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      An intronic LINE-1 element insertion in the dystrophin gene aborts dystrophin expression and results in Duchenne-like muscular dystrophy in the corgi breed

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          Abstract

          Duchenne muscular dystrophy (DMD) is a dystrophin-deficient lethal muscle disease. To date, the catastrophic muscle wasting phenotype has only been seen in dystrophin-deficient humans and dogs. While Duchenne-like symptoms have been observed in more than a dozen dog breeds, the mutation is often not known and research colonies are rarely established. Here we report an independent canine DMD model originally derived from the Pembroke Welsh corgi breed. The affected dogs presented clinical signs of muscular dystrophy. Immunostaining revealed the absence of dystrophin and up-regulation of utrophin. Histopathologic examination showed variable fiber size, central nucleation, calcification, fibrosis, neutrophil and macrophage infiltration and cardiac focal vacuolar degeneration. Carrier dogs also displayed mild myopathy. The mutation was identified as a long interspersed repetitive element-1 (LINE-1) insertion in intron 13 which introduced a new exon containing an in-frame stop codon. Similar mutations have been seen in human patients. A colony was generated by crossing carrier females with normal males. Affected puppies had a normal birth weight but they experienced a striking growth delay in the first 5 days. In summary, the new corgi DMD model offers an excellent opportunity to study DMD pathogenesis and to develop novel therapies.

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          Most cited references59

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          Mobile elements: drivers of genome evolution.

          Mobile elements within genomes have driven genome evolution in diverse ways. Particularly in plants and mammals, retrotransposons have accumulated to constitute a large fraction of the genome and have shaped both genes and the entire genome. Although the host can often control their numbers, massive expansions of retrotransposons have been tolerated during evolution. Now mobile elements are becoming useful tools for learning more about genome evolution and gene function.
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            An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs.

            Retrotransposition of processed mRNAs is a common source of novel sequence acquired during the evolution of genomes. Although the vast majority of retroposed gene copies, or retrogenes, rapidly accumulate debilitating mutations that disrupt the reading frame, a small percentage become new genes that encode functional proteins. By using a multibreed association analysis in the domestic dog, we demonstrate that expression of a recently acquired retrogene encoding fibroblast growth factor 4 (fgf4) is strongly associated with chondrodysplasia, a short-legged phenotype that defines at least 19 dog breeds including dachshund, corgi, and basset hound. These results illustrate the important role of a single evolutionary event in constraining and directing phenotypic diversity in the domestic dog.
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              Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase.

              UMD-DMD France is a knowledgebase developed through a multicenter academic effort to provide an up-to-date resource of curated information covering all identified mutations in patients with a dystrophinopathy. The current release includes 2,411 entries consisting in 2,084 independent mutational events identified in 2,046 male patients and 38 expressing females, which corresponds to an estimated number of 39 people per million with a genetic diagnosis of dystrophinopathy in France. Mutations consist in 1,404 large deletions, 215 large duplications, and 465 small rearrangements, of which 39.8% are nonsense mutations. The reading frame rule holds true for 96% of the DMD patients and 93% of the BMD patients. Quality control relies on the curation by four experts for the DMD gene and related diseases. Data on dystrophin and RNA analysis, phenotypic groups, and transmission are also available. About 24% of the mutations are de novo events. This national centralized resource will contribute to a greater understanding of prevalence of dystrophinopathies in France, and in particular, of the true frequency of BMD, which was found to be almost half (43%) that of DMD. UMD-DMD is a searchable anonymous database that includes numerous newly developed tools, which can benefit to all the scientific community interested in dystrophinopathies. Dedicated functions for genotype-based therapies allowed the prediction of a new multiexon skipping (del 45-53) potentially applicable to 53% of the deleted DMD patients. Finally, such a national database will prove to be useful to implement the international global DMD patients' registries under development.
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                Author and article information

                Journal
                0376617
                5462
                Lab Invest
                Laboratory investigation; a journal of technical methods and pathology
                0023-6837
                1530-0307
                21 July 2010
                16 August 2010
                February 2011
                1 August 2011
                : 91
                : 2
                : 216-231
                Affiliations
                [1 ] Scott-Ritchey Research Center, College of Veterinary Medicine, Auburn University
                [2 ] Department of Pathobiology, College of Veterinary Medicine, Auburn University
                [3 ] Department of Molecular Microbiology and Immunology, School of Medicine, The University of Missouri
                [4 ] Dogwood Equine Veterinary Clinic, PO Box 2196, Southern Pines, NC 28388
                [5 ] Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill
                Author notes
                [* ]Corresponding Address: Bruce F. Smith V.M.D, Ph.D., Professor, Scott-Ritchey Research Center, Auburn University, Auburn, AL 36849, Phone: 334-844-5587, Fax: 334-844-5850, smithbf@ 123456auburn.edu . Dongsheng Duan Ph.D., Associate Professor, Department of Molecular Microbiology and Immunology, The University of Missouri School of Medicine, One Hospital Dr. M610G, MSB, Columbia, MO 65212, Phone: 573-884-9584, Fax: 573-882-4287 duand@ 123456missouri.edu
                Article
                nihpa221290
                10.1038/labinvest.2010.146
                2999660
                20714321
                7e39a328-283b-4c72-97eb-1d96b6833d18

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                History
                Funding
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: R21 AR057209-01A1 ||AR
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: R03 AR048650-03 ||AR
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: R01 AR049419-07 ||AR
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                Pathology
                Pathology

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