title: The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development.
abstract: Exon duplication mutations account for up to 11% of all cases of Duchenne muscular dystrophy (DMD), and a duplication of exon 2 is the most common duplication in patients. For use as a platform for testing of duplication-specific therapies, we developed a mouse model that carries a Dmd exon 2 duplication. By using homologous recombination we duplicated exon 2 within intron 2 at a location consistent with a human duplication hotspot. mRNA analysis confirms the inclusion of a duplicated exon 2 in mouse muscle. Dystrophin expression is essentially absent by immunofluorescent and immunoblot analysis, although some muscle specimens show very low-level trace dystrophin expression. Phenotypically, the mouse shows similarities to mdx, the standard laboratory model of DMD. In skeletal muscle, areas of necrosis and phagocytosis are seen at 3 weeks, with central nucleation prominent by four weeks, recapitulating the "crisis" period in mdx. Marked diaphragm fibrosis is noted by 6 months, and remains unchanged at 12 months. Our results show that the Dup2 mouse is both pathologically (in degree and distribution) and physiologically similar to mdx. As it recapitulates the most common single exon duplication found in DMD patients, this new model will be a useful tool to assess the potential of duplicated exon skipping.
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: Adeline
authors.initials: A
authors.lastname: Vulin
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Wein
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: Tabatha R
authors.initials: TR
authors.lastname: Simmons
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Rutherford
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Findlay
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Yurkoski
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Kaminoh
authors.affiliation: The Center for Gene Therapy, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA; Department of Neurology, The Ohio State University, Columbus, OH, USA. Electronic address: kevin.flanigan@nationwidechildrens.org.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Flanigan
mesh_terms: D000818:Animals; D001835:Body Weight; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D005091:Exons; D020440:Gene Duplication; D055879:Gene Knock-In Techniques / Q000379:methods; D008297:Male; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D003402:Creatine Kinase
keywords: Duchenne muscular dystrophy; Duplication; Exon skipping; Mouse model