Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

Frédérique Rau, Jeanne Lainé, Laetitita Ramanoudjame, Arnaud Ferry, Ludovic Arandel, Olivier Delalande, Arnaud Jollet, Florent Dingli, Kuang Yung Lee, Cécile Peccate, Stéphanie Lorain, Edor Kabashi, Takis Athanasopoulos, Taeyoung Koo, Damarys Loew, Maurice S. Swanson, Elisabeth Le Rumeur, George Dickson, Valérie Allamand, Joëlle MarieDenis Furling*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

70 Scopus citations


Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1.

Original languageEnglish
Article number7205
JournalNature Communications
StatePublished - 28 05 2015
Externally publishedYes

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