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Hichem Tasfaout, Valentina M Lionello, Christine Kretz, Pascale Koebel, Nadia Messaddeq, Deborah Bitz, Jocelyn Laporte, Belinda S Cowling
Myotubular myopathy, or X-linked centronuclear myopathy, is a severe muscle disorder representing a significant burden for patients and their families. It is clinically characterized by neonatal and severe muscle weakness and atrophy. Mutations in the myotubularin (MTM1) gene cause myotubular myopathy, and no specific curative treatment is available. We previously found that dynamin 2 (DNM2) is upregulated in both Mtm1 knockout and patient muscle samples, whereas its reduction through antisense oligonucleotides rescues the clinical and histopathological features of this myopathy in mice...
February 14, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
Virginia Huntoon, Jeffrey J Widrick, Colline Sanchez, Samantha M Rosen, Candice Kutchukian, Siqi Cao, Christopher R Pierson, Xiaoli Liu, Mark A Perrella, Alan H Beggs, Vincent Jacquemond, Pankaj B Agrawal
Centronuclear myopathies (CNM) are a subtype of congenital myopathies (CM) characterized by skeletal muscle weakness and an increase in the number of central myonuclei. We have previously identified three CNM probands, two with associated dilated cardiomyopathy, carrying striated preferentially expressed gene (SPEG) mutations. Currently, the role of SPEG in skeletal muscle function is unclear as constitutive SPEG-deficient mice developed severe dilated cardiomyopathy and died in-utero. We have generated a conditional Speg-KO mouse model and excised Speg by crosses with striated muscle-specific cre-expressing mice (MCK-Cre)...
February 20, 2018: Human Molecular Genetics
Heinz Jungbluth, Susan Treves, Francesco Zorzato, Anna Sarkozy, Julien Ochala, Caroline Sewry, Rahul Phadke, Mathias Gautel, Francesco Muntoni
The congenital myopathies are a group of early-onset, non-dystrophic neuromuscular conditions with characteristic muscle biopsy findings, variable severity and a stable or slowly progressive course. Pronounced weakness in axial and proximal muscle groups is a common feature, and involvement of extraocular, cardiorespiratory and/or distal muscles can implicate specific genetic defects. Central core disease (CCD), multi-minicore disease (MmD), centronuclear myopathy (CNM) and nemaline myopathy were among the first congenital myopathies to be reported, and they still represent the main diagnostic categories...
February 2, 2018: Nature Reviews. Neurology
Delphine Trochet, Bernard Prudhon, Maud Beuvin, Cécile Peccate, Stéphanie Lorain, Laura Julien, Sofia Benkhelifa-Ziyyat, Aymen Rabai, Kamel Mamchaoui, Arnaud Ferry, Jocelyn Laporte, Pascale Guicheney, Stéphane Vassilopoulos, Marc Bitoun
Rapid advances in allele-specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. We used this strategy for autosomal-dominant centronuclear myopathy (CNM), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the DNM2 gene encoding Dynamin 2. Allele-specific siRNA sequences were developed in order to specifically knock down the human and murine DNM2-mRNA harbouring the p.R465W mutation without affecting the wild-type allele...
December 15, 2017: EMBO Molecular Medicine
Ruple S Laughlin, Zhiyv Niu, Eric Wieben, Margherita Milone
BACKGROUND: Congenital myopathies due to ryanodine receptor (RYR1) mutations are increasingly identified and correlate with a wide range of phenotypes, most commonly that of malignant hyperthermia susceptibility and central cores on muscle biopsy with rare reports of distal muscle weakness, but in the setting of early onset global weakness. METHODS: We report a case of a patient presenting with childhood onset hand stiffness and adult onset progressive hand weakness and jaw contractures discovered to have two variants in the RYR1 gene...
November 2017: Molecular Genetics & Genomic Medicine
Nathalie Couturier, Vincent Gache
In the normal course of muscle fiber development, myonuclei actively position and adapt a precise localization in mature fibers, shaping MyoNuclear Domains (MNDs). Myonuclei positioning in fibers appears to be essential for muscle function as defects in MNDs settings are always associated with dysfunction (i.e., centronuclear myopathy, sarcopenia). Previous studies have shown that myonuclei positioning in fibers is reversible, suggesting that in pathologies presenting MNDs impairment, myonuclei could be re-addressed to the "correct" position in fibers and this could benefit to muscle function...
November 2017: Médecine Sciences: M/S
Belinda S Cowling, Ivana Prokic, Hichem Tasfaout, Aymen Rabai, Frédéric Humbert, Bruno Rinaldi, Anne-Sophie Nicot, Christine Kretz, Sylvie Friant, Aurélien Roux, Jocelyn Laporte
Regulation of skeletal muscle development and organization is a complex process that is not fully understood. Here, we focused on amphiphysin 2 (BIN1, also known as bridging integrator-1) and dynamin 2 (DNM2), two ubiquitous proteins implicated in membrane remodeling and mutated in centronuclear myopathies (CNMs). We generated Bin1-/- Dnm2+/- mice to decipher the physiological interplay between BIN1 and DNM2. While Bin1-/- mice die perinatally from a skeletal muscle defect, Bin1-/- Dnm2+/- mice survived at least 18 months, and had normal muscle force and intracellular organization of muscle fibers, supporting BIN1 as a negative regulator of DNM2...
November 13, 2017: Journal of Clinical Investigation
Carlyn Kouwenberg, Johann Bohm, Corrie Erasmus, Irene van Balken, Sandra Vos, Benno Kusters, Erik-Jan Kamsteeg, Valerie Biancalana, Catherine Koch, Nicolas Dondaine, Jocelyn Laporte, Nicol Voermans
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...
2017: Journal of Neuromuscular Diseases
Candice Kutchukian, Peter Szentesi, Bruno Allard, Delphine Trochet, Maud Beuvin, Christine Berthier, Yves Tourneur, Pascale Guicheney, Laszlo Csernoch, Marc Bitoun, Vincent Jacquemond
Mutations in the gene encoding dynamin 2 (DNM2) are responsible for autosomal dominant centronuclear myopathy (AD-CNM). We studied the functional properties of Ca(2+) signalling and excitation-contraction (EC) coupling in muscle fibres isolated from a knock-in (KI) mouse model of the disease, using confocal imaging and voltage-clamp. The transverse-tubule network organization looked unaltered in the diseased fibres but its density was reduced by ∼10% as compared to that in control fibres. The density of Ca(2+) current through CaV1...
October 26, 2017: Journal of Physiology
Shuyun Chen, Ping Huang, Yusen Qiu, Qian Zhou, Xiaobing Li, Min Zhu, Daojun Hong
Mutations of Dynamin 2 (DNM2) are responsible for several forms of neuromuscular disorder such as centronuclear myopathy, Charcot-Marie-Tooth disease (CMT) dominant intermediate type B, CMT 2M, and lethal congenital contracture syndrome 5. We describe a young man manifesting as length-dependent sensorimotor neuropathy with hypertrophic cardiomyopathy, but his mother only had very mild symptoms of peripheral neuropathy. The electrophysiological data meet the criteria of intermediate CMT. The main pathological findings of sural nerve biopsy reveal a severe loss of large myelinating fibers and some clusters of regenerative fibers in fascicles, which are consistent with an axonal neuropathy...
October 3, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Matthieu A Raess, Belinda S Cowling, Dimitri L Bertazzi, Christine Kretz, Bruno Rinaldi, Jean-Marie Xuereb, Pascal Kessler, Norma B Romero, Bernard Payrastre, Sylvie Friant, Jocelyn Laporte
Myotubularins (MTMs) are active or dead phosphoinositides phosphatases defining a large protein family conserved through evolution and implicated in different neuromuscular diseases. Loss-of-function mutations in MTM1 cause the severe congenital myopathy called myotubular myopathy (or X-linked centronuclear myopathy) while mutations in the MTM1-related protein MTMR2 cause a recessive Charcot-Marie-Tooth peripheral neuropathy. Here we aimed to determine the functional specificity and redundancy of MTM1 and MTMR2, and to assess their abilities to compensate for a potential therapeutic strategy...
October 1, 2017: Human Molecular Genetics
James B Papizan, Glynnis A Garry, Svetlana Brezprozvannaya, John R McAnally, Rhonda Bassel-Duby, Ning Liu, Eric N Olson
Maintenance of muscle structure and function depends on the precise organization of contractile proteins into sarcomeres and coupling of the contractile apparatus to the sarcoplasmic reticulum (SR), which serves as the reservoir for calcium required for contraction. Several members of the Kelch superfamily of proteins, which modulate protein stability as substrate-specific adaptors for ubiquitination, have been implicated in sarcomere formation. The Kelch protein Klhl31 is expressed in a muscle-specific manner under control of the transcription factor MEF2...
October 2, 2017: Journal of Clinical Investigation
Osorio Abath Neto, Cristiane de Araújo Martins Moreno, Edoardo Malfatti, Sandra Donkervoort, Johann Böhm, Júlio Brandão Guimarães, A Reghan Foley, Payam Mohassel, Jahannaz Dastgir, Diana Xerxes Bharucha-Goebel, Soledad Monges, Fabiana Lubieniecki, James Collins, Līvija Medne, Mariarita Santi, Sabrina Yum, Brenda Banwell, Emmanuelle Salort-Campana, John Rendu, Julien Fauré, Uluc Yis, Bruno Eymard, Chrystel Cheraud, Raphaël Schneider, Julie Thompson, Xaviere Lornage, Lilia Mesrob, Doris Lechner, Anne Boland, Jean-François Deleuze, Umbertina Conti Reed, Acary Souza Bulle Oliveira, Valérie Biancalana, Norma B Romero, Carsten G Bönnemann, Jocelyn Laporte, Edmar Zanoteli
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...
November 2017: Neuromuscular Disorders: NMD
Amir Ghorbani Aghbolaghi, Mirna Lechpammer
Centronuclear myopathy (CNM) is a group of rare genetic muscle disorders characterized by muscle fibers with centrally located nuclei. The most common forms of CNM have been attributed to X-linked recessive mutations in the MTM1 gene; autosomal-dominant mutations in the DNM2 gene-encoding dynamin-2, the BIN1 gene; and autosomal-recessive mutations in BIN1, RYR1, and TTN genes. Dominant CNM due to DNM2 mutations usually follows a mild clinical course with the onset in adolescence. Currently, around 35 mutations of the DNM2 gene have been identified in CNM; however, the underlying molecular mechanism of DNM2 mutation in the pathology of CNM remains elusive, and the standard clinical characteristics have not yet been defined...
April 2017: Autopsy & Case Reports
Valérie Biancalana, Sophie Scheidecker, Marguerite Miguet, Annie Laquerrière, Norma B Romero, Tanya Stojkovic, Osorio Abath Neto, Sandra Mercier, Nicol Voermans, Laura Tanner, Curtis Rogers, Elisabeth Ollagnon-Roman, Helen Roper, Célia Boutte, Shay Ben-Shachar, Xavière Lornage, Nasim Vasli, Elise Schaefer, Pascal Laforet, Jean Pouget, Alexandre Moerman, Laurent Pasquier, Pascale Marcorelle, Armelle Magot, Benno Küsters, Nathalie Streichenberger, Christine Tranchant, Nicolas Dondaine, Raphael Schneider, Claire Gasnier, Nadège Calmels, Valérie Kremer, Karine Nguyen, Julie Perrier, Erik Jan Kamsteeg, Pierre Carlier, Robert-Yves Carlier, Julie Thompson, Anne Boland, Jean-François Deleuze, Michel Fardeau, Edmar Zanoteli, Bruno Eymard, Jocelyn Laporte
X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels...
July 6, 2017: Acta Neuropathologica
Arlek M González-Jamett, Ximena Baez-Matus, María José Olivares, Fernando Hinostroza, Maria José Guerra-Fernández, Jacqueline Vasquez-Navarrete, Mai Thao Bui, Pascale Guicheney, Norma Beatriz Romero, Jorge A Bevilacqua, Marc Bitoun, Pablo Caviedes, Ana M Cárdenas
Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4...
July 4, 2017: Scientific Reports
Mary Ann Collins, Torrey R Mandigo, Jaclyn M Camuglia, Gabriella A Vazquez, Alyssa J Anderson, Christine H Hudson, John L Hanron, Eric S Folker
Muscle cells are a syncytium in which the many nuclei are positioned to maximize the distance between adjacent nuclei. Although mispositioned nuclei are correlated with many muscle disorders, it is not known whether this common phenotype is the result of a common mechanism. To answer this question, we disrupted the expression of genes linked to Emery-Dreifuss muscular dystrophy (EDMD) and centronuclear myopathy (CNM) in Drosophila and evaluated the position of the nuclei. We found that the genes linked to EDMD and CNM were each necessary to properly position nuclei...
August 15, 2017: Molecular Biology of the Cell
Haicui Wang, Claudia Castiglioni, Ayşe Kaçar Bayram, Fabiana Fattori, Serdar Pekuz, Diego Araneda, Hüseyin Per, Ricardo Erazo, Hakan Gümüş, Suzan Zorludemir, Kerstin Becker, Ximena Ortega, Jorge Alfredo Bevilacqua, Enrico Bertini, Sebahattin Cirak
Centronuclear myopathies (CNM) are a clinically and genetically heterogeneous group of congenital myopathies, defined histologically by increased number of fibres with centrally located nuclei, and type I fibre predominance in muscle biopsy. Myotubular myopathy, the X-linked form of CNM caused by mutations in the phosphoinositide phosphatase MTM1, is histologically characteristic since muscle fibres resemble myotubes. Here we present two unrelated patients with CNM and typical myotubular fibres in the muscle biopsy caused by mutations in striated muscle preferentially expressed protein kinase (SPEG)...
September 2017: Neuromuscular Disorders: NMD
Carola Hedberg-Oldfors, Kittichate Visuttijai, Alexandra Topa, Mar Tulinius, Anders Oldfors
X-linked recessive myotubular myopathy (XLMTM) is a disorder associated with mutations in the myotubularin gene (MTM1) that usually affects boys, with transmission of the mutated allele from the mother. Here we describe a family with unexpected grand paternal transmission of a novel mutation in MTM1 (c.646_648dupGTT; p.Val216dup) identified in a severely affected infant boy with a centronuclear myopathy. We confirmed the carrier status of the mother, but surprisingly we found that her father was a carrier of the mutated MTM1 gene together with wild-type MTM1...
September 2017: Neuromuscular Disorders: NMD
Hichem Tasfaout, Suzie Buono, Shuling Guo, Christine Kretz, Nadia Messaddeq, Sheri Booten, Sarah Greenlee, Brett P Monia, Belinda S Cowling, Jocelyn Laporte
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, X-linked CNM, is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We previously showed that genetic reduction of DNM2 expression in Mtm1 knockout (Mtm1KO) mice prevents development of muscle pathology. Here we show that systemic delivery of Dnm2 antisense oligonucleotides (ASOs) into Mtm1KO mice efficiently reduces DNM2 protein level in muscle and prevents the myopathy from developing...
June 7, 2017: Nature Communications
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