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Exon skipping in a Dysf-missense mutant mouse model

Authors

  • J. Malcher
  • L. Heidt
  • A. Goyenvalle
  • H. Escobar
  • A. Marg
  • C. Beley
  • R. Benchaouir
  • M. Bader
  • S. Spuler
  • L. García
  • V. Schöwel

Journal

  • Molecular Therapy - Nucleic Acids

Citation

  • Mol Ther Nucleic Acids 13: 198-207

Abstract

  • Limb girdle muscular dystrophy 2B (LGMD2B) is without treatment and caused by mutations in the dysferlin gene (DYSF). One third are missense mutations leading to dysferlin aggregation and amyloid formation in addition to defects in sarcolemmal repair and progressive muscle wasting. Dysferlin-null mouse models do not allow to study the consequences of missense mutations. We generated a new mouse model (MMex38) carrying a missense mutation in exon 38 in analogy to a clinically relevant human DYSF variant (DYSF p.Leu1341Pro). The targeted mutation induces all characteristics of missense mutant dysferlinopathy including a progressive dystrophic pattern, amyloid formation and defects in membrane repair. We chose U7 snRNAs-based splice switching to demonstrate a possible exon skipping strategy in this new animal model. We show that Dysf exons 37 and 38 can successfully be skipped in vivo. Overall, the MMex38 mouse model provides an ideal tool for preclinical development of treatment strategies for dysferlinopathy.


DOI

doi:10.1016/j.omtn.2018.08.013