TY - JOUR
T1 - Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy
AU - Rau, Frédérique
AU - Lainé, Jeanne
AU - Ramanoudjame, Laetitita
AU - Ferry, Arnaud
AU - Arandel, Ludovic
AU - Delalande, Olivier
AU - Jollet, Arnaud
AU - Dingli, Florent
AU - Lee, Kuang Yung
AU - Peccate, Cécile
AU - Lorain, Stéphanie
AU - Kabashi, Edor
AU - Athanasopoulos, Takis
AU - Koo, Taeyoung
AU - Loew, Damarys
AU - Swanson, Maurice S.
AU - Le Rumeur, Elisabeth
AU - Dickson, George
AU - Allamand, Valérie
AU - Marie, Joëlle
AU - Furling, Denis
N1 - Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.
PY - 2015/5/28
Y1 - 2015/5/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84930669555&partnerID=8YFLogxK
U2 - 10.1038/ncomms8205
DO - 10.1038/ncomms8205
M3 - Article
C2 - 26018658
AN - SCOPUS:84930669555
SN - 2041-1723
VL - 6
JO - Nature Communications
JF - Nature Communications
M1 - 7205
ER -