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2013-11-27 - Colloque/Présentation - communication orale - Anglais - 2 page(s)

Vanderplanck Céline, Tassin Alexandra , Lancelot Céline , Ansseau Eugénie , Nonclercq Denis , Delrée Paul, Laoudj-Chenivesse Dalila, Belayew Alexandra , Coppée Frédérique , "DUX4c, a DUX4-homologue, causes the FSHD disorganized myotube phenotype: an additional target for therapeutic strategies" in Colloque Myogenèse XVI, 11, 98, Montpellier, France, 2013

  • Codes CREF : Pathologies particulières (DI3370)
  • Unités de recherche UMONS : Biologie moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
  • Centres UMONS : Mind & Health (CREMH)
Texte intégral :

Abstract(s) :

(Anglais) Background: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder affecting 1/17,000 births. The FSHD-linked deletion in the D4Z4 repeat array at 4q35 opens an inhibitory chromatin structure and activates transcription of several genes in the vicinity. Our laboratory has identified two similar candidate genes encoding transcription factors: DUX4 within the D4Z4 unit itself, and DUX4c located 42-kb centromeric of the D4Z4 repeat array. In healthy primary myotube cultures DUX4 is expressed at very low level in about 1% myonuclei but induced 4-7 fold in 8-12% myonuclei of FSHD cultures. It initiates a gene deregulation cascade causing muscle atrophy, differentiation defects and oxidative stress. We have previously shown by gain and loss of function experiments that DUX4 expression in primary myoblasts induced an atrophic myotube phenotype. Besides this atrophic phenotype FSHD cultures also present disorganized myotubes. The DUX4c protein has a shorter carboxyl terminal domain than DUX4 and does not share its toxicity. DUX4c is detected at higher level in control myoblasts and induced in FSHD. Its overexpression induces myoblast proliferation suggesting a function in muscle regeneration. Methodology/Principal Findings: We now show that transfection of healthy primary myoblasts with a DUX4c expression vector leads to the formation of disorganized myotubes. We further show that DUX4c overexpression in control myoblasts causes differentiation defects characterized by perturbations of proteins associated with the cytoskeleton and the contractile-apparatus leading to sarcomere malformation and contraction defects. We developed specific siRNAs targeting the DUX4c mRNA. Addition of these inhibitors to FSHD primary myoblast cultures that would normally fuse to disorganized myotubes suppressed DUX4c expression and led to a normal myotube phenotype. Conclusions/Significance: These gain and loss of function experiments suggest that besides DUX4, DUX4c could be an additional target for the development of therapeutic approaches against FSHD.