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197 results on '"Norma B Romero"'

1. Caveolae and Bin1 form ring-shaped platforms for T-tubule initiation

Author: Eline Lemerle, Jeanne Lainé, Marion Benoist, Gilles Moulay, Anne Bigot, Clémence Labasse, Angéline Madelaine, Alexis Canette, Perrine Aubin, Jean-Michel Vallat, Norma B Romero, Marc Bitoun, Vincent Mouly, Isabelle Marty, Bruno Cadot, Laura Picas, and Stéphane Vassilopoulos
Subjects: caveolae, T-tubules, caveolin 3, correlative microscopy, caveolinopathies, Medicine, Science, Biology (General), QH301-705.5
Abstract: Excitation-contraction coupling requires a highly specialized membrane structure, the triad, composed of a plasma membrane invagination, the T-tubule, surrounded by two sarcoplasmic reticulum terminal cisternae. Although the precise mechanisms governing T-tubule biogenesis and triad formation remain largely unknown, studies have shown that caveolae participate in T-tubule formation and mutations of several of their constituents induce muscle weakness and myopathies. Here, we demonstrate that, at the plasma membrane, Bin1 and caveolae composed of caveolin-3 assemble into ring-like structures from which emerge tubes enriched in the dihydropyridine receptor. Bin1 expression lead to the formation of both rings and tubes and we show that Bin1 forms scaffolds on which caveolae accumulate to form the initial T-tubule. Cav3 deficiency caused by either gene silencing or pathogenic mutations results in defective ring formation and perturbed Bin1-mediated tubulation that may explain defective T-tubule organization in mature muscles. Our results uncover new pathophysiological mechanisms that may prove relevant to myopathies caused by Cav3 or Bin1 dysfunction.
Published: 2023
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2. QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease

Author: Virginia Guarani, Claude Jardel, Dominique Chrétien, Anne Lombès, Paule Bénit, Clémence Labasse, Emmanuelle Lacène, Agnès Bourillon, Apolline Imbard, Jean-François Benoist, Imen Dorboz, Mylène Gilleron, Eric S Goetzman, Pauline Gaignard, Abdelhamid Slama, Monique Elmaleh-Bergès, Norma B Romero, Pierre Rustin, Hélène Ogier de Baulny, Joao A Paulo, J Wade Harper, and Manuel Schiff
Subjects: QIL1, MICOS, mitochondrial disease, early-onset fatal mitochondrial encephalopathy, 3-methylglutaconic aciduria, liver disease, Medicine, Science, Biology (General), QH301-705.5
Abstract: Previously, we identified QIL1 as a subunit of mitochondrial contact site (MICOS) complex and demonstrated a role for QIL1 in MICOS assembly, mitochondrial respiration, and cristae formation critical for mitochondrial architecture (Guarani et al., 2015). Here, we identify QIL1 null alleles in two siblings displaying multiple clinical symptoms of early-onset fatal mitochondrial encephalopathy with liver disease, including defects in respiratory chain function in patient muscle. QIL1 absence in patients’ fibroblasts was associated with MICOS disassembly, abnormal cristae, mild cytochrome c oxidase defect, and sensitivity to glucose withdrawal. QIL1 expression rescued cristae defects, and promoted re-accumulation of MICOS subunits to facilitate MICOS assembly. MICOS assembly and cristae morphology were not efficiently rescued by over-expression of other MICOS subunits in patient fibroblasts. Taken together, these data provide the first evidence of altered MICOS assembly linked with a human mitochondrial disease and confirm a central role for QIL1 in stable MICOS complex formation.
Published: 2016
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3. Generation of iPSC lines from three Laing distal myopathy patients with a recurrent MYH7 p.Lys1617del variant

Author: Joshua S. Clayton, Christina Vo, Jordan Crane, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Edoardo Malfatti, Norma B. Romero, Gianina Ravenscroft, Nigel G. Laing, and Rhonda L. Taylor
Subjects: Biology (General), QH301-705.5
Abstract: Variants in MYH7 cause cardiomyopathies as well as myosin storage myopathy and Laing early-onset distal myopathy (MPD1). MPD1 is characterized by muscle weakness and atrophy usually beginning in the lower legs. Here, we generated iPSC lines from lymphoblastoid cells of three unrelated individuals heterozygous for the most common MPD1-causing variant; p.Lys1617del. iPSC lines showed typical morphology, expressed pluripotency markers, demonstrated trilineage differentiation potential, and had a normal karyotype. These lines represent the first iPSCs derived from MPD1 patients and complement existing MPD1 animal models. They can provide in vitro platforms to better understand and model MPD1 pathomechanisms and test therapies.
Published: 2024
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4. An integrated diagnosis strategy for congenital myopathies.

Author: Johann Böhm, Nasim Vasli, Edoardo Malfatti, Stéphanie Le Gras, Claire Feger, Bernard Jost, Nicole Monnier, Julie Brocard, Hatice Karasoy, Marion Gérard, Maggie C Walter, Peter Reilich, Valérie Biancalana, Christine Kretz, Nadia Messaddeq, Isabelle Marty, Joël Lunardi, Norma B Romero, and Jocelyn Laporte
Subjects: Medicine, Science
Abstract: Congenital myopathies are severe muscle disorders affecting adults as well as children in all populations. The diagnosis of congenital myopathies is constrained by strong clinical and genetic heterogeneity. Moreover, the majority of patients present with unspecific histological features, precluding purposive molecular diagnosis and demonstrating the need for an alternative and more efficient diagnostic approach. We used exome sequencing complemented by histological and ultrastructural analysis of muscle biopsies to identify the causative mutations in eight patients with clinically different skeletal muscle pathologies, ranging from a fatal neonatal myopathy to a mild and slowly progressive myopathy with adult onset. We identified RYR1 (ryanodine receptor) mutations in six patients and NEB (nebulin) mutations in two patients. We found novel missense and nonsense mutations, unraveled small insertions/deletions and confirmed their impact on splicing and mRNA/protein stability. Histological and ultrastructural findings of the muscle biopsies of the patients validated the exome sequencing results. We provide the evidence that an integrated strategy combining exome sequencing with clinical and histopathological investigations overcomes the limitations of the individual approaches to allow a fast and efficient diagnosis, accelerating the patient's access to a better healthcare and disease management. This is of particular interest for the diagnosis of congenital myopathies, which involve very large genes like RYR1 and NEB as well as genetic and phenotypic heterogeneity.
Published: 2013
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5. Generation of two iPSC lines from patients with inherited central core disease and concurrent malignant hyperthermia caused by dominant missense variants in the RYR1 gene

Author: Joshua S. Clayton, Christina Vo, Jordan Crane, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Edoardo Malfatti, Norma B. Romero, Gianina Ravenscroft, Nigel G. Laing, and Rhonda L. Taylor
Subjects: Biology (General), QH301-705.5
Abstract: RYR1 variants are the most common genetic cause of congenital myopathies, and typically cause central core disease (CCD) and/or malignant hyperthermia (MH). Here, we generated iPSC lines from two patients with CCD and MH caused by dominant RYR1 variants within the central region of the protein (p.Val2168Met and p.Arg2508Cys). Both lines displayed typical iPSC morphology, uniform expression of pluripotency markers, trilineage differentiation potential, and had normal karyotypes. These are the first RYR1 iPSC lines from patients with both CCD and MH. As these are common CCD/MH variants, these lines should be useful to study these conditions and test therapeutics.
Published: 2024
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6. Generation of two iPSC lines from adult central core disease patients with dominant missense variants in the RYR1 gene

Author: Joshua S. Clayton, Christina Vo, Jordan Crane, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Edoardo Malfatti, Norma B. Romero, Gianina Ravenscroft, Nigel G. Laing, and Rhonda L. Taylor
Subjects: Biology (General), QH301-705.5
Abstract: RYR1 variants are a common cause of congenital myopathies, including multi-minicore disease (MmD) and central core disease (CCD). Here, we generated iPSC lines from two CCD patients with dominant RYR1 missense variants that affect the transmembrane (pore) and SPRY3 protein domains (p.His4813Tyr and p.Asn1346Lys, respectively). Both lines had typical iPSC morphology, expressed canonical pluripotency markers, exhibited trilineage differentiation potential, and had normal karyotypes. Together with existing RYR1 iPSC lines, these represent important tools to study and develop treatments for RYR1-related myopathies.
Published: 2024
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7. Generation of two induced pluripotent stem cell lines from a 33-year-old central core disease patient with a heterozygous dominant c.14145_14156delCTACTGGGACA (p.Asn4715_Asp4718del) deletion in the RYR1 gene

Author: Karrison Driver, Christina Vo, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Edoardo Malfatti, Norma B. Romero, Gianina Ravenscroft, Nigel G. Laing, Rhonda L. Taylor, and Joshua S. Clayton
Subjects: Biology (General), QH301-705.5
Abstract: Central core disease (CCD) is a congenital disorder that results in hypotonia, delayed motor development, and areas of reduced oxidative activity in the muscle fibre. Two induced pluripotent stem cell (iPSC) lines were generated from the lymphoblastoid cells of a 33-year-old male with CCD, caused by a previously unreported dominant c.14145_14156delCTACTGGGACA (p.Asn4715_Asp4718del) deletion in the RYR1 gene. Both lines demonstrated typical morphology, pluripotency, trilineage differentiation, and had a normal karyotype. As the first published iPSC model of CCD caused by an RYR1 variant these lines are a potential resource for further investigation of RYR1-related myopathies in a human context.
Published: 2023
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8. A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course

Author: Valérie Biancalana, John Rendu, Annabelle Chaussenot, Helen Mecili, Eric Bieth, Mélanie Fradin, Sandra Mercier, Maud Michaud, Marie-Christine Nougues, Laurent Pasquier, Sabrina Sacconi, Norma B. Romero, Pascale Marcorelles, François Jérôme Authier, Antoinette Gelot Bernabe, Emmanuelle Uro-Coste, Claude Cances, Bertrand Isidor, Armelle Magot, Marie-Christine Minot-Myhie, Yann Péréon, Julie Perrier-Boeswillwald, Gilles Bretaudeau, Nicolas Dondaine, Alison Bouzenard, Mégane Pizzimenti, Bruno Eymard, Ana Ferreiro, Jocelyn Laporte, Julien Fauré, and Johann Böhm
Subjects: Neuromuscular disorder, Congenital myopathy, Calcium, Muscle weakness, Excitation–contraction coupling, Triad, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
Published: 2021
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9. In vivo RyR1 reduction in muscle triggers a core-like myopathy

Author: Laurent Pelletier, Anne Petiot, Julie Brocard, Benoit Giannesini, Diane Giovannini, Colline Sanchez, Lauriane Travard, Mathilde Chivet, Mathilde Beaufils, Candice Kutchukian, David Bendahan, Daniel Metzger, Clara Franzini Armstrong, Norma B. Romero, John Rendu, Vincent Jacquemond, Julien Fauré, and Isabelle Marty
Subjects: Ryanodine receptor, Calcium, Skeletal muscle, Excitation–contraction coupling, Congenital myopathies, Central core disease, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.
Published: 2020
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10. rAAV-related therapy fully rescues myonuclear and myofilament function in X-linked myotubular myopathy

Author: Jacob A. Ross, Hichem Tasfaout, Yotam Levy, Jennifer Morgan, Belinda S. Cowling, Jocelyn Laporte, Edmar Zanoteli, Norma B. Romero, Dawn A. Lowe, Heinz Jungbluth, Michael W. Lawlor, David L. Mack, and Julien Ochala
Subjects: Skeletal muscle, Congenital myopathy, Myotubularin, Myonuclear domain, Myofilament, Force production, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract X-linked myotubular myopathy (XLMTM) is a life-threatening skeletal muscle disease caused by mutations in the MTM1 gene. XLMTM fibres display a population of nuclei mispositioned in the centre. In the present study, we aimed to explore whether positioning and overall distribution of nuclei affects cellular organization and contractile function, thereby contributing to muscle weakness in this disease. We also assessed whether gene therapy alters nuclear arrangement and function. We used tissue from human patients and animal models, including XLMTM dogs that had received increasing doses of recombinant AAV8 vector restoring MTM1 expression (rAAV8-cMTM1). We then used single isolated muscle fibres to analyze nuclear organization and contractile function. In addition to the expected mislocalization of nuclei in the centre of muscle fibres, a novel form of nuclear mispositioning was observed: irregular spacing between those located at the fibre periphery, and an overall increased number of nuclei, leading to dramatically smaller and inconsistent myonuclear domains. Nuclear mislocalization was associated with decreases in global nuclear synthetic activity, contractile protein content and intrinsic myofilament force production. A contractile deficit originating at the myofilaments, rather than mechanical interference by centrally positioned nuclei, was supported by experiments in regenerated mouse muscle. Systemic administration of rAAV8-cMTM1 at doses higher than 2.5 × 1013 vg kg−1 allowed a full rescue of all these cellular defects in XLMTM dogs. Altogether, these findings identify previously unrecognized pathological mechanisms in human and animal XLMTM, associated with myonuclear defects and contractile filament function. These defects can be reversed by gene therapy restoring MTM1 expression in dogs with XLMTM.
Published: 2020
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11. A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

Author: Aurélien Perrin, Corinne Metay, Marcello Villanova, Robert‐Yves Carlier, Elena Pegoraro, Raul Juntas Morales, Tanya Stojkovic, Isabelle Richard, Pascale Richard, Norma B. Romero, Henk Granzier, Michel Koenig, Edoardo Malfatti, and Mireille Cossée
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Congenital titinopathies are myopathies with variable phenotypes and inheritance modes. Here, we fully characterized, using an integrated approach (deep phenotyping, muscle morphology, mRNA and protein evaluation in muscle biopsies), two siblings with congenital multicore myopathy harboring three TTN variants predicted to affect titin stability and titin‐myosin interactions. Muscle biopsies showed multicores, type 1 fiber uniformity and sarcomeric structure disruption with some thick filament loss. Immunohistochemistry and Western blotting revealed a marked reduction of fast myosin heavy chain isoforms. This is the first observation of a titinopathy suggesting that titin defect leads to secondary loss of fast myosin heavy chain isoforms.
Published: 2020
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12. Generation of two isogenic induced pluripotent stem cell lines from a 10-year-old typical nemaline myopathy patient with a heterozygous dominant c.541G>A (p.Asp179Asn) pathogenic variant in the ACTA1 gene

Author: Joshua S. Clayton, Carolin K. Scriba, Norma B. Romero, Edoardo Malfatti, Safaa Saker, Thierry Larmonier, Kristen J. Nowak, Gianina Ravenscroft, Nigel G. Laing, and Rhonda L. Taylor
Subjects: Biology (General), QH301-705.5
Abstract: Nemaline myopathy (NM) is a congenital myopathy typically characterized by skeletal muscle weakness and the presence of nemaline bodies in myofibres. Approximately 25% of NM cases are caused by variants in ACTA1. We generated two induced pluripotent stem cell lines from lymphoblastoid cells of a 10-year-old female with typical NM harbouring a dominant pathogenic variant in ACTA1 (c.541C>A). The isogenic lines displayed typical iPSC morphology, expressed pluripotency markers, and could differentiate into each of the three germ layers. Although the lines have partial or complete X chromosome duplication, they may still prove useful as models of human ACTA1 disease.
Published: 2021
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13. Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions

Author: Montse Olivé, Martin Engvall, Gianina Ravenscroft, Macarena Cabrera-Serrano, Hong Jiao, Carlo Augusto Bortolotti, Marcello Pignataro, Matteo Lambrughi, Haibo Jiang, Alistair R. R. Forrest, Núria Benseny-Cases, Stefan Hofbauer, Christian Obinger, Gianantonio Battistuzzi, Marzia Bellei, Marco Borsari, Giulia Di Rocco, Helena M. Viola, Livia C. Hool, Josep Cladera, Kristina Lagerstedt-Robinson, Fengqing Xiang, Anna Wredenberg, Francesc Miralles, Juan José Baiges, Edoardo Malfatti, Norma B. Romero, Nathalie Streichenberger, Christophe Vial, Kristl G. Claeys, Chiara S. M. Straathof, An Goris, Christoph Freyer, Martin Lammens, Guillaume Bassez, Juha Kere, Paula Clemente, Thomas Sejersen, Bjarne Udd, Noemí Vidal, Isidre Ferrer, Lars Edström, Anna Wedell, and Nigel G. Laing
Subjects: Science
Abstract: Myoglobin is a hemeprotein that reversibly binds oxygen and gives muscle its red color. Here, the authors report a genetic variant in the MB gene that associates with myoglobinopathy, an autosomal dominant progressive myopathy, and altered oxygen binding properties of the mutant protein.
Published: 2019
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14. Generation of two isogenic induced pluripotent stem cell lines from a 4-month-old severe nemaline myopathy patient with a heterozygous dominant c.553C > A (p.Arg183Ser) variant in the ACTA1 gene

Author: Joshua S. Clayton, Carolin K. Scriba, Norma B. Romero, Edoardo Malfatti, Safaa Saker, Thierry Larmonier, Kristen J. Nowak, Gianina Ravenscroft, Nigel G. Laing, and Rhonda L. Taylor
Subjects: Biology (General), QH301-705.5
Abstract: Nemaline myopathy (NM) is a congenital myopathy typically characterized by skeletal muscle weakness and the presence of abnormal thread- or rod-like structures (nemaline bodies) in myofibres. Pathogenic variants in the skeletal muscle alpha actin gene, ACTA1, cause approximately 25% of all NM cases. We generated two induced pluripotent stem cell lines from lymphoblastoid cells of a 4-month-old female with severe NM harbouring a dominant variant in ACTA1 (c.553C > A). The isogenic lines displayed characteristic iPSC morphology, expressed pluripotency markers, differentiated into cells of all three germ layers, and possessed normal karyotypes. These lines could be useful models of human ACTA1 disease.
Published: 2021
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15. Cuando el continente LatinoAmericano empezó a involucrarse más activamente en el tema neuromuscular …

Author: J. Andoni Urtizberea, MD, Norma B. Romero, MD, PhD, and Jorge A. Bevilacqua, MD, PhD
Subjects: Medicine
Abstract: RESUMEN: Desde el año 2008 un grupo de expertos europeos y latinoamericanos unen sus fuerzas para aumentar la consciencia y el conocimiento en este campo emergente de la medicina moderna. Gracias a un evento educacional anual llamado EVELAM, enseñaron a centenares de médicos especialistas del continente (pediatras y neurólogos, en su mayoría) cómo reconocer y manejar estas raras y complejas enfermedades para las cuales están apareciendo nuevas terapias en el horizonte. ABSTRACT: Since 2008, a group of european and latin-american experts in clinical myology have joined forces to raise awareness and knowledge in this emerging discipline of modern medicine. Through an annual teaching course called EVELAM, they trained hundreds of medical specialists of the continent (mostly neurologists and pediatricians) on how to recognize and manage these rare, complex conditions for which novel therapies are now on the horizon. Palabras clave: Miología, EVELAM, enfermedades neuromusculares, América Latina, Keywords: Myology, EVELAM, neuromuscular disorders, Latin America
Published: 2018
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16. Novel Phenotypes and Cardiac Involvement Associated With DNA2 Genetic Variants

Author: Ariadna González-del Angel, Michela Bisciglia, Steven Vargas-Cañas, Francisca Fernandez-Valverde, Ekaterina Kazakova, Rosa Elena Escobar, Norma B. Romero, Claude Jardel, Benoit Rucheton, Tanya Stojkovic, and Edoardo Malfatti
Subjects: mitochondrial disease, early onset myopathy, DNA2, cardiomyopathy, velopharyngeal weakness, rhabdomyolysis, Neurology. Diseases of the nervous system, RC346-429
Abstract: Objectives: To report two novel DNA2 gene mutations causing early onset myopathy with cardiac involvement and late onset mitochondriopathy with rhabdomyolysis.Methods: We performed detailed clinical, muscle histopathology and molecular studies including mitochondrial gene NGS analysis in two patients (Patient 1 and 2), a mother and her son, belonging to a Mexican family, and a third sporadic French patient.Results: Patient 1 and 2 presented with an early onset myopathy associated with ptosis, velopharyngeal weakness, and cardiac involvement. Patient 3 presented rhabdomyolysis unmasking a mitochondrial disease characterized by a sensorineural hearing loss, ptosis, and lipomas. Muscle biopsies performed in all patients showed variable mitochondrial alterations. Patient 3 had multiple mtDNA deletion in his muscle. Genetic studies revealed a novel heterozygous frameshift mutation in DNA2 gene (c.2346delT p.Phe782Leufs*3) in P1 and P2, and a novel heterozygous missense mutation in DNA2 gene (c.578T>C p.Leu193Ser) in the P3.Conclusions: To date only few AD cases presenting either missense or truncating DNA2 variants have been reported. None of them presented with a cardiac involvement or rhabdomyolysis. Here we enlarge the genetic and phenotypic spectrum of DNA2-related mitochondrial disorders.
Published: 2019
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17. Diagnostic work-up and phenotypic characteristics of a family with variable severity of distal arthrogryposis type 2B (Sheldon-Hall syndrome) and TNNT3 pathogenic variant

Author: Ivana Dabaj, Robert Y. Carlier, Klaus Dieterich, Isabelle Desguerre, Julien Faure, Norma B. Romero, Wenting Trang, Susana Quijano-Roy, and Dominique P. Germain
Subjects: Genetics, Molecular Medicine, Genetics (clinical)
Abstract: Background: Sheldon–Hall syndrome (SHS) or distal arthrogryposis 2B (DA2B) is a rare clinically and genetically heterogeneous multiple congenital contracture syndrome characterized by contractures of the distal joints of the limbs and mild facial involvement, due to pathogenic variants in genes encoding the fast-twitch skeletal muscle contractile myofiber complex (TNNT3, TNNI2, TMP2, and MYH3 genes).Patients and methods: A 16-year-old boy with a history of congenital distal arthrogryposis developed severe kyphoscoliosis and respiratory insufficiency. His mother and younger sister had phenotypes compatible with SHS but to a much lesser extent. Diagnostic work-up included physical examination and whole-body muscular MRI (WBMRI) in all three patients and electroneuromyography (ENMG) and paravertebral muscle biopsy in the proband. DNA sequencing was used to confirm the diagnosis.Results: Physical examination suggested the diagnosis of SHS. No muscle signal abnormalities were found in WBMRI. Large motor unit potentials and reduced recruitment suggestive of neurogenic changes were observed on needle EMG in distal and paravertebral muscles in the proband. DNA sequencing revealed a pathogenic variant in TNNT3 (c.187C>T), which segregated as a dominant trait with the phenotype.Discussion: This is the first report on neurogenic features in a patient with DA2B and a pathogenic variant in TNNT3 encoding the fast-twitch skeletal muscle contractile myofiber complex. A superimposed length-dependent motor nerve involvement was unexpected. Whether developmental disarrangements in number, distribution, or innervation of the motor unit in fetal life might lead to pseudo-neurogenic EMG features warrants further studies, as well as the role of genetic modifiers in SHS variability.
Published: 2023
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18. L’Atlas du Muscle : une banque d’images de biopsies musculaires

Author: Bruno Cadot and Norma B. Romero
Abstract: L’analyse des biopsies musculaires constitue un outil essentiel dans le domaine de la recherche et pour le diagnostic. La biopsie musculaire est régulièrement utilisée dans le diagnostic et l’évaluation de nombreuses maladies neuromusculaires survenant chez l’enfant ou chez l’adulte, ainsi que dans l’étude des modèles animaux correspondants. Nous décrivons ici l’Atlas du Muscle, une banque d’images de biopsies musculaires saines et pathologiques, dont les objectifs sont de documenter les données morphologiques d’une myopathie donnée bien caractérisée, de faciliter le diagnostic des différentes myopathies, et de fournir du matériel pour des approches faisant appel à l’intelligence artificielle (IA).
Published: 2021
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19. Severe ACTA1-related nemaline myopathy: intranuclear rods, cytoplasmic bodies, and enlarged perinuclear space as characteristic pathological features on muscle biopsies

Author: Clémence Labasse, Guy Brochier, Ana-Lia Taratuto, Bruno Cadot, John Rendu, Soledad Monges, Valérie Biancalana, Susana Quijano-Roy, Mai Thao Bui, Anaïs Chanut, Angéline Madelaine, Emmanuelle Lacène, Maud Beuvin, Helge Amthor, Laurent Servais, Yvan de Feraudy, Marcela Erro, Maria Saccoliti, Osorio Abath Neto, Julien Fauré, Béatrice Lannes, Vincent Laugel, Sandra Coppens, Fabiana Lubieniecki, Ana Buj Bello, Nigel Laing, Teresinha Evangelista, Jocelyn Laporte, Johann Böhm, and Norma B. Romero
Subjects: Muscle Weakness, Nuclear Envelope, Biopsy, Myopathies, Nemaline, Actins, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Pregnancy, Mutation, Humans, Female, Neurology (clinical), Child, Muscle, Skeletal
Abstract: Nemaline myopathy (NM) is a muscle disorder with broad clinical and genetic heterogeneity. The clinical presentation of affected individuals ranges from severe perinatal muscle weakness to milder childhood-onset forms, and the disease course and prognosis depends on the gene and mutation type. To date, 14 causative genes have been identified, and ACTA1 accounts for more than half of the severe NM cases. ACTA1 encodes α-actin, one of the principal components of the contractile units in skeletal muscle. We established a homogenous cohort of ten unreported families with severe NM, and we provide clinical, genetic, histological, and ultrastructural data. The patients manifested antenatal or neonatal muscle weakness requiring permanent respiratory assistance, and most deceased within the first months of life. DNA sequencing identified known or novel ACTA1 mutations in all. Morphological analyses of the muscle biopsy specimens showed characteristic features of NM histopathology including cytoplasmic and intranuclear rods, cytoplasmic bodies, and major myofibrillar disorganization. We also detected structural anomalies of the perinuclear space, emphasizing a physiological contribution of skeletal muscle α-actin to nuclear shape. In-depth investigations of the nuclei confirmed an abnormal localization of lamin A/C, Nesprin-1, and Nesprin-2, forming the main constituents of the nuclear lamina and the LINC complex and ensuring nuclear envelope integrity. To validate the relevance of our findings, we examined muscle samples from three previously reported ACTA1 cases, and we identified the same set of structural aberrations. Moreover, we measured an increased expression of cardiac α-actin in the muscle samples from the patients with longer lifespan, indicating a potential compensatory effect. Overall, this study expands the genetic and morphological spectrum of severe ACTA1-related nemaline myopathy, improves molecular diagnosis, highlights the enlargement of the perinuclear space as an ultrastructural hallmark, and indicates a potential genotype/phenotype correlation.
Published: 2022
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20. Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy

Author: A. Madelaine, Julie Brocard, Mireille Cossée, Isabelle Marty, Anne-Cécile Coville, Michel Koenig, Christine Ioos, C. Thèze, John Rendu, Klaus Dieterich, Aurore Siegfried, Julien Fauré, Claude Cances, Henri Pegeot, Eloïse Baudou, Pascale Marcorelle, Norma B. Romero, Emmanuelle Lacène, Emmanuelle Uro Coste, Murielle Dobrzynski, Raul Juntas Morales, Justine Géraud, Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHRU Brest, Pôle de Biologie Pathologie (CHU - BREST - Biologie pathologie), Hôpital Raymond Poincaré [AP-HP], 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), 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 Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Institut des Neurosciences de Montpellier (INM)
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, diagnosis, [SDV]Life Sciences [q-bio], Biopsy, Nonsense mutation, neuromuscular diseases, Slow skeletal muscle troponin T, Myopathies, Nemaline, 03 medical and health sciences, Exon, 0302 clinical medicine, Nemaline myopathy, Troponin T, Genetics, medicine, Humans, Genetic Predisposition to Disease, Diagnostics, Genetics (clinical), Genetic Association Studies, Sequence Deletion, business.industry, Homozygote, Skeletal muscle, Muscle weakness, Computational Biology, High-Throughput Nucleotide Sequencing, Infant, Sequence Analysis, DNA, medicine.disease, musculoskeletal system, Immunohistochemistry, Hypotonia, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Phenotype, Child, Preschool, Mutation, Female, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: BackgroundCongenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres.MethodsUsing next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform.ResultsThe clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations.DiscussionThe clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.
Published: 2020
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21. A new congenital multicore titinopathy associated with fast myosin heavy chain deficiency

Author: Robert Carlier, Mireille Cossée, Corinne Metay, Edoardo Malfatti, Pascale Richard, Norma B. Romero, Henk Granzier, Isabelle Richard, Michel Koenig, Elena Pegoraro, Aurélien Perrin, Tanya Stojkovic, Raul Juntas Morales, Marcello Villanova, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Myologie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service de Biochimie Métabolique et Centre de Génétique moléculaire et chromosomique [CHU Pitié Salpêtrière], Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universita degli Studi di Padova, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, University of Arizona, Gestionnaire, Hal Sorbonne Université, Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de recherche en Myologie – U974 SU-INSERM, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Università degli Studi di Padova = University of Padua (Unipd), and Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Gene isoform, Male, Fast myosin, Adolescent, [SDV]Life Sciences [q-bio], Child, Connectin, Deltoid Muscle, Female, Humans, Myosin Heavy Chains, Pedigree, Siblings, Muscular Diseases, Neurosciences. Biological psychiatry. Neuropsychiatry, macromolecular substances, Brief Communication, 03 medical and health sciences, 0302 clinical medicine, Myosin, Medicine, RC346-429, Messenger RNA, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, biology, business.industry, General Neuroscience, Phenotype, Cell biology, [SDV] Life Sciences [q-bio], Blot, 030104 developmental biology, biology.protein, Immunohistochemistry, Titin, Neurology. Diseases of the nervous system, Neurology (clinical), business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, RC321-571
Abstract: International audience; Congenital titinopathies are myopathies with variable phenotypes and inheritance modes. Here, we fully characterized, using an integrated approach (deep phenotyping, muscle morphology, mRNA and protein evaluation in muscle biopsies), two siblings with congenital multicore myopathy harboring three TTN variants predicted to affect titin stability and titin-myosin interactions. Muscle biopsies showed multicores, type 1 fiber uniformity and sarcomeric structure disruption with some thick filament loss. Immunohistochemistry and Western blotting revealed a marked reduction of fast myosin heavy chain iso-forms. This is the first observation of a titinopathy suggesting that titin defect leads to secondary loss of fast myosin heavy chain isoforms.
Published: 2020
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22. Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

Author: Hong Joo Kim, Payam Mohassel, Sandra Donkervoort, Lin Guo, Kevin O’Donovan, Maura Coughlin, Xaviere Lornage, Nicola Foulds, Simon R. Hammans, A. Reghan Foley, Charlotte M. Fare, Alice F. Ford, Masashi Ogasawara, Aki Sato, Aritoshi Iida, Pinki Munot, Gautam Ambegaonkar, Rahul Phadke, Dominic G. O’Donovan, Rebecca Buchert, Mona Grimmel, Ana Töpf, Irina T. Zaharieva, Lauren Brady, Ying Hu, Thomas E. Lloyd, Andrea Klein, Maja Steinlin, Alice Kuster, Sandra Mercier, Pascale Marcorelles, Yann Péréon, Emmanuelle Fleurence, Adnan Manzur, Sarah Ennis, Rosanna Upstill-Goddard, Luca Bello, Cinzia Bertolin, Elena Pegoraro, Leonardo Salviati, Courtney E. French, Andriy Shatillo, F. Lucy Raymond, Tobias B. Haack, Susana Quijano-Roy, Johann Böhm, Isabelle Nelson, Tanya Stojkovic, Teresinha Evangelista, Volker Straub, Norma B. Romero, Jocelyn Laporte, Francesco Muntoni, Ichizo Nishino, Mark A. Tarnopolsky, James Shorter, Carsten G. Bönnemann, J. Paul Taylor, Kim, Hong Joo [0000-0002-9157-1612], Mohassel, Payam [0000-0001-5313-9514], Fare, Charlotte M [0000-0003-0394-6435], Iida, Aritoshi [0000-0001-7538-1651], Buchert, Rebecca [0000-0001-7576-3326], Lloyd, Thomas E [0000-0003-4756-3700], Fleurence, Emmanuelle [0000-0002-6717-3737], Ennis, Sarah [0000-0003-2648-0869], Upstill-Goddard, Rosanna [0000-0002-2666-0934], Bello, Luca [0000-0002-3075-6525], Salviati, Leonardo [0000-0001-5642-9963], French, Courtney E [0000-0001-7620-1544], Shatillo, Andriy [0000-0003-3630-6880], Raymond, F Lucy [0000-0003-2652-3355], Straub, Volker [0000-0001-9046-3540], Laporte, Jocelyn [0000-0001-8256-5862], Nishino, Ichizo [0000-0001-9452-112X], Tarnopolsky, Mark A [0000-0003-0312-3746], Bönnemann, Carsten G [0000-0002-5930-2324], Taylor, J Paul [0000-0002-5794-0349], Apollo - University of Cambridge Repository, Physiopathologie des Adaptations Nutritionnelles (PhAN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), and European Project: 861960 ,INDUSTRIAL LEADERSHIP - Leadership in enabling and industrial technologies - Advanced materials,RECYCALYSE (2020)
Subjects: Heterozygote, Multidisciplinary, [SDV]Life Sciences [q-bio], Amyotrophic Lateral Sclerosis, General Physics and Astronomy, 610 Medicine & health, General Chemistry, General Biochemistry, Genetics and Molecular Biology, Muscular Dystrophy, Oculopharyngeal, Heterogeneous-Nuclear Ribonucleoprotein Group A-B, Animals, Humans, Frameshift Mutation
Abstract: Funder: Howard Hughes Medical Institute, Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
Published: 2022
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23. Generation of two isogenic induced pluripotent stem cell lines from a 1-month-old nemaline myopathy patient harbouring a homozygous recessive c.121C T (p.Arg39Ter) variant in the ACTA1 gene

Author: Isabella S. Suleski, Robert Smith, Christina Vo, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Edoardo Malfatti, Norma B. Romero, Peter J. Houweling, Kristen J. Nowak, Nigel G. Laing, Rhonda L. Taylor, and Joshua S. Clayton
Subjects: Male, Homozygote, Induced Pluripotent Stem Cells, Mutation, Humans, Infant, Cell Biology, General Medicine, Muscle, Skeletal, Myopathies, Nemaline, Actins, Developmental Biology
Abstract: Nemaline myopathy (NM) is a congenital skeletal muscle disorder that typically results in muscle weakness and the presence of rod-like structures (nemaline bodies) in the sarcoplasma and/or in the nuclei of myofibres. Two induced pluripotent stem cell (iPSC) lines were generated from the lymphoblastoid cells of a 1-month-old male with severe NM caused by a homozygous recessive mutation in the ACTA1 gene (c.121C T, p.Arg39Ter). The iPSC lines demonstrated typical morphology, expressed pluripotency markers, exhibited trilineage differentiation potential and displayed a normal karyotype. These isogenic lines represent a potential resource to investigate and model recessive ACTA1 disease in a human context.
Published: 2022

24. Congenital Nemaline Myopathy with Dense Protein Masses

Author: Jorge A Bevilacqua, Edoardo Malfatti, Clémence Labasse, Guy Brochier, Angeline Madelaine, Emmanuelle Lacène, Bérénice Doray, Pascal Laforêt, Bruno Eymard, John Rendu, and Norma B Romero
Subjects: Cellular and Molecular Neuroscience, Neurology, Muscular Diseases, Humans, Muscle Proteins, Neurology (clinical), General Medicine, Muscle, Skeletal, Myopathies, Nemaline, Pathology and Forensic Medicine
Published: 2022

25. [JAG2-related muscular dystrophy: When differential diagnosis matters]

Author: Rocio, Nur Villar-Quiles, Norma B, Romero, and Stojkovic, Tanya
Subjects: Diagnosis, Differential, Muscular Diseases, Humans, Jagged-2 Protein, Muscular Dystrophies
Abstract: JAG2 has recently been involved in autosomal recessive forms of muscular dystrophy as illustrated in this clinical vignette. In many ways, this disease can mimick a COL6-related retractile myopathy including at the imaging level.
Published: 2021

26. [AcadeMYO, a successful bet]

Author: J Andoni, Urtizberea and Norma B, Romero
Subjects: Education, Distance, COVID-19, Humans, Mycology, Program Development, Program Evaluation
Published: 2021

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

Author: Julie Perrier-Boeswillwald, Johann Böhm, Eric Bieth, Marie-Christine Minot-Myhie, Marie-Christine Nougues, Annabelle Chaussenot, Helen Mecili, François-Jérôme Authier, Maud Michaud, Sandra Mercier, Norma B. Romero, Claude Cances, Julien Fauré, Mégane Pizzimenti, Nicolas Dondaine, Valérie Biancalana, Sabrina Sacconi, Antoinette Gelot Bernabe, John Rendu, Alison Bouzenard, Armelle Magot, Bertrand Isidor, Yann Péréon, Mélanie Fradin, Emmanuelle Uro-Coste, Jocelyn Laporte, Pascale Marcorelles, Gilles Bretaudeau, Laurent Pasquier, Ana Ferreiro, Bruno Eymard, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Hôpital l'Archet, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Génétique [Purpan], CHU Toulouse [Toulouse], Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], Centre de référence Maladies Rares CLAD-Ouest [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), Reference Centre for Neuromuscular Disorders ( FILNEMUS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Université de Bretagne Occidentale - UFR Médecine et Sciences de la Santé (UBO UFR MSS), Université de Brest (UBO), Hôpital Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U1249), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Dynamique et Structure du Cytosquelette Neuronal, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Service Génétique Médicale [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Laporte, Jocelyn
Subjects: Male, Pathology, Triad, Neuromuscular disorder, Case Report, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 0302 clinical medicine, Age of Onset, 0303 health sciences, Congenital myopathy, medicine.diagnostic_test, Muscle weakness, Middle Aged, musculoskeletal system, Hypotonia, 3. Good health, Pedigree, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Child, Preschool, Disease Progression, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Muscle Hypotonia, Female, medicine.symptom, Adult, medicine.medical_specialty, Adolescent, [SDV.GEN.GA] Life Sciences [q-bio]/Genetics/Animal genetics, Muscle disorder, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, Excitation–contraction coupling, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Humans, Centronuclear myopathy, RC346-429, 030304 developmental biology, Aged, RYR1, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Muscle biopsy, business.industry, Ryanodine Receptor Calcium Release Channel, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Calcium, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, Central core disease
Abstract: The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca2+-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
Published: 2021
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28. Generation of two isogenic induced pluripotent stem cell lines from a 10-year-old typical nemaline myopathy patient with a heterozygous dominant c.541G>A (p.Asp179Asn) pathogenic variant in the ACTA1 gene

Author: Kristen J. Nowak, Thierry Larmonier, Safaa Saker, Rhonda L. Taylor, Gianina Ravenscroft, Carolin K. Scriba, Norma B. Romero, Nigel G. Laing, Edoardo Malfatti, Joshua S. Clayton, The University of Western Australia (UWA), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Généthon, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and HAL-SU, Gestionnaire
Subjects: [SDV.BIO]Life Sciences [q-bio]/Biotechnology, QH301-705.5, Induced Pluripotent Stem Cells, Germ layer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Myopathies, Nemaline, 03 medical and health sciences, 0302 clinical medicine, Nemaline myopathy, Gene duplication, medicine, Humans, Biology (General), Child, Muscle, Skeletal, Nemaline bodies, Induced pluripotent stem cell, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Gene, 030304 developmental biology, 0303 health sciences, Lymphoblast, Cell Biology, General Medicine, medicine.disease, Congenital myopathy, Molecular biology, Actins, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, 3. Good health, Mutation, Female, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Nemaline myopathy (NM) is a congenital myopathy typically characterized by skeletal muscle weakness and the presence of nemaline bodies in myofibres. Approximately 25% of NM cases are caused by variants in ACTA1. We generated two induced pluripotent stem cell lines from lymphoblastoid cells of a 10-year-old female with typical NM harbouring a dominant pathogenic variant in ACTA1 (c.541C>A). The isogenic lines displayed typical iPSC morphology, expressed pluripotency markers, and could differentiate into each of the three germ layers. Although the lines have partial or complete X chromosome duplication, they may still prove useful as models of human ACTA1 disease.
Published: 2021
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29. ASC‐1 Is a Cell Cycle Regulator Associated with Severe and Mild Forms of Myopathy

Author: Teresa Gidaro, Julien Durigneux, Emma Pierce-Hoffman, Fabio Catervi, Johann Böhm, Alan H. Beggs, Adnan Yuksel, Montse Olivé, Casie A. Genetti, Raul Juntas-Morales, Isabelle Duband-Goulet, Nicolas Deconinck, Norma B. Romero, Eva Cabet, Rocío-Nur Villar-Quiles, Asuman Koparir, Ana Ferreiro, Jocelyn Laporte, Xavière Lornage, Mireille Cossée, John Rendu, Sandra Coppens, Lara Servais, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), 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), Biruni University, Children's University Hospital Queen Fabiola [Bruxelles, Belgium], Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA, Partenaires INRAE, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des Maladies Neuromusculaires AOC, Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Children's Hospital and Harvard Medical School, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and Mühendislik ve Doğa Bilimleri Fakültesi
Subjects: Male, TRANSCRIPTION COACTIVATOR, 0301 basic medicine, Pathology, animal diseases, [SDV]Life Sciences [q-bio], Cardiomyopathy, Muscle Proteins, medicine.disease_cause, SIGNAL COINTEGRATOR 1, 0302 clinical medicine, Fibroblasts -- physiology, Amyotrophic lateral sclerosis, Child, Cells, Cultured, Mutation, ABNORMALITIES, Cell Cycle -- physiology, Cell Cycle, PROLIFERATION, hemic and immune systems, Sciences bio-médicales et agricoles, Middle Aged, MUSCLE, Pedigree, 3. Good health, Phenotype, Neurology, Child, Preschool, Female, Transcription Factors -- genetics, medicine.symptom, tissues, D3, G1 phase, Adult, endocrine system, medicine.medical_specialty, Amino Acid Transport System y+, DISORDERS, Muscle Proteins -- genetics, Muscle, Skeletal -- pathology -- physiopathology, Article, 03 medical and health sciences, Muscular Diseases, Neurologie, medicine, Humans, Amino Acid Transport System y+ -- metabolism -- physiology, Muscle, Skeletal, Cell Cycle Protein, Myopathy, business.industry, Infant, Spinal muscular atrophy, Fibroblasts, medicine.disease, GENE, Congenital myopathy, eye diseases, MUSCULAR-DYSTROPHY, ADIPOGENESIS, 030104 developmental biology, Muscular Diseases -- genetics -- physiopathology, Neurology (clinical), business, 030217 neurology & neurosurgery, Transcription Factors
Abstract: Objective: Recently, the ASC-1 complex has been identified as a mechanistic link between amyotrophic lateral sclerosis and spinal muscular atrophy (SMA), and 3 mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. Methods: Clinical, molecular, histological, and magnetic resonance imaging studies were made in 5 families with 7 novel TRIP4 mutations. Fluorescence activated cell sorting and Western blot were performed in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. Results: All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure, and in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers, and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins, and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. Interpretation: Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with isolated primary muscle involvement, and establish TRIP4 as a causative gene for several congenital muscle diseases, including nemaline, core, centronuclear, and cytoplasmic-body myopathies. They also identify ASC-1 as a novel cell cycle regulator with a key role in cell proliferation, and underline transcriptional coregulation defects as a novel pathophysiological mechanism. ANN NEUROL 2020;87:217–232., SCOPUS: ar.j, info:eu-repo/semantics/published
Published: 2019
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30. Generation of an induced pluripotent stem cell line from a 3-month-old nemaline myopathy patient with a heterozygous dominant c.515C > A (p.Ala172Glu) variant in the ACTA1 gene

Author: Joshua S. Clayton, Isabella Suleski, Christina Vo, Robert Smith, Carolin K. Scriba, Safaa Saker, Thierry Larmonier, Edoardo Malfatti, Norma B. Romero, Peter J. Houweling, Kristen J. Nowak, Gianina Ravenscroft, Nigel G. Laing, and Rhonda L. Taylor
Subjects: Child, Preschool, Induced Pluripotent Stem Cells, Mutation, Infant, Newborn, Humans, Infant, Female, Cell Biology, General Medicine, Muscle, Skeletal, Myopathies, Nemaline, Actins, Developmental Biology
Abstract: Variants in the ACTA1 gene are a common cause of nemaline myopathy (NM); a muscle disease that typically presents at birth or early childhood with hypotonia and muscle weakness. Here, we generated an induced pluripotent stem cell line (iPSC) from lymphoblastoid cells of a 3-month-old female patient with intermediate NM caused by a dominant ACTA1 variant (c.515C A (p.Ala172Glu)). iPSCs showed typical morphology, expressed pluripotency markers, demonstrated trilineage differentiation potential, and had a normal karyotype. This line complements our previously published ACTA1 iPSC lines derived from patients with typical and severe NM.
Published: 2022
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31. Diagnostic interest of whole-body MRI in early- and late-onset LAMA2 muscular dystrophies: a large international cohort

Author: Ivana Dabaj, Corinne Metay, Tanya Stojkovic, Nicolas Leboucq, Susana Quijano-Roy, Jana Haberlová, François Rivier, John Rendu, Giorgio Tasca, David Gómez-Andrés, Audrey Benezit, Ximena Ortega, Fabiana Fattori, Helge Amthor, Edoardo Malfatti, Jana Zídková, Angel Sanchez-Montanez, Norma B. Romero, John Vissing, Clara Gontijo Camelo, Claudia Castiglioni, Marta Gómez García de la Banda, Laura Costa Comellas, Robert Carlier, Pascal Laforêt, Nicoline Løkken, Francina Munell, Christophe Béroud, Martin Kyncl, Eliana Cavassa, AP-HP. Université Paris Saclay, Hôpital Raymond Poincaré [AP-HP], Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Motol [Prague], University of Copenhagen = Københavns Universitet (UCPH), Vall d'Hebron University Hospital [Barcelona], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Cancer and Brain Genomics (CBG), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamique et Structure du Cytosquelette Neuronal, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire [Grenoble] (CHU), Sorbonne Université (SU), Bambino Gesù Children’s Hospital [Rome, Italy], Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital Brno, CHU Montpellier, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service d'Imagerie Médicale [Raymond-Poincaré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP], We thank ISCIII for the fnancial support for studying LAMA2-RD in Spain., CHU Henri Mondor, Unité clinique de pathologie neuromusculaire [CHU Pitié-Salpêtrière], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Génétique Moléculaire [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et Cellulaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), MORNET, Dominique, Clinica Las Condes, University of Copenhagen = Københavns Universitet (KU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Fondazione 'Policlinico Universitario A. Gemelli' [Rome], Faculdade de Medicina da Universidade de São Paulo [São Paulo, Brésil], Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de recherche en myologie, and Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, medicine.medical_specialty, Congenital muscular dystrophy, Myopathy, [SDV]Life Sciences [q-bio], Muscle MRI, Biceps, Muscular Dystrophies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Whole Body Imaging, Heatmap, Muscular dystrophy, Muscle, Skeletal, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Muscle biopsy, biology, medicine.diagnostic_test, business.industry, Gluteus minimus, 030305 genetics & heredity, Posterior compartment of thigh, medicine.disease, biology.organism_classification, Magnetic Resonance Imaging, [SDV] Life Sciences [q-bio], Medius, Neurology, Neurology (clinical), Laminin, medicine.symptom, Merosin, business, 030217 neurology & neurosurgery
Abstract: Background: LAMA2-related muscular dystrophy (LAMA2-RD) encompasses a group of recessive muscular dystrophies caused by mutations in the LAMA2 gene, which codes for the alpha-2 chain of laminin-211 (merosin). Diagnosis is straightforward in the classic congenital presentation with no ambulation and complete merosin deficiency in muscle biopsy, but is far more difficult in milder ambulant individuals with partial merosin deficiency. Objective: To investigate the diagnostic utility of muscle imaging in LAMA2-RD using whole-body magnetic resonance imaging (WBMRI). Results: 27 patients (2–62 years, 21–80% with acquisition of walking ability and 6 never ambulant) were included in an international collaborative study. All carried two pathogenic mutations, mostly private missense changes. An intronic variant (c.909 + 7A > G) was identified in all the Chilean cases. Three patients (two ambulant) showed intellectual disability, epilepsy, and brain structural abnormalities. WBMRI T1w sequences or T2 fat-saturated images (Dixon) revealed abnormal muscle fat replacement predominantly in subscapularis, lumbar paraspinals, gluteus minimus and medius, posterior thigh (adductor magnus, biceps femoris, hamstrings) and soleus. This involvement pattern was consistent for both ambulant and non-ambulant patients. The degree of replacement was predominantly correlated to the disease duration, rather than to the onset or the clinical severity. A “COL6-like sandwich sign” was observed in several muscles in ambulant adults, but different involvement of subscapularis, gluteus minimus, and medius changes allowed distinguishing LAMA2-RD from collagenopathies. The thigh muscles seem to be the best ones to assess disease progression. Conclusion: WBMRI in LAMA2-RD shows a homogeneous pattern of brain and muscle imaging, representing a supportive diagnostic tool.
Published: 2021
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32. Generation of two isogenic induced pluripotent stem cell lines from a 4-month-old severe nemaline myopathy patient with a heterozygous dominant c.553C > A (p.Arg183Ser) variant in the ACTA1 gene

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

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

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

Author: Nicol C. Voermans, Claire Boulogne, Benno Küsters, Clémence Labasse, Baziel G.M. van Engelen, Coen A.C. Ottenheijm, Josine M. de Winter, Guy Brochier, Karlijn Bouman, Lilian Eshuis, Esmee S.B. Van Kleef, Norma B. Romero, A. Madelaine, Cynthia Gillet, Edoardo Malfatti, Physiology, and ACS - Pulmonary hypertension & thrombosis
Subjects: Adult, Male, Pathology, medicine.medical_specialty, genetic structures, Muscle Fibers, Skeletal, Muscle Proteins, Myopathies, Nemaline, Sarcomere, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Nemaline myopathy, law, medicine, Myotilin, Humans, Myopathy, Actin, 030304 developmental biology, Aged, Netherlands, 0303 health sciences, biology, Chemistry, General Medicine, Middle Aged, medicine.disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Congenital myopathy, Neurology, biology.protein, Titin, Female, Neurology (clinical), sense organs, medicine.symptom, Electron microscope, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 232919.pdf (Publisher’s version ) (Closed access) Nemaline myopathy type 6 (NEM6), KBTBD13-related congenital myopathy is caused by mutated KBTBD13 protein that interacts improperly with thin filaments/actin, provoking impaired muscle-relaxation kinetics. We describe muscle morphology in 18 Dutch NEM6 patients and correlate it with clinical phenotype and pathophysiological mechanisms. Rods were found in in 85% of biopsies by light microscopy, and 89% by electron microscopy. A peculiar ring disposition of rods resulting in ring-rods fiber was observed. Cores were found in 79% of NEM6 biopsies by light microscopy, and 83% by electron microscopy. Electron microscopy also disclosed granulofilamentous protein material in 9 biopsies. Fiber type 1 predominance and prominent nuclear internalization were found. Rods were immunoreactive for α-actinin and myotilin. Areas surrounding the rods showed titin overexpression suggesting derangement of the surrounding sarcomeres. NEM6 myopathology hallmarks are prominent cores, rods including ring-rods fibers, nuclear clumps, and granulofilamentous protein material. This material might represent the histopathologic epiphenomenon of altered interaction between mutated KBTBD13 protein and thin filaments. We claim to classify KBTBD13-related congenital myopathy as rod-core myopathy.
Published: 2021
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35. Clinical correlations and long-term follow-up in 100 patients with sarcoglycanopathies

Author: D. Orlikowski, M C Nougues, P. Laforêt, Anthony Behin, Gorka Fernández-Eulate, Abdallah Fayssoil, Isabelle Desguerre, F. Leturcq, Sarah Leonard-Louis, Bruno Eymard, B Estournet-Mathiaud, Isabelle Richard, B Fauroux, A Isapof, Edoardo Malfatti, Karim Wahbi, Raquel Guimarães-Costa, T. Stojkovic, Claudio Semplicini, Susana Quijano-Roy, Norma B. Romero, Giorgia Querin, Christine Barnerias, 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), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Handicap neuromusculaire : Physiopathologie, Biothérapie et Pharmacologies appliquées (END-ICAP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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, 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), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, and Richard, Isabelle
Subjects: medicine.medical_specialty, Adolescent, neuromuscular diseases, Exercise intolerance, 03 medical and health sciences, outcome measures, 0302 clinical medicine, Internal medicine, Sarcoglycans, sarcoglycan, medicine, Sarcoglycanopathies, Humans, 030212 general & internal medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Muscle, Skeletal, Retrospective Studies, Muscle biopsy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, business.industry, Genetic heterogeneity, Homozygote, Dilated cardiomyopathy, Retrospective cohort study, limb-girdle muscular dystrophies, medicine.disease, 3. Good health, Sarcoglycan, Sarcoglycanopathy, Neurology, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), medicine.symptom, genetic, business, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract: International audience; Background and purpose: To describe a large series of patients with α, β, and γ sarcoglycanopathies (LGMD-R3, R4, and R5) and study phenotypic correlations and disease progression. Methods: A multicentric retrospective study in four centers in the Paris area collecting neuromuscular, respiratory, cardiac, histologic, and genetic data. The primary outcome of progression was age of loss of ambulation (LoA); disease severity was established according to LoA before or after 18 years of age. Time-to-event analysis was performed. Results: One hundred patients (54 γ-SG; 41 α-SG; 5 β-SG) from 80 families were included. The γ-SG patients had earlier disease onset than α-SG patients (5.5 vs. 8 years; p = 0.022) and β-SG patients (24.4 years). Axial muscle weakness and joint contractures were frequent and exercise intolerance was observed. At mean follow-up of 22.9 years, 65.3% of patients were wheelchair-bound (66.7% α-SG, 67.3% γ-SG, 40% β-SG). Dilated cardiomyopathy occurred in all sarcoglycanopathy subtypes, especially in γ-SG patients (p = 0.01). Thirty patients were ventilated and six died. Absent sarcoglycan protein expression on muscle biopsy and younger age at onset were associated with earlier time to LoA (p = 0.021 and p = 0.002). Age at onset was an independent predictor of both severity and time to LoA (p = 0.0004 and p = 0.009). The α-SG patients showed genetic heterogeneity, whereas >90% of γ-SG patients carried the homozygous c.525delT frameshift variant. Five new mutations were identified. Conclusions: This large multicentric series delineates the clinical spectrum of patients with sarcoglycanopathies. Age at disease onset is an independent predictor of severity of disease and LoA, and should be taken into account in future clinical trials.
Published: 2021
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36. rAAV-related therapy fully rescues myonuclear and myofilament function in X-linked myotubular myopathy

Author: Belinda S. Cowling, Julien Ochala, Jocelyn Laporte, Edmar Zanoteli, David L. Mack, Jennifer E. Morgan, Yotam Levy, Hichem Tasfaout, Heinz Jungbluth, Michael W. Lawlor, Jacob A. Ross, Dawn A. Lowe, Norma B. Romero, King‘s College London, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University College of London [London] (UCL), Universidade de São Paulo Medical School (FMUSP), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Guy's and St Thomas' Hospital [London], Institute of Psychiatry, Psychology & Neuroscience, King's College London, Medical College of Wisconsin [Milwaukee] (MCW), University of Washington [Seattle], IT University of Copenhagen, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), IT University of Copenhagen (ITU), and Gestionnaire, Hal Sorbonne Université
Subjects: Male, Myofilament, Myotubularin, Genetic enhancement, Muscle Fibers, Skeletal, Skeletal muscle, lcsh:RC346-429, Mice, 0302 clinical medicine, Myofibrils, Congenital myopathy, 0303 health sciences, education.field_of_study, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Dependovirus, Protein Tyrosine Phosphatases, Non-Receptor, X-linked myotubular myopathy, Cell biology, Phenotype, medicine.anatomical_structure, Child, Preschool, Female, medicine.symptom, Muscle Contraction, Myopathies, Structural, Congenital, Adult, Adolescent, Force production, Genetic Vectors, Population, Biology, Pathology and Forensic Medicine, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, Dogs, medicine, Animals, Humans, Myonuclear domain, education, lcsh:Neurology. Diseases of the nervous system, 030304 developmental biology, Research, Infant, Muscle weakness, Genetic Therapy, medicine.disease, Disease Models, Animal, Microscopy, Electron, Neurology (clinical), [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: X-linked myotubular myopathy (XLMTM) is a life-threatening skeletal muscle disease caused by mutations in the MTM1 gene. XLMTM fibres display a population of nuclei mispositioned in the centre. In the present study, we aimed to explore whether positioning and overall distribution of nuclei affects cellular organization and contractile function, thereby contributing to muscle weakness in this disease. We also assessed whether gene therapy alters nuclear arrangement and function. We used tissue from human patients and animal models, including XLMTM dogs that had received increasing doses of recombinant AAV8 vector restoring MTM1 expression (rAAV8-cMTM1). We then used single isolated muscle fibres to analyze nuclear organization and contractile function. In addition to the expected mislocalization of nuclei in the centre of muscle fibres, a novel form of nuclear mispositioning was observed: irregular spacing between those located at the fibre periphery, and an overall increased number of nuclei, leading to dramatically smaller and inconsistent myonuclear domains. Nuclear mislocalization was associated with decreases in global nuclear synthetic activity, contractile protein content and intrinsic myofilament force production. A contractile deficit originating at the myofilaments, rather than mechanical interference by centrally positioned nuclei, was supported by experiments in regenerated mouse muscle. Systemic administration of rAAV8-cMTM1 at doses higher than 2.5 × 1013 vg kg−1 allowed a full rescue of all these cellular defects in XLMTM dogs. Altogether, these findings identify previously unrecognized pathological mechanisms in human and animal XLMTM, associated with myonuclear defects and contractile filament function. These defects can be reversed by gene therapy restoring MTM1 expression in dogs with XLMTM.
Published: 2020
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37. In vivo RyR1 reduction in muscle triggers a core-like myopathy

Author: Daniel Metzger, Diane Giovannini, Vincent Jacquemond, Lauriane Travard, Colline Sanchez, Isabelle Marty, Norma B. Romero, Anne Petiot, Mathilde Beaufils, Candice Kutchukian, Benoît Giannesini, Laurent Pelletier, Julie Brocard, John Rendu, Mathilde Chivet, Clara Franzini Armstrong, Julien Fauré, David Bendahan, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), 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), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Pennsylvania [Philadelphia], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Jacquemond, Vincent, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Dusty core disease, Skeletal muscle, Mice, Transgenic, lcsh:RC346-429, Mouse model, RyR1 reduction induces a myopathy Ryanodine receptor, 03 medical and health sciences, Mice, Excitation–contraction coupling, Congenital myopathies, Atrophy, Calcium flux, medicine, Animals, Central core disease, Myopathy, Central Core, Myopathy, Muscle, Skeletal, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, RYR1, 0303 health sciences, Muscle Weakness, Chemistry, Calcium channel, Research, 030302 biochemistry & molecular biology, Autophagy, Ryanodine Receptor Calcium Release Channel, medicine.disease, musculoskeletal system, Excitation-contraction coupling, Cell biology, Mitochondria, Muscle, [SDV] Life Sciences [q-bio], Disease Models, Animal, Muscular Atrophy, medicine.anatomical_structure, Ryanodine receptor, Gene Knockdown Techniques, Calcium, medicine.symptom, tissues
Abstract: Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction. Electronic supplementary material The online version of this article (10.1186/s40478-020-01068-4) contains supplementary material, which is available to authorized users.
Published: 2020
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38. Physiological impact and disease reversion for the severe form of centronuclear myopathy linked to dynamin

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

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

Author: Gillian Butler-Browne, Julien Messéant, Norma B. Romero, Emmanuelle Lacène, Sophie Moog, Catherine Coirault, Arnaud Ferry, Gisèle Bonne, Astrid Brull, Kamel Mamchaoui, Daniel J. Owens, and Mark Viggars
Subjects: Myogenesis, Skeletal muscle, Biology, medicine.disease, Muscle atrophy, Muscle hypertrophy, Cell biology, LMNA, medicine.anatomical_structure, medicine, Congenital muscular dystrophy, medicine.symptom, Muscular dystrophy, Lamin
Abstract: BackgroundLaminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that impair skeletal muscle growth may contribute to the disease severity.MethodsWe used human muscle stem cells (MuSCs) carrying 4 different LMNA mutations and two mouse models of muscle laminopathies, representing a spectrum of disease severity, to investigate the ability of skeletal muscle to differentiate and to hypertrophy in response to mechanical challenges. We extended these finding to individuals with LMNA-related muscular dystrophy using muscle biopsies.ResultsIn vitro, we observe impaired myogenic differentiation with disorganized cadherin/β catenin adhesion complexes in MuSCs carrying LMNA-CMD. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective accretion of activated MuSCs, defective protein synthesis and defective remodeling of the neuro-muscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the Yes-Associated Protein (YAP), a key sensor and mediator of mechanical cues. We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely-related EDMD models.ConclusionsCombining studies in vitro, in vivo and patient samples, we find that LMNA-CMD mutations interfere with mechano-signaling pathways in skeletal muscle, implicating defective skeletal muscle growth as a pathogenic contributor for the severity of LMNA-related muscular dystrophy.
Published: 2020
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40. SH3KBP1 scaffolds endoplasmic reticulum and controls skeletal myofibers architecture and integrity

Author: Emilie Christin, Marc Bitoun, Alexandre Guiraud, Alexandre Janin, David Arnould, Nathalie Couturier, Vincent Gache, Alireza Ghasemizadeh, Carole Kretz-Remy, Norma B. Romero, Thao Mai Bui, Anne-Cécile Durieux, Laura Julien, and Vladimir L. Buchman
Subjects: medicine.anatomical_structure, Myogenesis, Chemistry, Regeneration (biology), Calnexin, Endoplasmic reticulum, Precursor cell, medicine, Skeletal muscle, Myocyte, Autosomal dominant centronuclear myopathy, Cell biology
Abstract: The building block of skeletal muscle is the multinucleated muscle fiber, formed by the fusion of hundreds of mononucleated precursor cells, myoblasts. In the normal course of muscle fiber development or regeneration, myonuclei are actively positioned throughout muscular development and adopt special localization in mature fibers: regular spacing along muscle fibers periphery, raising the notion of MyoNuclear Domains (MNDs). There is now growing support for a direct connection between myonuclear positioning and normal function of muscles, but how myonuclei affects muscle function remains poorly characterized.To identify new factors regulating forces applied on myonuclei in muscles fibers, we performed a siRNA screen and identified SH3KBP1 as a new factor controlling myonuclear positioning in early phases of myofibers formation. Depletion of SH3KBP1 induces a reset of MNDs establishment in mature fibers reflected by a dramatic reduction in pairwise distance between myonuclei. We show that SH3KBP1 scaffolds Endoplasmic Reticulum (ER) in myotubes that in turn controls myonuclei velocity and localization and thus myonuclear domains settings. Additionally, we show that in later phases of muscle maturation, SH3KBP1 contributes to the formation and maintenance of Sarcoplasmic Reticulum (SR) and Transverse-tubules (T-tubules). We also demonstrate that in muscle fibers, GTPase dynamin-2 (DNM2) binds to SH3 domains of SH3KBP1. Interestingly, we observed thatSh3kbp1mRNA is up regulated in a mouse model harboring the most frequent mutation for Autosomal Dominant CentroNuclear Myopathy (AD-CNM):Dnm2+/R465W. SH3KBP1 thus appears as a compensation mechanism in this CNM model since its depletion contributes to an increase of CNM-like phenotypes (reduction of muscle fibers Cross-section Areas (CSA) and increase in slow fibers content).Altogether our results identify SH3KBP1 as a new regulator of myonuclear domains establishment in the early phase of muscle fibers formation through ER scaffolding and later in myofibers integrity through T-tubules scaffolding/maintenance.SummaryMyonuclei are actively positioned throughout muscular development. Guiraud, Christin, Couturieret alshow that SH3KBP1 scaffolds the ER through Calnexin interaction and controls myonuclei motion during early steps of muscle fibers formation. Besides SH3KBP1 participates in cell fusion and T-tubules formation/maintenance in mature skeletal muscle fibers and contributes to slow-down CNM-like phenotypes.
Published: 2020
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41. ACTN2 mutations cause 'Multiple structured Core Disease' (MsCD)

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

Author: Jeanne Lainé, Pascale Guicheney, Guy Brochier, Stéphane Vassilopoulos, Mai Thao Bui, Agathe Franck, E. Lacène, Eline Lemerle, Norma B. Romero, Marc Bitoun, Gilles Moulay, Sofia Benkhelifa-Ziyyat, Michael Trichet, Christel Gentil, Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie et diversité cellulaire (NDC), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Centre de recherche en myologie, Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Microscopie Electronique [IBPS] (IBPS-ME), Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Morphologie Neuromusculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Coeur, Muscle et Vaisseaux, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Gestionnaire, Hal Sorbonne Université, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche en Myologie, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Intermediate Filaments, macromolecular substances, Clathrin, Desmin, 03 medical and health sciences, Dynamin II, 0302 clinical medicine, medicine, Animals, Humans, Intermediate filament, Muscle, Skeletal, Molecular Biology, Actin, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Dynamin, Mice, Knockout, 0303 health sciences, Costameres, Sarcolemma, biology, Skeletal muscle, Cell Biology, Articles, Actins, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cell Biology of Disease, Mutation, biology.protein, 030217 neurology & neurosurgery, Wiskott-Aldrich Syndrome Protein, Myopathies, Structural, Congenital
Abstract: International audience; Clathrin plaques are stable features of the plasma membrane observed in several cell types. They are abundant in muscle, where they localize at costameres that link the contractile apparatus to the sarcolemma and connect the sarcolemma to the basal lamina. Here, we show that clathrin plaques and surrounding branched actin filaments form microdomains that anchor a three-dimensional desmin intermediate filament (IF) web. Depletion of clathrin plaque and branched actin components causes accumulation of desmin tangles in the cytoplasm. We show that dynamin 2, whose mutations cause centronuclear myopathy (CNM), regulates both clathrin plaques and surrounding branched actin filaments, while CNM-causing mutations lead to desmin disorganization in a CNM mouse model and patient biopsies. Our results suggest a novel paradigm in cell biology, wherein clathrin plaques act as platforms capable of recruiting branched cortical actin, which in turn anchors IFs, both essential for striated muscle formation and function.
Published: 2019
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43. Mild clinical presentation in KLHL40-related nemaline myopathy (NEM 8)

Author: John Rendu, Julien Fauré, Laurent Pelletier, Pierre G. Carlier, Laurent Servais, Norma B. Romero, Andreea Mihaela Seferian, Véronique Forin, Edoardo Malfatti, Teresa Gidaro, Jessica Taytard, E. Gargaun, C Bosson, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de réhabilitation pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), NMR Laboratory, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie (U153 Inserm - IM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], and HAL-UPMC, Gestionnaire
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, Muscle Proteins, KLHL40, Biology, medicine.disease_cause, Myopathies, Nemaline, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Nemaline myopathy, medicine, Humans, Nemaline bodies, Child, Muscle, Skeletal, Genetics (clinical), Sanger sequencing, Mutation, Muscle biopsy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Genetic heterogeneity, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Phenotype, Neurology, Pediatrics, Perinatology and Child Health, symbols, Female, Neurology (clinical), Presentation (obstetrics), medicine.symptom, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy.
Published: 2020
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44. Novel ASCC1 mutations causing prenatal-onset muscle weakness with arthrogryposis and congenital bone fractures

Author: Johann Böhm, Guy Brochier, Edoardo Malfatti, Anne Boland, Emily C. Oates, Jocelyn Laporte, Kristi J. Jones, Norma B. Romero, and Jean-François Deleuze
Subjects: 0301 basic medicine, Arthrogryposis, Mutation, Pathology, medicine.medical_specialty, Sarcolemma, business.industry, Muscle weakness, 030105 genetics & heredity, medicine.disease_cause, Sarcomere, Frameshift mutation, 03 medical and health sciences, 030104 developmental biology, Neonatal hypotonia, Genetics, medicine, medicine.symptom, business, Myopathy, Genetics (clinical)
Abstract: BackgroundThe activating signal cointegrator 1 (ASC-1) complex acts as a transcriptional coactivator for a variety of transcription factors and consists of four subunits: ASCC1, ASCC2, ASCC3 and TRIP4. A single homozygous mutation in ASCC1 has recently been reported in two families with a severe muscle and bone disorder.ObjectiveWe aim to contribute to a better understanding of the ASCC1-related disorder.MethodsHere, we provide a clinical, histological and genetic description of three additional ASCC1 families.ResultsAll patients presented with severe prenatal-onset muscle weakness, neonatal hypotonia and arthrogryposis, and congenital bone fractures. The muscle biopsies from the affected infants revealed intense oxidative rims beneath the sarcolemma and scattered remnants of sarcomeres with enlarged Z-bands, potentially representing a histopathological hallmark of the disorder. Sequencing identified recessive nonsense or frameshift mutations in ASCC1, including two novel mutations.ConclusionOverall, this work expands the ASCC1 mutation spectrum, sheds light on the muscle histology of the disorder and emphasises the physiological importance of the ASC-1 complex in fetal muscle and bone development.
Published: 2018
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45. Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families

Author: X. Ferrer, Isabelle Richard, Johanna Palmio, Anne Boland, Françoise Chapon, Cécile Masson, Ana Ferreiro, Nicolas Wiart, Anni Evilä, T. Stojkovic, Peter Hackman, Jean-François Deleuze, Isabelle Nelson, Guilhem Solé, Gisèle Bonne, Bjarne Udd, Sini Penttilä, Norma B. Romero, Vincent Meyer, Per Harald Jonson, Mridul Johari, Folkhälsan Research Center, Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of Tampere [Finland], Tampere University Hospital, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), 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)-Université Paris Cité (UPCité), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Bordeaux [Bordeaux], Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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, Fondation Maladies Rares within the Myocapture sequencing project, ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), SOREL, EVE, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, University of Helsinki-University of Helsinki, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre de référence des maladies rares neuromusculaires, 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), 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), Laboratoire de chimie de coordination (LCC), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie de Toulouse (ICT-FR 2599), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], 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 National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Centre de Recherche en Myologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], [SHS.PSY]Humanities and Social Sciences/Psychology, Nerve Tissue Proteins, neuromuscular diseases, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Gene mutation, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, Muscular dystrophy, genetic and inherited disorders, Myopathy, Exome sequencing, Aged, Aged, 80 and over, Genetics, Mutation, Muscle Weakness, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, HSP40 Heat-Shock Proteins, Middle Aged, medicine.disease, Phenotype, Dysphagia, Pedigree, Distal Myopathies, [SDV] Life Sciences [q-bio], 030104 developmental biology, Muscular Dystrophies, Limb-Girdle, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Neurology, Disease Progression, myopathies, Female, France, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Molecular Chaperones, Limb-girdle muscular dystrophy
Abstract: International audience; Background and purposeThe aim was to determine the genetic background of unknown muscular dystrophy in five French families.MethodsTwelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested invitro.ResultsFive patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation.ConclusionsThe mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
Published: 2018
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46. Two new cases of mitochondrial myopathy with exercise intolerance, hyperlactatemia and cardiomyopathy, caused by recessive SLC25A4 mutations

Author: Pascale de Lonlay, Nicol C. Voermans, Pascal Laforêt, Jean-Yves Hogrel, Constantinos Papadopoulos, Claude Jardel, Isabelle Lemière, Karim Wahbi, Norma B. Romero, and Anouk Tosserams
Subjects: Adult, 0301 basic medicine, Respiratory chain, Cardiomyopathy, Genes, Recessive, Exercise intolerance, Gene mutation, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Mitochondrial myopathy, medicine, Humans, Hyperlactatemia, Exercise, Molecular Biology, Genetics, business.industry, Muscles, Hypertrophic cardiomyopathy, Adenine Nucleotide Translocator 1, Mitochondrial Myopathies, Cell Biology, Middle Aged, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Phenotype, Mitochondria, 030104 developmental biology, Mutation, Immunology, Molecular Medicine, Female, medicine.symptom, Cardiomyopathies, business
Abstract: We report the clinical, morphological and molecular features of two patients with autosomal recessive SLC25A4 (ANT1) gene mutations. Furthermore, all previously published cases are reviewed to identify valuable features for future diagnosis. Patients present a common phenotype with exercise intolerance, hyperlactatemia, and hypertrophic cardiomyopathy. Muscle biopsies show wide sub-sarcolemmal mitochondrial aggregates, and increased activities of all respiratory chain complexes. The phenotype of recessive SLC25A4 (ANT1) mutations although rare, is homogenous and easily recognizable and could help orientate the molecular analysis in adults with exercise intolerance associated with hyperlactatemia.
Published: 2018
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47. Dysfunctional sarcomere contractility contributes to muscle weakness in ACTA1 -related nemaline myopathy (NEM3)

Author: Edoardo Malfatti, Dilson E. Rassier, Nigel F. Clarke, Stefan Conijn, Weikang Ma, Norma B. Romero, Malin Persson, Albert Kalganov, Sylvia J. P. Bogaards, Igor Kovacevic, Ger J.M. Stienen, Johan Lindqvist, Alan H. Beggs, Michaela Yuen, Josine M. de Winter, Barbara Joureau, Coen A.C. Ottenheijm, and Thomas C. Irving
Subjects: 0301 basic medicine, medicine.medical_specialty, business.industry, Muscle weakness, medicine.disease, Sarcomere, Contractility, 03 medical and health sciences, Myosin head, 030104 developmental biology, 0302 clinical medicine, Endocrinology, Nemaline myopathy, Neurology, Internal medicine, medicine, Neurology (clinical), medicine.symptom, business, Myofibril, 030217 neurology & neurosurgery, Actin, Muscle contraction
Abstract: Objective Nemaline myopathy (NM) is one of the most common congenital nondystrophic myopathies and is characterized by muscle weakness, often from birth. Mutations in ACTA1 are a frequent cause of NM (ie, NEM3). ACTA1 encodes alpha-actin 1, the main constituent of the sarcomeric thin filament. The mechanisms by which mutations in ACTA1 contribute to muscle weakness in NEM3 are incompletely understood. We hypothesized that sarcomeric dysfunction contributes to muscle weakness in NEM3 patients. Methods To test this hypothesis, we performed contractility measurements in individual muscle fibers and myofibrils obtained from muscle biopsies of 14 NEM3 patients with different ACTA1 mutations. To identify the structural basis for impaired contractility, low angle X-ray diffraction and stimulated emission-depletion microscopy were applied. Results Our findings reveal that muscle fibers of NEM3 patients display a reduced maximal force-generating capacity, which is caused by dysfunctional sarcomere contractility in the majority of patients, as revealed by contractility measurements in myofibrils. Low angle X-ray diffraction and stimulated emission-depletion microscopy indicate that dysfunctional sarcomere contractility in NEM3 patients involves a lower number of myosin heads binding to actin during muscle activation. This lower number is not the result of reduced thin filament length. Interestingly, the calcium sensitivity of force is unaffected in some patients, but decreased in others. Interpretation Dysfunctional sarcomere contractility is an important contributor to muscle weakness in the majority of NEM3 patients. This information is crucial for patient stratification in future clinical trials. Ann Neurol 2018;83:269-282.
Published: 2018
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48. AcadeMYO, un pari réussi

Author: J. Andoni Urtizberea and Norma B. Romero
Subjects: General Medicine, General Biochemistry, Genetics and Molecular Biology
Published: 2021
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49. CONGENITAL MYOPATHIES – NEMALINE MYOPATHIES

Author: L. Servais, Susana Quijano-Roy, Johann Böhm, Teresinha Evangelista, John Rendu, Guy Brochier, Sandra Coppens, M.T. Bui, Ana Lia Taratuto, Nigel G. Laing, Valérie Biancalana, Jocelyn Laporte, E. Lacène, Helge Amthor, Soledad Monges, Norma B. Romero, Clémence Labasse, A. Madelaine, Anna Buj-Bello, and Fabiana Lubieniecki
Subjects: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published: 2021
Full Text: View/download PDF

50. CHANNELOPATHIES AND RELATED DISORDERS

Author: Bertrand Fontaine, T. Stojkovic, Damien Sternberg, P. Laforêt, Marianne Arzel-Hézode, Norma B. Romero, Savine Vicart, Emmanuel Fournier, Sabrina Sacconi, R. Villar Quiles, G. Tredez, Pascal Cintas, Guilhem Solé, Saïd Bendahhou, and Teresinha Evangelista
Subjects: Neurology, Pediatrics, Perinatology and Child Health, Neurology (clinical), Genetics (clinical)
Published: 2021
Full Text: View/download PDF

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