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      Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

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          A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx ( X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats ( Dmd mdx ) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmd mdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmd mdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmd mdx rats represent a new faithful small animal model of DMD.

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          Most cited references 29

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          Dystrophin: the protein product of the Duchenne muscular dystrophy locus.

          The protein product of the human Duchenne muscular dystrophy locus (DMD) and its mouse homolog (mDMD) have been identified by using polyclonal antibodies directed against fusion proteins containing two distinct regions of the mDMD cDNA. The DMD protein is shown to be approximately 400 kd and to represent approximately 0.002% of total striated muscle protein. This protein is also detected in smooth muscle (stomach). Muscle tissue isolated from both DMD-affected boys and mdx mice contained no detectable DMD protein, suggesting that these genetic disorders are homologous. Since mdx mice present no obvious clinical abnormalities, the identification of the mdx mouse as an animal model for DMD has important implications with regard to the etiology of the lethal DMD phenotype. We have named the protein dystrophin because of its identification via the isolation of the Duchenne muscular dystrophy locus.
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            A TALE nuclease architecture for efficient genome editing.

            Nucleases that cleave unique genomic sequences in living cells can be used for targeted gene editing and mutagenesis. Here we develop a strategy for generating such reagents based on transcription activator-like effector (TALE) proteins from Xanthomonas. We identify TALE truncation variants that efficiently cleave DNA when linked to the catalytic domain of FokI and use these nucleases to generate discrete edits or small deletions within endogenous human NTF3 and CCR5 genes at efficiencies of up to 25%. We further show that designed TALEs can regulate endogenous mammalian genes. These studies demonstrate the effective application of designed TALE transcription factors and nucleases for the targeted regulation and modification of endogenous genes.
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              X chromosome-linked muscular dystrophy (mdx) in the mouse.

              An X chromosome-linked mouse mutant (gene symbol, mdx) has been found that has elevated plasma levels of muscle creatine kinase and pyruvate kinase and exhibits histological lesions characteristic of muscular dystrophy. The mutants show mild clinical symptoms and are viable and fertile. Linkage analysis with four X chromosome loci indicates that mdx maps in the Hq Bpa region of the mouse X chromosome. This gives a gene order of mdx-Tfm-Pgk-1-Ags, the same as for the equivalent genes on the human X chromosome.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                13 October 2014
                : 9
                : 10
                [1 ]INRA, UMR703 APEX, Oniris, Atlantic Gene Therapies, Université de Nantes, Oniris, École nationale vétérinaire, agro-alimentaire et de l'alimentation, Nantes, France
                [2 ]INSERM, UMR 1087/CNRS 6291 Institut du Thorax, Université de Nantes, Faculté des Sciences et des Techniques, Nantes, France
                [3 ]INSERM, UMR 1064-Center for Research in Transplantation and Immunology, ITUN, CHU Nantes, Université de Nantes, Faculté de Médecine, Nantes, France
                [4 ]INSERM, UMR 1089, Atlantic Gene Therapies, Thérapie génique pour les maladies de la rétine et les maladies neuromusculaires, Université de Nantes, Faculté de Médecine, Nantes, France
                [5 ]Genethon, Evry, France
                [6 ]INSERM, U1154, CNRS, UMR 7196, Muséum National d’Histoire Naturelle, Paris, France
                University of Minnesota Medical School, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YC CG JPC IA CH. Performed the experiments: TL AL LT SR VT VF CLG HG MD LG GT ADC CB JBR YC CG JPC IA CH. Analyzed the data: TL AL LT SR VT VF CLG HG MD LG GT ADC CB JBR YC CG JPC IA CH. Contributed to the writing of the manuscript: IA CH.

                ¶ These authors are first authors on this work.

                † Deceased


                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Pages: 13
                Funding was provided by Région Pays de la Loire through Biogenouest, IBiSA program, Fondation Progreffe and TEFOR (Infrastructures d’Avenir of the French goverment), and the integrative genomic facility of Nantes for sequencing experiments. The authors thank the Wolfson Centre for Inherited Neuromuscular Disease for kindly supplying dystrophin monoclonal antibody. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Cell Biology
                Molecular Biology
                Medicine and Health Sciences
                Congenital Disorders
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                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.



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