{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T23:39:44Z","timestamp":1793403584642,"version":"4.5.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"31","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,8]]},"abstract":"<jats:p>\n                    RNA-mediated pathogenesis is a recently developed disease model that proposes that certain types of mutant genes produce toxic transcripts that inhibit the activities of specific proteins. This pathogenesis model was proposed first for the neuromuscular disease myotonic dystrophy (DM), which is associated with the expansion of structurally related (CTG)\n                    <jats:sub>n<\/jats:sub>\n                    and (CCTG)\n                    <jats:sub>n<\/jats:sub>\n                    microsatellites in two unrelated genes. At the RNA level, these expansions form stable hairpins that alter the pre-mRNA splicing activities of two antagonistic factor families, the MBNL and CELF proteins. It is unclear which altered activity is primarily responsible for disease pathogenesis and whether other factors and biochemical pathways are involved. Here, we show that overexpression of Mbnl1\n                    <jats:italic>in vivo<\/jats:italic>\n                    mediated by transduction of skeletal muscle with a recombinant adeno-associated viral vector rescues disease-associated muscle hyperexcitability, or myotonia, in the\n                    <jats:italic>HSA<\/jats:italic>\n                    <jats:sup>LR<\/jats:sup>\n                    poly(CUG) mouse model for DM. Myotonia reversal occurs concurrently with restoration of the normal adult-splicing patterns of four pre-mRNAs that are misspliced during postnatal development in DM muscle. Our results support the hypothesis that the loss of MBNL1 activity is a primary pathogenic event in the development of RNA missplicing and myotonia in DM and provide a rationale for therapeutic strategies designed either to overexpress MBNL1 or inhibit MBNL1 interactions with CUG and CCUG repeat expansions.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0604970103","type":"journal-article","created":{"date-parts":[[2006,7,24]],"date-time":"2006-07-24T20:33:52Z","timestamp":1153773232000},"page":"11748-11753","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":355,"title":["Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy"],"prefix":"10.1073","volume":"103","author":[{"given":"Rahul N.","family":"Kanadia","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"Genetics Institute, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihae","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"Genetics Institute, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"Genetics Institute, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart G.","family":"Beattie","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"Genetics Institute, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thurman M.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles A.","family":"Thornton","sequence":"additional","affiliation":[{"name":"Department of Neurology, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurice S.","family":"Swanson","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology,"},{"name":"Genetics Institute, University of Florida College of Medicine, 1600 Southwest Archer Road, Gainesville, FL 32610; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00019.2003"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2004.08.004"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-74266-1_3"},{"key":"e_1_3_4_4_2","volume-title":"Genetic Instabilities and Hereditary Neurological Diseases","author":"Thornton C. 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