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

Frédérique Rau (1) , Jeanne Lainé (2, 1) , Laetitita Ramanoudjame (3, 1) , Arnaud Ferry (1) , Ludovic Arandel (1) , Olivier Delalande (4) , Arnaud Jollet (1) , Florent Dingli (5, 1) , Kuang-Yung Lee (6, 7) , Cécile Peccate (1) , Stéphanie Lorain (1) , Edor Kabashi (8) , Takis Athanasopoulos (9) , Taeyoung Koo (9) , Damarys Loew (5) , Maurice S. Swanson (6) , Elisabeth Le Rumeur (4) , George Dickson (9) , Valérie Allamand (1) , Joëlle Marie (1) , Denis Furling (1)

1 Centre de recherche en myologie
2 département de physiologie
3 Institut de Myologie
4 IGDR - Institut de Génétique et Développement de Rennes
5 Spectrométrie de Masse des Protéines
6 Department of Molecular Genetics and Microbiology and the Center for NeuroGenetics
7 Department of Neurology
8 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
9 School of Biological Sciences

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

Keywords: Biological sciences; Medical research

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Genetics; Human genetics

Frédérique Rau, Jeanne Lainé, Laetitita Ramanoudjame, Arnaud Ferry, Ludovic Arandel, et al.. Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy. Nature Communications, 2015, 6 (1), pp.7205. ⟨10.1038/ncomms8205⟩. ⟨hal-01162385⟩