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Johann Bohm - One of the best experts on this subject based on the ideXlab platform.

  • common and variable clinical histological and imaging findings of recessive ryr1 related Centronuclear Myopathy patients
    Neuromuscular Disorders, 2017
    Co-Authors: Johann Bohm, Osorio Abath Neto, Cristiane Araujo Martins Moreno, Edoardo Malfatti, Sandra Donkervoort, Julio Brandao Guimaraes, Reghan A Foley, Payam Mohassel
    Abstract:

    Mutations in RYR1 give rise to diverse skeletal muscle phenotypes, ranging from classical central core disease to susceptibility to malignant hyperthermia. Next-generation sequencing has recently shown that RYR1 is implicated in a wide variety of additional myopathies, including Centronuclear Myopathy. In this work, we established an international cohort of 21 patients from 18 families with autosomal recessive RYR1-related Centronuclear Myopathy, to better define the clinical, imaging, and histological spectrum of this disorder. Early onset of symptoms with hypotonia, motor developmental delay, proximal muscle weakness, and a stable course were common clinical features in the cohort. Ptosis and/or ophthalmoparesis, facial weakness, thoracic deformities, and spinal involvement were also frequent but variable. A common imaging pattern consisted of selective involvement of the vastus lateralis, adductor magnus, and biceps brachii in comparison to adjacent muscles. In addition to a variable prominence of central nuclei, muscle biopsy from 20 patients showed type 1 fiber predominance and a wide range of intermyofibrillary architecture abnormalities. All families harbored compound heterozygous mutations, most commonly a truncating mutation combined with a missense mutation. This work expands the phenotypic characterization of patients with recessive RYR1-related Centronuclear Myopathy by highlighting common and variable clinical, histological, and imaging findings in these patients.

  • dominant Centronuclear Myopathy with early childhood onset due to a novel mutation in bin1
    Journal of neuromuscular diseases, 2017
    Co-Authors: Carlyn V Kouwenberg, Johann Bohm, Nicolas Dondaine, Valérie Biancalana, Catherine Koch, Corrie E Erasmus, Irene Van Balken, Benno Kusters, Erikjan Kamsteeg, Jocelyn Laporte
    Abstract:

    : Autosomal dominant Centronuclear Myopathy (CNM) caused by mutations in the gene coding for amphiphysin-2 (BIN1) typically presents in adulthood with progressive muscle weakness. We report a Dutch family with AD CNM due to a novel BIN1 mutation (c.53T>A (p.Val18Glu)), strongly impairing the membrane tubulation activity of amphiphysin-2. The main features were mild proximal weakness with pronounced myalgia, exercise intolerance and large muscle mass, with a childhood onset in the youngest generation and mild cognitive features. This suggests BIN1 mutations should be considered in patients with isolated exercise intolerance and myalgia, even in childhood.

  • novel dominant mutation in bin1 gene causing mild Centronuclear Myopathy revealed by myalgias and ck elevation
    Journal of neuromuscular diseases, 2016
    Co-Authors: Matteo Garibaldi, Johann Bohm, Jocelyn Laporte, Fabiana Fattori, Catherine Koch, Cecilia Surace, Pierfrancesco Ottaviani, Francesco Laschena, Enrico Bertini, Giovanni Antonini
    Abstract:

    : We present the clinical, morphological and molecular data of an Italian family with Centronuclear Myopathy, carrying a novel pathogenic mutation of BIN1 gene in heterozygous state, consistent with autosomal dominant inheritance. The proband, a 56-years-old man suffered of lower limbs myalgia and slight CK elevation. Clinical examination revealed no muscle weakness, short stature, mild symmetric eyelid ptosis, scapular winging, ankle retraction and well-developed muscles. Muscle biopsy showed nuclear centralization and clustering, deep sarcolemmal invaginations and type 1 fibers hypotrophy. Muscle MRI revealed fatty infiltration of posterior legs compartments, lumbar paraspinal and serratus muscles. By sequencing BIN1, we identified a heterozygous pathogenic mutation [c.107C>A (p.A36E)], and we demonstrate that the mutation strongly impairs the membrane tubulation property of the protein. One affected sister with similar phenotype carried the same mutation. Our findings expand the clinical, morphological and genetic spectrum of the autosomal dominant CNM associated with BIN1 mutations.

  • adult onset autosomal dominant Centronuclear Myopathy due to bin1 mutations
    Brain, 2014
    Co-Authors: Johann Bohm, Nicolas Dondaine, Valérie Biancalana, Wolfram Kress, Catherine Koch, Nasim Vasli, Edoardo Malfatti, Matthias Strittmatter, A L Taratuto
    Abstract:

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

  • altered splicing of the bin1 muscle specific exon in humans and dogs with highly progressive Centronuclear Myopathy
    PLOS Genetics, 2013
    Co-Authors: Johann Bohm, Ivana Prokic, Anne Toussaint, Belinda S Cowling, Wolfram Kress, Diane G Shelton, Nasim Vasli, Marie Maurer, U Schara
    Abstract:

    Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive Centronuclear Myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal Centronuclear Myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for Centronuclear Myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies.

Marc Bitoun - One of the best experts on this subject based on the ideXlab platform.

  • Nuclear defects in skeletal muscle from a Dynamin 2-linked Centronuclear Myopathy mouse model
    Scientific Reports, 2019
    Co-Authors: Anais Fongy, Bernard Prudhon, Jeanne Lainé, Sestina Falcone, Aurea Martins-bach, Marc Bitoun
    Abstract:

    Dynamin 2 (DNM2) is a key protein of the endocytosis and intracellular membrane trafficking machinery. Mutations in the DNM2 gene cause autosomal dominant Centronuclear Myopathy (CNM) and a knock-in mouse model expressing the most frequent human DNM2 mutation in CNM (Knock In-Dnm2R465W/+) develops a Myopathy sharing similarities with human disease. Using isolated muscle fibres from Knock In-Dnm2R465W/+ mice, we investigated number, spatial distribution and morphology of myonuclei. We showed a reduction of nuclear number from 20 weeks of age in Tibialis anterior muscle from heterozygous mice. This reduction is associated with a decrease in the satellite cell content in heterozygous muscles. The concomitant reduction of myonuclei number and cross-section area in the heterozygous fibres contributes to largely maintain myonuclear density and volume of myonuclear domain. Moreover, we identified signs of impaired spatial nuclear distribution including alteration of distance from myonuclei to their nearest neighbours and change in orientation of the nuclei. This study highlights reduction of number of myonuclei, a key regulator of the myofiber size, as a new pathomechanism underlying muscle atrophy in the dominant Centronuclear Myopathy. In addition, this study opens a new line of investigation which could prove particularly important on satellite cells in dominant Centronuclear Myopathy.

  • Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing
    Molecular Therapy - Nucleic Acids, 2016
    Co-Authors: Delphine Trochet, Arnaud Jollet, Bernard Prudhon, Stéphanie Lorain, Marc Bitoun
    Abstract:

    Dynamin 2 (DNM2) is a large GTPase, ubiquitously expressed, involved in membrane trafficking and regulation of actin and microtubule cytoskeletons. DNM2 mutations cause autosomal dominant Centronuclear Myopathy which is a rare congenital Myopathy characterized by skeletal muscle weakness and histopathological features including nuclear centralization in absence of regeneration. No curative treatment is currently available for the DNM2-related autosomal dominant Centronuclear Myopathy. In order to develop therapeutic strategy, we evaluated here the potential of Spliceosome-Mediated RNA Trans-splicing technology to reprogram the Dnm2-mRNA in vitro and in vivo in mice. We show that classical 3′-trans-splicing strategy cannot be considered as accurate therapeutic strategy regarding toxicity of the pre-trans-splicing molecules leading to low rate of trans-splicing in vivo. Thus, we tested alternative strategies devoted to prevent this toxicity and enhance frequency of trans-splicing events. We succeeded to overcome the toxicity through a 5′-trans-splicing strategy which also allows detection of trans-splicing events at mRNA and protein levels in vitro and in vivo. These results suggest that the Spliceosome-Mediated RNA Trans-splicing strategy may be used to reprogram mutated Dnm2-mRNA but highlight the potential toxicity linked to the molecular tools which have to be carefully investigated during preclinical development.

  • Characterization of the muscle involvement in dynamin 2-related Centronuclear Myopathy
    2015
    Co-Authors: Dirk Fischer, Marc Bitoun, Pascale Guicheney, Muriel Herasse, Jacques Chiras, Michel Fardeau, Bruno Eymard, Norma B. Romero
    Abstract:

    Centronuclear Myopathy (CNM) is a slowly progressive congenital Myopathy characterized by abnormal centrally located nuclei in a large number of muscle fibres. Recently, different missense mutations affecting the middle domain of the dynamin 2 (DNM2) have been shown to cause autosomal dominant CNM. In order to better define the phenotype of DNM2-related CNM, we report here on the clinical andmuscle imaging findings of 10 patients harbouring DNM2 mutations. DNM2-CNM is characterized by slowly progressive muscular weakness usually beginning in adolescence or early adulthood. In addition to bilateral ptosis, our data show that distal muscle weakness often exceeds proximal involvement. Furthermore, electrophysiological investiga-tions frequently demonstrated signs of mild axonal peripheral nerve involvement, and electromyographical examinationmay show neuropathic changes in addition to the predominantmyopathic changes. These features overlap with findings seen in the phenotype of DNM2-related autosomal dominant Charcot–Marie–Tooth disease type 2B. In all 10 DNM2-CNM patients, muscle computer tomography assessment showed a consistent pattern of muscular involvement and a characteristic temporal course with early and predominant distal muscle involvement, and later affection of the posterior thigh compartment and gluteus minimus muscles. The recognition of this specific imaging pattern of muscle involvement—distinct to the reported patterns i

  • phenotype of a patient with recessive Centronuclear Myopathy and a novel bin1 mutation
    Neurology, 2010
    Co-Authors: Kristl G Claeys, Johann Bohm, Jocelyn Laporte, Marc Bitoun, Norma B. Romero, T Maisonobe, M Hezode, G Brochier, R Y Carlier, T Stojkovic
    Abstract:

    Centronuclear myopathies (CNM) are rare congenital myopathies characterized by centrally located nuclei in a variable number of muscle fibers. CNM are caused by mutations in myotubularin ( MTM1 ; X-linked)1 or dynamin-2 ( DNM2 ; autosomal dominant or sporadic).2 One patient with sporadic CNM harboring a ryanodine receptor-1 gene mutation was also described.3 Recently, mutations in amphiphysin-2 ( BIN1 ) were shown to cause autosomal recessive (AR) CNM in 3 consanguineous families.4 We characterize the phenotype of an adult patient with CNM with a novel BIN1 mutation. ### Case report. The male patient belonged to a Moroccan family with 5 siblings of which 1 boy died at age 1 year of unknown cause. There was no familial history of neuromuscular diseases and no known consanguinity. Pregnancy and birth were normal. He had delayed motor milestones, walked at age 3.5 years, and experienced difficulties in running and climbing stairs since childhood. He developed speech at 3.5 years of age, had mild mental retardation (IQ 70), and had ptosis since childhood. Since 11 years of age, he showed diffuse muscle atrophy and progressive muscle weakness, resulting in difficulties in walking, with frequent falls. Subsequently, he developed problems carrying weights and fatigability. At age 21 years (figure, A), he showed weakness in axial muscles (2–4/5), diffuse weakness in upper limbs (2–3/5), in proximal (3–4/5) and distal lower limbs, with ankle dorsiflexion and plantar flexion equally affected (2/5), foot eversion at 0/5 and inversion at 4/5. He had symmetric scapular winging, Gowers' sign, hyperlordosis, and waddling gait. He presented facial diplegia (figure, B), ptosis, vertical ophthalmoparesis, dysphonia, and dysarthria, without dysphagia. He presented an elongated face, high-arched palate, retrognathism, protruding ears, thin hands with long small fingers, left-sided kyphoscoliosis, bilateral pes cavus, and equinovarus. Tendon reflexes were absent and sensory testing was normal. He had no clinical …

  • dynamin 2 mutations cause sporadic Centronuclear Myopathy with neonatal onset
    Annals of Neurology, 2007
    Co-Authors: Bernard Prudhon, Marc Bitoun, Svetlana Maugenre, Jorge A Bevilacqua, Ana Lia Taratuto, S Monges
    Abstract:

    We report four heterozygous dynamin 2 (DNM2) mutations in five Centronuclear Myopathy patients aged 1 to 15 years. They all presented with neonatal hypotonia with weak suckling. Thereafter, their phenotype progressively improved. All patients demonstrated muscle weakness prominent in the lower limbs, and most of them also presented with facial weakness, open mouth, arched palate, ptosis, and ophthalmoparesis. Electrophysiology showed only myopathic changes, and muscle biopsies showed central nuclei and type 1 fiber hypotrophy and predominance. Our results expand the phenotypic spectrum of dynamin 2-related Centronuclear Myopathy from the classic mild form to the more severe neonatal phenotype.

Valérie Biancalana - One of the best experts on this subject based on the ideXlab platform.

  • a roma founder bin1 mutation causes a novel phenotype of Centronuclear Myopathy with rigid spine
    Neurology, 2018
    Co-Authors: Macarena Cabreraserrano, Valérie Biancalana, Fabiola Mavillard, Eloy Rivas, Bharti Morar, Aurelio Hernandezlain, Montse Olive, N Muelas, Eduardo Khan, Alejandra Carvajal
    Abstract:

    Objective To describe a large series of BIN1 patients, in which a novel founder mutation in the Roma population of southern Spain has been identified. Methods Patients diagnosed with Centronuclear Myopathy (CNM) at 5 major reference centers for neuromuscular disease in Spain (n = 53) were screened for BIN1 mutations. Clinical, histologic, radiologic, and genetic features were analyzed. Results Eighteen patients from 13 families carried the p.Arg234Cys variant; 16 of them were homozygous for it and 2 had compound heterozygous p.Arg234Cys/p.Arg145Cys mutations. Both BIN1 variants have only been identified in Roma, causing 100% of CNM in this ethnic group in our cohort. The haplotype analysis confirmed all families are related. In addition to clinical features typical of CNM, such as proximal limb weakness and ophthalmoplegia, most patients in our cohort presented with prominent axial weakness, often associated with rigid spine. Severe fat replacement of paravertebral muscles was demonstrated by muscle imaging. This phenotype seems to be specific to the p.Arg234Cys mutation, not reported in other BIN1 mutations. Extreme clinical variability was observed in the 2 compound heterozygous patients for the p.Arg234Cys/p.Arg145Cys mutations, from a congenital onset with catastrophic outcome to a late-onset disease. Screening of European Roma controls (n = 758) for the p.Arg234Cys variant identified a carrier frequency of 3.5% among the Spanish Roma. Conclusion We have identified a BIN1 founder Roma mutation associated with a highly specific phenotype, which is, from the present cohort, the main cause of CNM in Spain.

  • dominant Centronuclear Myopathy with early childhood onset due to a novel mutation in bin1
    Journal of neuromuscular diseases, 2017
    Co-Authors: Carlyn V Kouwenberg, Johann Bohm, Nicolas Dondaine, Valérie Biancalana, Catherine Koch, Corrie E Erasmus, Irene Van Balken, Benno Kusters, Erikjan Kamsteeg, Jocelyn Laporte
    Abstract:

    : Autosomal dominant Centronuclear Myopathy (CNM) caused by mutations in the gene coding for amphiphysin-2 (BIN1) typically presents in adulthood with progressive muscle weakness. We report a Dutch family with AD CNM due to a novel BIN1 mutation (c.53T>A (p.Val18Glu)), strongly impairing the membrane tubulation activity of amphiphysin-2. The main features were mild proximal weakness with pronounced myalgia, exercise intolerance and large muscle mass, with a childhood onset in the youngest generation and mild cognitive features. This suggests BIN1 mutations should be considered in patients with isolated exercise intolerance and myalgia, even in childhood.

  • adult onset autosomal dominant Centronuclear Myopathy due to bin1 mutations
    Brain, 2014
    Co-Authors: Johann Bohm, Nicolas Dondaine, Valérie Biancalana, Wolfram Kress, Catherine Koch, Nasim Vasli, Edoardo Malfatti, Matthias Strittmatter, A L Taratuto
    Abstract:

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

  • Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant Centronuclear Myopathy.
    Human Mutation, 2012
    Co-Authors: Johann Bohm, Valérie Biancalana, Elizabeth T. Dechene, Christopher R. Pierson, Elise Schaefer, H. Karasoy, Melissa A Dempsey, Fabrice A.c. Klein, Nicolas Dondaine
    Abstract:

    Centronuclear Myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype-phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot-Marie-Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.

  • Expanding the clinical, pathological and MRI phenotype of DNM2-related Centronuclear Myopathy
    Neuromuscular Disorders, 2010
    Co-Authors: Rachel D. Susman, Valérie Biancalana, Nigel F Clarke, Richard Webster, Marina L. Kennerson, Susana Quijano-roy, Nan Yang, Jim Dowling, Garth A. Nicholson, Biljana Ilkovski
    Abstract:

    Mutations in dynamin-2 (DNM2) cause autosomal dominant Centronuclear Myopathy (CNM). We report a series of 12 patients from eight families with CNM in whom we have identified a number of novel features that expand the reported clinicopathological phenotype. We identified two novel and five recurrent missense mutations in DNM2. Early clues to the diagnosis include relative weakness of neck flexors, external ophthalmoplegia and ptosis, although these are not present in all patients. Pes cavus was present in two patients, and in another two members of one family there was mild slowing of nerve conduction velocities. Whole-body MRI examination in two children and one adult revealed a similar pattern of involvement of selective muscles in head (lateral pterygoids), neck (extensors), trunk (paraspinal) and upper limbs (deep muscles of forearm). Findings in lower limbs and pelvic region were similar to that previously reported in adults with DNM2 mutations. Two patients presented with dystrophic changes as the predominant pathological feature on muscle biopsies; one of whom had a moderately raised creatine kinase, and both patients were initially diagnosed as congenital muscular dystrophy. DNM2 mutation analysis should be considered in patients with a suggestive clinical phenotype despite atypical histopathology, and MRI findings can be used to guide genetic testing. Subtle neuropathic features in some patients suggest an overlap with the DNM2 neuropathy phenotype. Missense mutations in the C-terminal region of the PH domain appear to be associated with a more severe clinical phenotype evident from infancy.

Jocelyn Laporte - One of the best experts on this subject based on the ideXlab platform.

  • Physiological impact and disease reversion for the severe form of Centronuclear Myopathy linked to dynamin
    'American Society for Clinical Investigation', 2020
    Co-Authors: Xènia Massana Muñoz, Christine Kretz, Belinda S Cowling, Norma B. Romero, Roberto Silva-rojas, Julien Ochala, Alexia Menuet, Jocelyn Laporte
    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

  • dominant Centronuclear Myopathy with early childhood onset due to a novel mutation in bin1
    Journal of neuromuscular diseases, 2017
    Co-Authors: Carlyn V Kouwenberg, Johann Bohm, Nicolas Dondaine, Valérie Biancalana, Catherine Koch, Corrie E Erasmus, Irene Van Balken, Benno Kusters, Erikjan Kamsteeg, Jocelyn Laporte
    Abstract:

    : Autosomal dominant Centronuclear Myopathy (CNM) caused by mutations in the gene coding for amphiphysin-2 (BIN1) typically presents in adulthood with progressive muscle weakness. We report a Dutch family with AD CNM due to a novel BIN1 mutation (c.53T>A (p.Val18Glu)), strongly impairing the membrane tubulation activity of amphiphysin-2. The main features were mild proximal weakness with pronounced myalgia, exercise intolerance and large muscle mass, with a childhood onset in the youngest generation and mild cognitive features. This suggests BIN1 mutations should be considered in patients with isolated exercise intolerance and myalgia, even in childhood.

  • novel dominant mutation in bin1 gene causing mild Centronuclear Myopathy revealed by myalgias and ck elevation
    Journal of neuromuscular diseases, 2016
    Co-Authors: Matteo Garibaldi, Johann Bohm, Jocelyn Laporte, Fabiana Fattori, Catherine Koch, Cecilia Surace, Pierfrancesco Ottaviani, Francesco Laschena, Enrico Bertini, Giovanni Antonini
    Abstract:

    : We present the clinical, morphological and molecular data of an Italian family with Centronuclear Myopathy, carrying a novel pathogenic mutation of BIN1 gene in heterozygous state, consistent with autosomal dominant inheritance. The proband, a 56-years-old man suffered of lower limbs myalgia and slight CK elevation. Clinical examination revealed no muscle weakness, short stature, mild symmetric eyelid ptosis, scapular winging, ankle retraction and well-developed muscles. Muscle biopsy showed nuclear centralization and clustering, deep sarcolemmal invaginations and type 1 fibers hypotrophy. Muscle MRI revealed fatty infiltration of posterior legs compartments, lumbar paraspinal and serratus muscles. By sequencing BIN1, we identified a heterozygous pathogenic mutation [c.107C>A (p.A36E)], and we demonstrate that the mutation strongly impairs the membrane tubulation property of the protein. One affected sister with similar phenotype carried the same mutation. Our findings expand the clinical, morphological and genetic spectrum of the autosomal dominant CNM associated with BIN1 mutations.

  • primary t tubule and autophagy defects in the phosphoinositide phosphatase jumpy mtmr14 knockout mice muscle
    Advances in biological regulation, 2012
    Co-Authors: Karim Hnia, Christine Kretz, Johann Bohm, Leonela Amoasii, Xia Liu, Jocelyn Laporte
    Abstract:

    IntroductionMuscle fibers can efficiently contract to promote body movement and are site of energy storage.These important properties are sustained by their intricate intracellular structure. In particular,membrane remodelling and trafficking play a central role in these processes. The phosphoinositides(PIs)secondmessengersarekeyregulatorofintramembraneorganizationanddynamics.However,theroles of phosphoinositides and membrane organization in muscle functions under normal and path-ological conditions are not well defined.Two families of PI-phosphatases have been implicated in myopathies: myotubularins and Jumpy/MTMR14(Lecompte etal.,2008).Humanmyotubularins(MTM1andMTMR1-13)arephosphoinositide3-phosphatases or phosphatase-like proteins mutated in several neuromuscular disorders (Laporteet al., 2003; Previtali et al., 2007; Taylor and Dixon, 2003; Wishart and Dixon, 2002). MTM1 ismutated in X-linked myotubular (Centronuclear) Myopathy (XLMTM) (Laporte et al., 1996), whereasMTMR2 and MTMR13 are mutated in demyelinating Charcot–Marie–Tooth neuropathy types 4B1 and4B2,respectively(Azzedineetal.,2003;Bolinoetal.,2000;Sendereketal.,2003).Myotubularinssharehomology tothe catalytic domainsof protein tyrosine phosphatases and dual-specificity phosphatases

  • case report of intrafamilial variability in autosomal recessive Centronuclear Myopathy associated to a novel bin1 stop mutation
    Orphanet Journal of Rare Diseases, 2010
    Co-Authors: Johann Bohm, Ragip Ortac, Eray Dirik, Semra Hiz Kurul, Handan Cakmakci, Jocelyn Laporte
    Abstract:

    Centronuclear myopathies (CNM) describe a group of rare muscle diseases typically presenting an abnormal positioning of nuclei in muscle fibers. To date, three genes are known to be associated to a classical CNM phenotype. The X-linked neonatal form (XLCNM) is due to mutations in MTM1 and involves a severe and generalized muscle weakness at birth. The autosomal dominant form results from DNM2 mutations and has been described with early childhood and adult onset (ADCNM). Autosomal recessive Centronuclear Myopathy (ARCNM) is less characterized and has recently been associated to mutations in BIN1, encoding amphiphysin 2. Here we present the first clinical description of intrafamilal variability in two first-degree cousins with a novel BIN1 stop mutation. In addition to skeletal muscle defects, both patients have mild mental retardation and the more severely affected male also displays abnormal ventilation and cardiac arrhythmia, thus expanding the phenotypic spectrum of BIN1-related CNM to non skeletal muscle defects. We provide an up-to-date review of all previous cases with ARCNM and BIN1 mutations.

Bernard Prudhon - One of the best experts on this subject based on the ideXlab platform.

  • Nuclear defects in skeletal muscle from a Dynamin 2-linked Centronuclear Myopathy mouse model
    Scientific Reports, 2019
    Co-Authors: Anais Fongy, Bernard Prudhon, Jeanne Lainé, Sestina Falcone, Aurea Martins-bach, Marc Bitoun
    Abstract:

    Dynamin 2 (DNM2) is a key protein of the endocytosis and intracellular membrane trafficking machinery. Mutations in the DNM2 gene cause autosomal dominant Centronuclear Myopathy (CNM) and a knock-in mouse model expressing the most frequent human DNM2 mutation in CNM (Knock In-Dnm2R465W/+) develops a Myopathy sharing similarities with human disease. Using isolated muscle fibres from Knock In-Dnm2R465W/+ mice, we investigated number, spatial distribution and morphology of myonuclei. We showed a reduction of nuclear number from 20 weeks of age in Tibialis anterior muscle from heterozygous mice. This reduction is associated with a decrease in the satellite cell content in heterozygous muscles. The concomitant reduction of myonuclei number and cross-section area in the heterozygous fibres contributes to largely maintain myonuclear density and volume of myonuclear domain. Moreover, we identified signs of impaired spatial nuclear distribution including alteration of distance from myonuclei to their nearest neighbours and change in orientation of the nuclei. This study highlights reduction of number of myonuclei, a key regulator of the myofiber size, as a new pathomechanism underlying muscle atrophy in the dominant Centronuclear Myopathy. In addition, this study opens a new line of investigation which could prove particularly important on satellite cells in dominant Centronuclear Myopathy.

  • Reprogramming the Dynamin 2 mRNA by Spliceosome-mediated RNA Trans-splicing
    Molecular Therapy - Nucleic Acids, 2016
    Co-Authors: Delphine Trochet, Arnaud Jollet, Bernard Prudhon, Stéphanie Lorain, Marc Bitoun
    Abstract:

    Dynamin 2 (DNM2) is a large GTPase, ubiquitously expressed, involved in membrane trafficking and regulation of actin and microtubule cytoskeletons. DNM2 mutations cause autosomal dominant Centronuclear Myopathy which is a rare congenital Myopathy characterized by skeletal muscle weakness and histopathological features including nuclear centralization in absence of regeneration. No curative treatment is currently available for the DNM2-related autosomal dominant Centronuclear Myopathy. In order to develop therapeutic strategy, we evaluated here the potential of Spliceosome-Mediated RNA Trans-splicing technology to reprogram the Dnm2-mRNA in vitro and in vivo in mice. We show that classical 3′-trans-splicing strategy cannot be considered as accurate therapeutic strategy regarding toxicity of the pre-trans-splicing molecules leading to low rate of trans-splicing in vivo. Thus, we tested alternative strategies devoted to prevent this toxicity and enhance frequency of trans-splicing events. We succeeded to overcome the toxicity through a 5′-trans-splicing strategy which also allows detection of trans-splicing events at mRNA and protein levels in vitro and in vivo. These results suggest that the Spliceosome-Mediated RNA Trans-splicing strategy may be used to reprogram mutated Dnm2-mRNA but highlight the potential toxicity linked to the molecular tools which have to be carefully investigated during preclinical development.

  • dynamin 2 mutations cause sporadic Centronuclear Myopathy with neonatal onset
    Annals of Neurology, 2007
    Co-Authors: Bernard Prudhon, Marc Bitoun, Svetlana Maugenre, Jorge A Bevilacqua, Ana Lia Taratuto, S Monges
    Abstract:

    We report four heterozygous dynamin 2 (DNM2) mutations in five Centronuclear Myopathy patients aged 1 to 15 years. They all presented with neonatal hypotonia with weak suckling. Thereafter, their phenotype progressively improved. All patients demonstrated muscle weakness prominent in the lower limbs, and most of them also presented with facial weakness, open mouth, arched palate, ptosis, and ophthalmoparesis. Electrophysiology showed only myopathic changes, and muscle biopsies showed central nuclei and type 1 fiber hypotrophy and predominance. Our results expand the phenotypic spectrum of dynamin 2-related Centronuclear Myopathy from the classic mild form to the more severe neonatal phenotype.