title: Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy.
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.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Rau
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.|Sorbonne Universités, UPMC Paris 06, Département de Physiologie, Site Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Lainé
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Laetitita
authors.initials: L
authors.lastname: Ramanoudjame
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Ferry
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Arandel
authors.affiliation: Université de Rennes 1, Institut de Génétique et Développement de Rennes, F-35043 Rennes, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Delalande
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jollet
authors.affiliation: Institut Curie, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, F-75005 Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Dingli
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.|Department of Neurology, Chang Gung Memorial Hospital, Keelung 204, Taiwan.
authors.forename: Kuang-Yung
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Peccate
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lorain
authors.affiliation: Sorbonne Université, UPMC Univ Paris 06, UM 75, INSERM U1127, CNRS UMR7225, ICM, Paris, F-75013 Paris, France.
authors.forename: Edor
authors.initials: E
authors.lastname: Kabashi
authors.affiliation: School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey, TW20 0EX, UK.
authors.forename: Takis
authors.initials: T
authors.lastname: Athanasopoulos
authors.affiliation: School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey, TW20 0EX, UK.
authors.forename: Taeyoung
authors.initials: T
authors.lastname: Koo
authors.affiliation: Institut Curie, Centre de Recherche, Laboratoire de Spectrométrie de Masse Protéomique, F-75005 Paris, France.
authors.forename: Damarys
authors.initials: D
authors.lastname: Loew
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.affiliation: Université de Rennes 1, Institut de Génétique et Développement de Rennes, F-35043 Rennes, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Le Rumeur
authors.affiliation: School of Biological Sciences, Royal Holloway-University of London, Egham, Surrey, TW20 0EX, UK.
authors.forename: George
authors.initials: G
authors.lastname: Dickson
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Allamand
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Marie
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Center for Research in Myology, Institut de Myologie, GH Pitié-Salpêtrière, F-75013 Paris, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D018507:Gene Expression Regulation, Developmental; D006706:Homeostasis; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008854:Microscopy, Electron; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000235:genetics* / Q000473:pathology; D012326:RNA Splicing / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012519:Sarcoplasmic Reticulum / Q000648:ultrastructure; D053719:Tandem Mass Spectrometry; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C484258:DMD protein, human; D016189:Dystrophin; C493663:MBNL1 protein, human; D008565:Membrane Proteins; D009124:Muscle Proteins; D016601:RNA-Binding Proteins; D029961:Zebrafish Proteins; C085339:apo-dystrophin 1; C435224:dmd protein, zebrafish