherche et développement [Généthon, Evry] (R & D Généthon), Généthon [Evry], Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [CHU Pitié-Salpêtrière], 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)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [APHP], 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, University of Pennsylvania-University of Pennsylvania, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Myologie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Département de médecine interne et immunologie clinique [CHU Pitié-Salpêtrière] (DMIIC), Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Serotype, Male, MESH: Dependovirus, medicine.disease_cause, 0302 clinical medicine, MESH: Genetic Vectors, Muscular dystrophy, 10. No inequality, Adeno-associated virus, MESH: Treatment Outcome, 0303 health sciences, medicine.diagnostic_test, Gene Transfer Techniques, MESH: Follow-Up Studies, Dependovirus, musculoskeletal system, 3. Good health, Sarcoglycan, Treatment Outcome, Female, Adult, Adolescent, MESH: Muscular Dystrophies, Limb-Girdle, Genetic Vectors, MESH: Gene Transfer Techniques, Biology, Virus, 03 medical and health sciences, Sarcoglycans, Biopsy, medicine, Humans, MESH: Sarcoglycans, 030304 developmental biology, MESH: Adolescent, MESH: Genetic Therapy, Muscle biopsy, MESH: Humans, MESH: Adult, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Genetic Therapy, medicine.disease, Virology, MESH: Male, Muscular Dystrophies, Limb-Girdle, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy, Follow-Up Studies
Abstract: International audience; γ-Sarcoglycanopathy or limb girdle muscular dystrophy type 2C is an untreatable disease caused by autosomal recessively inherited mutations of the γ-sarcoglycan gene. Nine non-ambulatory patients (two males, seven females, mean age 27 years; range 16-38 years) with del525T homozygous mutation of the γ-sarcoglycan gene and no γ-sarcoglycan immunostaining on muscle biopsy were divided into three equal groups to receive three escalating doses of an adeno-associated virus serotype 1 vector expressing the human γ-sarcoglycan gene under the control of the desmin promoter, by local injection into the extensor carpi radialis muscle. The first group received a single injection of 3 × 10(9) viral genomes in 100 µl, the second group received a single injection of 1.5 × 10(10) viral genomes in 100 µl, and the third group received three simultaneous 100-µl injections at the same site, delivering a total dose of 4.5 × 10(10) viral genomes. No serious adverse effects occurred during 6 months of follow-up. All nine patients became adeno-associated virus serotype 1 seropositive and one developed a cytotoxic response to the adeno-associated virus serotype 1 capsid. Thirty days later, immunohistochemical analysis of injected-muscle biopsy specimens showed γ-sarcoglycan expression in all three patients who received the highest dose (4.7-10.5% positively stained fibres), while real-time polymerase chain reaction detected γ-sarcoglycan messenger RNA. In one patient, γ-sarcoglycan protein was detected by western blot. For two other patients who received the low and intermediate doses, discrete levels of γ-sarcoglycan expression (
Published: 2012
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20. Validation of comparative genomic hybridization arrays for the detection of genomic rearrangements of the calpain-3 and dysferlin genes

Author: Nicolas Wein, Patrice Bourgeois, Martin Krahn, P. Negre, Marc Bartoli, Christophe Pécheux, Nicolas Lévy, 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), Institut de Recherches sur les lois Fondamentales de l'Univers (IRFU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, 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), and 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)
Subjects: DNA Mutational Analysis, Muscle Proteins, Genome, Dysferlin, 03 medical and health sciences, 0302 clinical medicine, Genetics, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Gene Rearrangement, 0303 health sciences, Comparative Genomic Hybridization, biology, Calpain, Genome, Human, Membrane Proteins, Gene rearrangement, Muscular Dystrophies, Limb-Girdle, Mutation (genetic algorithm), Mutation, biology.protein, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract: International audience; no abstract
Published: 2012
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21. A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy

Author: William Lostal, Nicolas Wein, Danielle Depetris, Martin Krahn, Pierre Cau, Véronique Labelle, Isabelle Richard, Christophe Pécheux, Nicolas Lévy, Nathalie Bourg-Alibert, Karine Nguyen, Sébastien Courrier, Christophe Vial, Marc Bartoli, Nathalie Streichenberger, 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), Généthon, Hôpital neurologique, Hospices Civils de Lyon (HCL), Services de Neurochimie et de Pathologie, Hôpital Neurologique de Bron, Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Dysferlinopathy, Genetic enhancement, Muscle Proteins, Virus, law.invention, Dysferlin, 03 medical and health sciences, Mice, 0302 clinical medicine, law, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene, 030304 developmental biology, 0303 health sciences, Messenger RNA, biology, Membrane Proteins, General Medicine, Genetic Therapy, Dependovirus, medicine.disease, Virology, Disease Models, Animal, Muscular Dystrophies, Limb-Girdle, Cancer research, biology.protein, Recombinant DNA, Dystrophin, 030217 neurology & neurosurgery
Abstract: International audience; Dysferlinopathies are autosomal recessive, progressive muscle dystrophies caused by mutations in DYSF, leading to a loss or a severe reduction of dysferlin, a key protein in sarcolemmal repair. Currently, no etiological treatment is available for patients affected with dysferlinopathy. As for other muscular dystrophies, gene therapy approaches based on recombinant adeno-associated virus (rAAV) vectors are promising options. However, because dysferlin messenger RNA is far above the natural packaging size of rAAV, full-length dysferlin gene transfer would be problematic. In a patient presenting with a late-onset moderate dysferlinopathy, we identified a large homozygous deletion, leading to the production of a natural ``minidysferlin'' protein. Using rAAV-mediated gene transfer into muscle, we demonstrated targeting of the minidysferlin to the muscle membrane and efficient repair of sarcolemmal lesions in a mouse model of dysferlinopathy. Thus, as previously demonstrated in the case of dystrophin, a deletion mutant of the dysferlin gene is also functional, suggesting that dysferlin's structure is modular. This minidysferlin protein could be used as part of a therapeutic strategy for patients affected with dysferlinopathies.
Published: 2010
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22. Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies

Author: Nathalie Daniele, François Monjaret, Anne Tarrade, Anna Vihola, Jaakko Sarparanta, Bjarne Udd, Isabelle Richard, Evelyne Gicquel, Karine Charton, Carinne Roudaut, Maciejak, Olek, Généthon, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Folkhälsan Research Center, Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Structure et activité des biomolécules normales et pathologiques (SABNP), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Tampere University Hospital, Université Paris-Seine-Université Paris-Seine-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and University of Helsinki-University of Helsinki
Subjects: Sarcomeres, medicine.medical_specialty, Heterozygote, Genetic Linkage, [SDV]Life Sciences [q-bio], Blotting, Western, DNA Mutational Analysis, Muscle Proteins, medicine.disease_cause, Polymerase Chain Reaction, Pathogenesis, 03 medical and health sciences, Mice, 0302 clinical medicine, Internal medicine, Genetics, medicine, Animals, Genetic Predisposition to Disease, Connectin, Muscular dystrophy, Allele, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, Mutation, biology, Calpain, Skeletal muscle, Heterozygote advantage, General Medicine, medicine.disease, Distal Myopathies, [SDV] Life Sciences [q-bio], Disease Models, Animal, Microscopy, Electron, Endocrinology, medicine.anatomical_structure, Muscular Dystrophies, Limb-Girdle, Echocardiography, biology.protein, Titin, Protein Kinases, 030217 neurology & neurosurgery
Abstract: International audience; The dominant tibial muscular dystrophy (TMD) and recessive limb-girdle muscular dystrophy 2J are allelicdisorders caused by mutations in the C-terminus of titin, a giant sarcomeric protein. Both clinical presentationswere initially identified in a large Finnish family and linked to a founder mutation (FINmaj). To furtherunderstand the physiopathology of these two diseases, we generated a mouse model carrying the FINmajmutation. In heterozygous mice, dystrophic myopathology appears late at 9 months of age in few distalmuscles. In homozygous (HO) mice, the first signs appear in the Soleus at 1 month of age and extend tomost muscles at 6 months of age. Interestingly, the heart is also severely affected in HO mice. The mutationleads to the loss of the very C-terminal end of titin and to a secondary deficiency of calpain 3, a partner oftitin. By crossing the FINmaj model with a calpain 3-deficient model, the TMD phenotype was corrected,demonstrating a participation of calpain 3 in the pathogenesis of this disease.
Published: 2010
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23. POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation

Author: Pascale Guicheney, Nigel F. Clarke, Taratuto Ana Lia, Akiko Yanagisawa, Susana Quijano-Roy, Norma B. Romero, Sandrine Vuillaumier-Barrot, Diana Rodriguez, C. Bouchet, Makiko Osawa, Nathalie Seta, Sylvie Odent, Tamao Endo, 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), Department of Pediatrics, Tokyo Women's Medical University (TWMU), Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pédiatrie, Rééducation et Réanimation Neurorespiratoire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Glycobiology Research Group, Tokyo Metropolitan Institute of Gerontology, Institute for Neurological Research, Department of Neuropathology, Garrahan National Paediatric Hospital, Service de génétique clinique, hôpital Sud, Service de neurologie 1 [CHU Pitié-Salpétrière], 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), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), De Villemeur, Hervé, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Microcephaly, DNA, Complementary, Adolescent, RNA Splicing, DNA Mutational Analysis, Molecular Sequence Data, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Mannosyltransferases, Severity of Illness Index, Muscular Dystrophies, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual Disability, Genetics, medicine, Humans, Muscular dystrophy, Allele, Dystroglycans, Muscle, Skeletal, Genetics (clinical), Exome sequencing, Alleles, 030304 developmental biology, Sequence Deletion, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, fungi, General Medicine, DNA, Sequence Analysis, DNA, medicine.disease, 3. Good health, genomic DNA, Muscular Dystrophies, Limb-Girdle, Child, Preschool, Congenital muscular dystrophy, Female, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy
Abstract: Background Alpha-dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance characterized by abnormal glycosylation of alpha-dystroglycan. Although six genetic causes have been identified ( FKTN, POMGNT1, POMT1, POMT2, FKRP , and LARGE ) many alpha-dystroglycanopathy patients remain without a genetic diagnosis after standard exon sequencing. To date POMT2 mutations have been identified in CMD cases with a wide range of clinical severities from Walker–Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. Methods We analyzed POMT2 in six CMD patients, who had severe diffuse muscle weakness, generalized joint contractures, microcephaly, severe mental retardation and elevated CK levels. Eye involvement was absent or limited to myopia or strabismus. We sequenced the coding regions of POMT2 using genomic DNA and cDNA generated from blood lymphocytes or B lymphoblastoid cell lines. Quantitative PCR analysis of genomic DNA was used to identify and determine the breakpoints of large deletions. Results We report five novel mutations in POMT2 , four of which were outside of coding exons, two large genomic deletions and two intronic single base substitutions that induced aberrant mRNA splicing. Conclusions Large scale DNA rearrangements (such as large deletions) and cryptic splice mutations, that can be missed on standard sequencing of genomic DNA, may be relatively common in POMT2 . Additional techniques, such as sequencing of cDNA are needed to identify all mutations. These results also confirm that POMT2 mutations are an important cause of the less severe alpha-dystroglycanopathy phenotypes.
Published: 2009
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24. Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H

Author: Mireille Cossée, Clotilde Lagier-Tourenne, Claire Seguela, Michel Mohr, France Leturcq, Hulya Gundesli, Jamel Chelly, Christine Tranchant, Michel Koenig, Jean-Louis Mandel, Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Département de Pathologie, Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Medical Biology, Hacettepe University Faculty of Medicine, Département de Neurologie, CHU Strasbourg-Hopital Civil, Chaire Génétique Humaine, Collège de France (CdF (institution)), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génétique Humaine, and Peney, Maité
Subjects: Genetic Markers, Male, Genotype, Ubiquitin-Protein Ligases, DNA Mutational Analysis, Mutation, Missense, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Frameshift mutation, Tripartite Motif Proteins, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetic Testing, Muscular dystrophy, Muscle, Skeletal, Myopathy, Genetics (clinical), Oligonucleotide Array Sequence Analysis, 030304 developmental biology, Genetics, 0303 health sciences, Genetic heterogeneity, Homozygote, Middle Aged, medicine.disease, Arabs, Pedigree, Protein Structure, Tertiary, Muscular Dystrophies, Limb-Girdle, Neurology, Pediatrics, Perinatology and Child Health, Female, France, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Transcription Factors, SNP array, Limb-girdle muscular dystrophy
Abstract: International audience; Molecular diagnosis of monogenic diseases with high genetic heterogeneity is usually challenging. In the case of limb-girdle muscular dystrophy, multiplex Western blot analysis is a very useful initial step, but that often fails to identify the primarily affected protein. We report how homozygosity analysis using a genome-wide SNP array allowed us to solve the diagnostic enigma in a patient with a moderate form of LGMD, born from consanguineous parents. The genome-wide scan performed on the patient's DNA revealed several regions of homozygosity, that were compared to the location of known LGMD genes. One such region indeed contained the TRIM32 gene. This gene was previously found mutated in families with limb-girdle muscular dystrophy type 2H (LGMD2H), a mild autosomal recessive myopathy described in Hutterite populations and in 4 patients with a diagnosis of sarcotubular myopathy. A single missense mutation was found in all these patients, located in a conserved domain of the C-terminal part of the protein. Another missense mutation affecting the N-terminal part of TRIM32, observed in a single consanguineous Bedouin family, was reported to cause the phenotypically unrelated and genetically heterogeneous Bardet-Biedl syndrome, defining the BBS11 locus. Sequencing of TRIM32 in our patient revealed a distal frameshift mutation, c.1753_1766dup14 (p.Ile590Leu fsX38). Together with two recently reported mutations, this novel mutation confirms that integrity of the C-terminal domain of TRIM32 is necessary for muscle maintenance.
Published: 2009
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25. Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation

Author: Bjarne Udd, Laetitia Barrault, Marie Malissen, Isabelle Richard, Tayebeh Soheili, Norma Perez, Marc Bartoli, Bernard Malissen, Evelyne Gicquel, Olivier Danos, Nathalie Vincent-Lacaze, Généthon, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Neurological Department, Vaasa Central Hospital, and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Mannosidase, MESH: Muscles, Leupeptins, medicine.disease_cause, MESH: Muscular Dystrophy, Animal, MESH: Mice, Knockout, Mice, 0302 clinical medicine, Missense mutation, MESH: Animals, Muscular dystrophy, Genetics (clinical), Cellular localization, Mice, Knockout, 0303 health sciences, Mutation, Muscles, General Medicine, 16. Peace & justice, 3. Good health, Sarcoglycan, Protein Transport, Phenotype, Biochemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Protein Transport, MESH: Cell Line, Tumor, MESH: Muscular Dystrophies, Limb-Girdle, Mutation, Missense, Biology, MESH: Phenotype, 03 medical and health sciences, Alkaloids, MESH: Mannosidases, MESH: Alkaloids, Cell Line, Tumor, Sarcoglycans, Mannosidases, Genetics, medicine, Animals, Humans, Cysteine, MESH: Sarcoglycans, Molecular Biology, MESH: Mice, 030304 developmental biology, SGCA, MESH: Mutation, Missense, MESH: Humans, MESH: Leupeptins, Muscular Dystrophy, Animal, MESH: Cysteine, medicine.disease, Molecular biology, Muscular Dystrophies, Limb-Girdle, MESH: Female, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy
Abstract: International audience; Limb girdle muscular dystrophy type 2D (LGMD2D, OMIM600119) is a genetic progressive myopathy that is caused by mutations in the human alpha-sarcoglycan gene (SGCA). Here, we have introduced in mice the most prevalent LGMD2D mutation, R77C. It should be noted that the natural murine residue at this position is a histidine. The model is, therefore, referred as Sgca(H77C/H77C). Unexpectedly, we observed an absence of LGMD2D-like phenotype at histological or physiological level. Using a heterologous cellular model of the sarcoglycan complex formation, we showed that the R77C allele encodes a protein that fails to be delivered to its proper cellular localization in the plasma membrane, and consequently to the disappearance of a positively charged residue. Subsequently, we transferred an AAV vector coding for the human R77C protein in the muscle of Sgca-null mice and were able to pharmacologically rescue the R77C protein from endoplasmic reticulum-retention using proteasome or mannosidase I inhibitors. This suggests a therapeutic approach for LGMD2D patients carrying mutations that impair alpha-sarcoglycan trafficking.
Published: 2008
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26. NF-kappa B-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A

Author: Marc Bartoli, Gérard Lefranc, Nathalie Daniele, Alicia Lajmanovich, Laurence Suel, Béatrice Benayoun, Hanns Lochmüller, Nathalie Bourg, Marie-Anne Pasquier, Stephen Baghdiguian, Isabelle Richard, Evelyne Gicquel, Fabrice Raynaud, Institut des Sciences de l'Evolution de Montpellier (UMR ISEM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Centre National de la Recherche Scientifique (CNRS)-Institut de recherche pour le développement [IRD] : UR226, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Généthon, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Dynamique moléculaire des interactions membranaires (DMIM), Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2), Departement /u661 : Neurobiologie, Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Human Genetics, Newcastle University [Newcastle], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Institut de recherche pour le développement [IRD] : UR226-Centre National de la Recherche Scientifique (CNRS), and Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Interleukin-1beta, CASP8 and FADD-Like Apoptosis Regulating Protein, bcl-X Protein, Down-Regulation, Muscle Proteins, Apoptosis, Models, Biological, Biochemistry, Dysferlin, 03 medical and health sciences, 0302 clinical medicine, Bcl-2-associated X protein, Genetics, medicine, Humans, Myocyte, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscular dystrophy, Muscle, Skeletal, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, bcl-2-Associated X Protein, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, biology, Calpain, Tumor Necrosis Factor-alpha, Chemistry, NF-kappa B, Skeletal muscle, medicine.disease, Cell biology, medicine.anatomical_structure, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Muscular Dystrophies, Limb-Girdle, biology.protein, I-kappa B Proteins, ITGA7, 030217 neurology & neurosurgery, Biotechnology
Abstract: International audience; Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in the cysteine protease calpain 3 (CAPN3) that leads to selective muscle wasting. We previously showed that CAPN3 deficiency is associated with a profound perturbation of the NF-kappa B/I kappa B alpha survival pathway. In this study, the consequences of altered NF-kappa B/I kappa B alpha pathway were investigated using biological materials from LGMD2A patients. We first show that die antiapoptotic factor cellular-FUCE inhibitory protein (c-FLIP), which is dependent on the NF-kappa B pathway in normal muscle cells, is down-regulated in LGMD2A biopsies. In muscle cells isolated from LGMD2A patients, NF-kappa B is readily activated on cytokine induction as shown by an increase in its DNA binding activity. However, we observed discrepant transcriptional responses depending on the NF-kappa B target genes. I kappa B alpha is expressed following NF-kappa B activation independent of the CAPN3 status, whereas expression of c-FLIP is obtained only when CAPN3 is present. These data lead us to postulate that CAPN3 intervenes in the regulation of the expression of NF-kappa B-dependent survival genes to prevent apoptosis in skeletal muscle. Deregulations in the NF-kappa B pathway could be part of the mechanism responsible for the muscle wasting resulting from CAPN3 deficiency.
Published: 2008
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27. Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay

Author: Christophe Pécheux, Christophe Béroud, Rafaëlle Bernard, Isabelle Pénisson-Besnier, Jon Andoni Urtizberea, F. Leturcq, Valérie Drouin-Garraud, Françoise Chapon, Nicolas Lévy, Pascal Laforêt, Norma B. Romero, Martin Krahn, Service de Neurologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), 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 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), Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 (PhLAM), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-IFR3, and Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Subjects: Adult, Male, Adolescent, Transcription, Genetic, RNA Splicing, RNA Stability, Muscle Proteins, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Transcription (biology), Complementary DNA, Eosinophilia, Genetics, medicine, Humans, RNA, Messenger, Muscular dystrophy, Allele, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Aged, DNA Primers, Sequence Deletion, 030304 developmental biology, 0303 health sciences, Messenger RNA, Base Sequence, Myositis, Calpain, Middle Aged, medicine.disease, Molecular biology, 3. Good health, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, RNA splicing, Female, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], 030217 neurology & neurosurgery
Abstract: Mutations in the gene encoding calpain-3 (CAPN3) cause autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) and idiopathic eosinophilic myositis. Accurate diagnosis and genetic counselling are based on the identification of disease-causing mutations on both alleles of CAPN3 in the patients. In the present study, we used transcriptional analysis as a complementary approach for patients suspected of being affected with LGMD2A, in whom initial denaturing high-performance liquid chromatography genomic mutation screening evidenced no or only one CAPN3 mutation obviously considered as disease causing. This allowed to identify and characterize cDNA deletions. Further genomic analysis allowed to determine the origin of these deletions, either as splicing defects caused by intronic mutations or as an internal multi-exonic deletion. In particular, we report two novel CAPN3 mutations (c.1745 + 4_1745 + 7delAGTG in IVS13 and c.2185-16A>G in IVS20) and a recurrent large-sized genomic deletion including exons 2-8 for which genomic breakpoints have been characterized. In addition, our results indicate nonsense-mediated messenger RNA decay as a mechanism for under-expression of CAPN3 associated to some specific variations.
Published: 2007
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28. Ins and outs of therapy in limb girdle muscular dystrophies

Author: Marc Bartoli, Nathalie Daniele, Isabelle Richard, Généthon, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: musculoskeletal diseases, Duchenne muscular dystrophy, Limb girdle, Bioinformatics, Biochemistry, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, 0303 health sciences, business.industry, Skeletal muscle, Cell Biology, Anatomy, medicine.disease, 3. Good health, Transplantation, medicine.anatomical_structure, Muscular Dystrophies, Limb-Girdle, Stem cell, business, ITGA7, 030217 neurology & neurosurgery, Limb-girdle muscular dystrophy
Abstract: International audience; Muscular dystrophies are hereditary degenerative muscle diseases that cause life-long disability in patients. They comprise the well-known Duchenne Muscular Dystrophy (DMD) but also the group of Limb Girdle Muscular Dystrophies (LGMD) which account for a third to a fourth of DMD cases. From the clinical point of view, LGMD are characterised by predominant effects on the proximal limb muscles. The LGMD group is still growing today and consists of 19 autosomal dominant and recessive forms (LGMD1A to LGMD1G and LGMD2A to LGMD2M). The proteins involved are very diverse and include sarcomeric, sarcolemmal and enzymatic proteins. With respect to this variability and in line with the intense search for a potent therapeutic approach for DMD, many different strategies have been tested in rodent models. These include replacing the lost function by gene transfer or stem cell transplantation, using a related protein for functional substitution, increasing muscle mass, or blocking the molecular pathological mechanisms by pharmacological means to alleviate the symptoms. The purpose of this review is to summarize current data arising from these preclinical studies and to examine the potential of the tested strategies to lead to clinical applications. (c) 2007 Elsevier Ltd. All rights reserved.
Published: 2007
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29. Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A

Author: Olivier Danos, Fanny Noulet, Jérôme Poupiot, Marc Bartoli, Isabelle Richard, Françoise Fougerousse, Samia Martin, Evelyne Gicquel, Carinne Roudaut, Laurence Suel, Généthon, Laboratoire Analyse et Modélisation pour la Biologie et l'Environnement (LAMBE), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Transgene, Genetic enhancement, Genetic Vectors, Muscle Proteins, Mice, Transgenic, Biology, Sarcomere, Injections, Intramuscular, 03 medical and health sciences, Mice, 0302 clinical medicine, Atrophy, Drug Discovery, Enzyme Stability, medicine, Genetics, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscular dystrophy, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, Calpain, Gene Transfer Techniques, Genetic Therapy, Dependovirus, medicine.disease, Cysteine protease, 3. Good health, Cell biology, Enzyme Activation, Mice, Inbred C57BL, Disease Models, Animal, Muscular Dystrophies, Limb-Girdle, Toxicity, biology.protein, Molecular Medicine, 030217 neurology & neurosurgery
Abstract: International audience; Calpainopathy (limb-girdle muscular dystrophy type 2A, LGMD2A) is a recessive muscular disorder caused by deficiency in the calcium-dependent cysteine protease calpain 3. To date, no treatment exists for this disease. We evaluated the potential of recombinant adeno-associated virus (rAAV) vectors for gene therapy in a murine model for LGMD2A. To drive the expression of calpain 3, we used rAAV2/1 pseudotyped vectors and muscle-specific promoters to avoid calpain 3 cell toxicity. We report efficient and stable transgene expression in muscle with restoration of the proteolytic activity and without evident toxicity. In addition, calpain 3 was correctly targeted to the sarcomere. Moreover, its presence resulted in improvement of the histological features and in therapeutic efficacy at the physiological levels, including correction of atrophy and full rescue of the contractile force deficits. Our results establish the feasibility of AAV-mediated calpain 3 gene transfer as a therapeutic approach.
Published: 2006
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29 results on '"Muscular Dystrophies, Limb-Girdle"'

1. Deep phenotyping of an international series of patients with late‐onset dysferlinopathy

2. Late-onset camptocormia caused by a heterozygous in-frame CAPN3 deletion

3. Retrospective analysis and reclassification of DYSF variants in a large French series of dysferlinopathy patients

4. Lamin-Related Congenital Muscular Dystrophy Alters Mechanical Signaling and Skeletal Muscle Growth

5. Sarcoglycanopathies: state of the art and therapeutic perspectives

6. Splicing impact of deep exonic missense variants in CAPN3 explored systematically by minigene functional assay

7. A single c.1715G>C calpain 3 gene variant causes dominant calpainopathy with loss of calpain 3 expression and activity

8. New genotype-phenotype correlations in a large European cohort of patients with sarcoglycanopathy patients

9. Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2A

10. Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation

11. Muscle MRI in patients with dysferlinopathy: pattern recognition and implications for clinical trials

12. AAV-mediated transfer of FKRP shows therapeutic efficacy in a murine model but requires control of gene expression

13. Hip region muscular dystrophy and emergence of motor deficits in dysferlin-deficient Bla/J mice

14. Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D

15. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

16. The Phenotype of Dysferlin-Deficient Mice Is Not Rescued by Adeno-Associated Virus–Mediated Transfer of Anoctamin 5

17. Dual Effects of Exercise in Dysferlinopathy

18. Lack of Correlation between Outcomes of Membrane Repair Assay and Correction of Dystrophic Changes in Experimental Therapeutic Strategy in Dysferlinopathy

19. A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C

20. Validation of comparative genomic hybridization arrays for the detection of genomic rearrangements of the calpain-3 and dysferlin genes

21. A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy

22. Removal of the calpain 3 protease reverses the myopathology in a mouse model for titinopathies

23. POMT2 intragenic deletions and splicing abnormalities causing congenital muscular dystrophy with mental retardation

24. Use of SNP array analysis to identify a novel TRIM32 mutation in limb-girdle muscular dystrophy type 2H

25. Mannosidase I inhibition rescues the human alpha-sarcoglycan R77C recurrent mutation

26. NF-kappa B-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A

27. Transcriptional explorations of CAPN3 identify novel splicing mutations, a large-sized genomic deletion and evidence for messenger RNA decay

28. Ins and outs of therapy in limb girdle muscular dystrophies

29. Safety and efficacy of AAV-mediated calpain 3 gene transfer in a mouse model of limb-girdle muscular dystrophy type 2A

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