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Imene Dalichaouche, Yamina Sifi, Carinne Roudaut, Karima Sifi, Abdelmadjid Hamri, Leila Rouabah, Noureddine Abadi, Isabelle Richard
INTRODUCTION: We report the genetic analysis of a large series of 76 Algerian patients from 65 unrelated families that presented with early onset severe muscular dystrophy and a clinical phenotype resembling Limb-girdle muscular dystrophy type 2C (LGMD2C). METHODS: To define the genetic basis of the diseases in these families, we undertook a series of analysis of the γ-sarcoglycan (SGCG) and DMD genes. RESULTS: Fifteen families were shown to carry SGCG variants...
October 19, 2016: Muscle & Nerve
Y M Zheng, W Z Li, Z X Wang, W Zhang, H Lv, J X Xiao, Y Yuan
OBJECTIVE: To report thigh muscle magnetic resonance imaging (MRI) tests of four Chinese patients with dystrophinopathy with edema changes in adductor longus muscles that mimics adductor enthesopathy. METHODS: Four boys, who were from four unrelated families and aged from 5 to 11 years, were investigated because of the clinical manifestations including myalgia or muscle weakness or the incidental findings of elevated serum creatine kinase levels, and were diagnosed with dystrophinopathy by gene test of Duchenne muscular dystrophy (DMD)...
October 18, 2016: Beijing da Xue Xue Bao. Yi Xue Ban, Journal of Peking University. Health Sciences
Jingzi Zhong, Tiantian Xu, Gang Chen, Haixia Liao, Jiapeng Zhang, Dan Lan
Introduction Duchenne and Becker muscular dystrophies (DMD and BMD) are X-linked myopathies caused by mutations of the dystrophin gene. Methods Multiplex ligation-dependent probe amplification (MLPA) combined with next-generation sequencing (NGS) of the exons of the dystrophin gene were performed in 92 suspected DMD/BMD patients. Patients with negative results were subjected to additional muscle diseases panel tests. Results DNA rearrangements were detected in 65(70.65%) patients using MLPA. The deletions primarily clustered at exons 45-55, followed by exons 2-19...
October 17, 2016: Muscle & Nerve
Tahnee L Kennedy, Kristy Swiderski, Kate T Murphy, Stefan M Gehrig, Claire L Curl, Chanchal Chandramouli, Mark A Febbraio, Lea M D Delbridge, René Koopman, Gordon S Lynch
Duchenne muscular dystrophy is a severe and progressive striated muscle wasting disorder that leads to premature death from respiratory and/or cardiac failure. We have previously shown that treatment of young dystrophic mdx and dystrophin/utrophin null (dko) mice with BGP-15, a coinducer of heat shock protein 72, ameliorated the dystrophic pathology. We therefore tested the hypothesis that later-stage BGP-15 treatment would similarly benefit older mdx and dko mice when the dystrophic pathology was already well established...
October 14, 2016: American Journal of Pathology
Luca Bello, Kevin M Flanigan, Robert B Weiss, Pietro Spitali, Annemieke Aartsma-Rus, Francesco Muntoni, Irina Zaharieva, Alessandra Ferlini, Eugenio Mercuri, Sylvie Tuffery-Giraud, Mireille Claustres, Volker Straub, Hanns Lochmüller, Andrea Barp, Sara Vianello, Elena Pegoraro, Jaya Punetha, Heather Gordish-Dressman, Mamta Giri, Craig M McDonald, Eric P Hoffman
The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers...
October 12, 2016: American Journal of Human Genetics
Hong-Hao Yu, Heng Zhao, Yu-Bo Qing, Wei-Rong Pan, Bao-Yu Jia, Hong-Ye Zhao, Xing-Xu Huang, Hong-Jiang Wei
Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease...
October 9, 2016: International Journal of Molecular Sciences
J Patrick Gonzalez, Sergii Kyrychenko, Victoria Kyrychenko, Joel S Schneider, Celine J Granier, Eric Himelman, Kevin Lahey, Qingshi Zhao, Ghassan Yehia, Yuan-Xiang Tao, Mantu Bhaumik, Natalia Shirokova, Diego Fraidenraich
Duchenne muscular dystrophy (DMD) is characterized by the loss of the protein dystrophin, leading to muscle fragility, progressive weakening, and susceptibility to mechanical stress. Although dystrophin-negative mdx mouse models have classically been used to study DMD, phenotypes appear mild compared to patients. As a result, characterization of muscle pathology, especially in the heart, has proven difficult. We report that injection of mdx embryonic stem cells (ESCs) into Wild Type (WT) blastocysts produces adult mouse chimeras with severe DMD phenotypes in the heart and skeletal muscle...
October 13, 2016: Stem Cells
Lygia M Malvestio, Mara Rúbia N Celes, Linda A Jelicks, Herbert B Tanowitz, Cibele M Prado
Dystrophin, an important protein of the dystrophin-glycoprotein complex, has been implicated in the pathogenesis of experimental Chagas disease. It is important for the maintenance of cell shape and contraction force transmission. Dystrophin loss has been related to end-stage cardiac myopathies and proposed as a common route for myocardial dysfunction and progression to advanced heart failure. Evidence suggests that calpains, calcium-dependent proteases, digest dystrophin when the calcium concentration is compatible with their activation...
October 11, 2016: Parasitology Research
Sheryl Southard, Ju-Ryoung Kim, SiewHui Low, Richard W Tsika, Christoph Lepper
When unperturbed, somatic stem cells are poised to affect immediate tissue restoration upon trauma. Yet, little is known regarding the mechanistic basis controlling initial and homeostatic 'scaling' of stem cell pool sizes relative to their target tissues for effective regeneration. Here, we show that TEAD1-expressing skeletal muscle of transgenic mice features a dramatic hyperplasia of muscle stem cells (i.e. satellite cells, SCs) but surprisingly without affecting muscle tissue size. Super-numeral SCs attain a 'normal' quiescent state, accelerate regeneration, and maintain regenerative capacity over several injury-induced regeneration bouts...
October 11, 2016: ELife
S M Klein, L Prantl, S Geis, O Felthaus, J Dolderer, A Anker, K Zeitler, E Alt, J Vykoukal
BACKGROUND: Duchenne muscular dystrophy (DMD) consists of a lack in the expression of the subsarcolemmal protein dystrophin causing progressive muscle dysfunction. Among the widely applied animal models in DMD research is the C57BL/1010ScSn-Dmdmdx mouse, commonly referred to as the "mdx mouse". The potential benefit of novel interventions in this model is often assessed by variables such as functional improvement, histological changes, and creatine kinase (CK) serum levels as an indicator for the extent of in situ muscle damage...
October 3, 2016: Clinical Hemorheology and Microcirculation
Cynthia Machado Cascabulho, Daniela Gois Beghini, Marcelo Meuser-Batista, Carmen Penido, Andrea Henriques-Pons
Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder caused by mutations in the dystrophin gene that lead to degeneration of skeletal and cardiac muscles and to chronic inflammation. Despite the importance of γδ T cells in many diseases, this cellular subpopulation has not been described in DMD patients or in mdx mice, a widely used mouse model for studying DMD. Therefore, in this study, we aimed to evaluate the migration of γδ T cells to the cardiac muscle of mdx mice and to characterize their phenotype and functional activity...
October 5, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Simon Früh, Jennifer Romanos, Patrizia Panzanelli, Daniela Bürgisser, Shiva K Tyagarajan, Kevin P Campbell, Mirko Santello, Jean-Marc Fritschy
: Distinct types of GABAergic interneurons target different subcellular domains of pyramidal cells, thereby shaping pyramidal cell activity patterns. Whether the presynaptic heterogeneity of GABAergic innervation is mirrored by specific postsynaptic factors is largely unexplored. Here we show that dystroglycan, a protein responsible for the majority of congenital muscular dystrophies when dysfunctional, has a function at postsynaptic sites restricted to a subset of GABAergic interneurons...
October 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Ronald K H Liem
This review discusses the spectrin superfamily of proteins that function to connect cytoskeletal elements to each other, the cell membrane, and the nucleus. The signature domain is the spectrin repeat, a 106-122-amino-acid segment comprising three α-helices. α-actinin is considered to be the ancestral protein and functions to cross-link actin filaments. It then evolved to generate spectrin and dystrophin that function to link the actin cytoskeleton to the cell membrane, as well as the spectraplakins and plakins that link cytoskeletal elements to each other and to junctional complexes...
October 3, 2016: Cold Spring Harbor Perspectives in Biology
Ute Ulrike Botzenhart, Constantin Wegenstein, Teodor Todorov, Christiane Kunert-Keil
The most widespread animal model to investigate Duchenne muscular dystrophy is the mdx-mouse. In contrast to humans, phases of muscle degeneration are replaced by regeneration processes; hence there is only a restricted time slot for research. The aim of the study was to investigate if an intramuscular injection of BTX-A is able to break down muscle regeneration and has direct implications on the gene expression of myosin heavy chains in the corresponding treated and untreated muscles. Therefore, paralysis of the right masseter muscle was induced in adult healthy and dystrophic mice by a specific intramuscular injection of BTX-A...
2016: BioMed Research International
M S Alexander, M J Gasperini, P T Tsai, D E Gibbs, J M Spinazzola, J L Marshall, M J Feyder, M T Pletcher, E L P Chekler, C A Morris, M Sahin, J F Harms, C J Schmidt, R J Kleiman, L M Kunkel
Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice...
2016: Translational Psychiatry
Antonio L Serrano, Pura Muñoz-Cánoves
Duchenne muscular dystrophy (DMD) is one of the most devastating neuromuscular genetic diseases caused by the absence of dystrophin. The continuous episodes of muscle degeneration and regeneration in dystrophic muscle are accompanied by chronic inflammation and fibrosis deposition, which exacerbate disease progression. Thus, in addition of investigating strategies to cure the primary defect by gene/cell therapeutic strategies, increasing efforts are being placed on identifying the causes of the substitution of muscle by non-functional fibrotic tissue in DMD, aiming to attenuate its severity...
September 23, 2016: Seminars in Cell & Developmental Biology
Davy Vanhoutte, Tobias G Schips, Jennifer Q Kwong, Jennifer Davis, Andoria Tjondrokoesoemo, Matthew J Brody, Michelle A Sargent, Onur Kanisicak, Hong Yi, Quan Q Gao, Joseph E Rabinowitz, Talila Volk, Elizabeth M McNally, Jeffery D Molkentin
Skeletal muscle is highly sensitive to mutations in genes that participate in membrane stability and cellular attachment, which often leads to muscular dystrophy. Here we show that Thrombospondin-4 (Thbs4) regulates skeletal muscle integrity and its susceptibility to muscular dystrophy through organization of membrane attachment complexes. Loss of the Thbs4 gene causes spontaneous dystrophic changes with aging and accelerates disease in 2 mouse models of muscular dystrophy, while overexpression of mouse Thbs4 is protective and mitigates dystrophic disease...
September 26, 2016: ELife
Matthew S Alexander, Anete Rozkalne, Alessandro Colletta, Janelle M Spinazzola, Samuel Johnson, Fedik Rahimov, Hui Meng, Michael W Lawlor, Elicia Estrella, Louis M Kunkel, Emanuela Gussoni
Cell-surface markers for prospective isolation of stem cells from human skeletal muscle have been difficult to identify. Such markers would be powerful tools for studying satellite cell function during homeostasis and in pathogenesis of diseases such as muscular dystrophies. In this study, we show that the tetraspanin KAI/CD82 is an excellent marker for prospectively isolating stem cells from human fetal and adult skeletal muscle. Human CD82(+) muscle cells robustly engraft into a mouse model of muscular dystrophy...
September 7, 2016: Cell Stem Cell
Joseph J Belanto, John T Olthoff, Tara L Mader, Christopher M Chamberlain, D'anna M Nelson, Preston M McCourt, Dana M Talsness, Gregg G Gunderson, Dawn A Lowe, James M Ervasti
Absence of the protein dystrophin causes Duchenne muscular dystrophy. Dystrophin directly binds to microtubules in vitro, and its absence in vivo correlates with disorganization of the subsarcolemmal microtubule lattice, increased detyrosination of α-tubulin, and altered redox signaling. We previously demonstrated that the dystrophin homologue utrophin neither binds microtubules in vitro nor rescues microtubule lattice organization when overexpressed in muscles of dystrophin-deficient mdx mice. Here, we fine-mapped the dystrophin domain necessary for microtubule binding to spectrin-like repeats 20-22...
September 16, 2016: Human Molecular Genetics
Thomas Fröhlich, Elisabeth Kemter, Florian Flenkenthaler, Nikolai Klymiuk, Kathrin A Otte, Andreas Blutke, Sabine Krause, Maggie C Walter, Rüdiger Wanke, Eckhard Wolf, Georg J Arnold
Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs...
2016: Scientific Reports
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