The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development

Adeline Vulin, Nicolas Wein, Tabatha R. Simmons, Andrea M. Rutherford, Andrew R. Findlay, Jacqueline A. Yurkoski, Yuuki Kaminoh, Kevin M. Flanigan

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish
Article number3082
Pages (from-to)827-834
Number of pages8
JournalNeuromuscular Disorders
Volume25
Issue number11
DOIs
StatePublished - Nov 2015

Keywords

  • Duchenne muscular dystrophy
  • Duplication
  • Exon skipping
  • Mouse model

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