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 Marie and Denis Furling ()
Additional contact information
Frédérique Rau: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Jeanne Lainé: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Laetitita Ramanoudjame: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Arnaud Ferry: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Ludovic Arandel: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Olivier Delalande: Université de Rennes 1, Institut de Génétique et Développement de Rennes
Arnaud Jollet: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Florent Dingli: Institut Curie, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique
Kuang-Yung Lee: Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine
Cécile Peccate: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Stéphanie Lorain: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Edor Kabashi: Sorbonne Université, UPMC Univ Paris 06, UM 75, INSERM U1127, CNRS UMR7225, ICM, Paris
Takis Athanasopoulos: School of Biological Sciences, Royal Holloway—University of London
Taeyoung Koo: School of Biological Sciences, Royal Holloway—University of London
Damarys Loew: Institut Curie, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique
Maurice S. Swanson: Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine
Elisabeth Le Rumeur: Université de Rennes 1, Institut de Génétique et Développement de Rennes
George Dickson: School of Biological Sciences, Royal Holloway—University of London
Valérie Allamand: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Joëlle Marie: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière
Denis Furling: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8205

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