Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy - Université de Rennes Access content directly
Journal Articles Nature Communications Year : 2015

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

Frédérique Rau
Arnaud Ferry
Ludovic Arandel
Cécile Peccate
Damarys Loew
George Dickson
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Valérie Allamand
Denis Furling

Abstract

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
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Dates and versions

hal-01162385 , version 1 (08-01-2016)

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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⟩
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