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2016-03-14 - Colloque/Présentation - poster - Anglais - 1 page(s)

Vanderplanck Céline, Tassin Alexandra , Ansseau Eugénie , Lancelot Céline , Derenne Aline , Conotte Stéphanie , Dudome Virginie , Leroy Baptiste , Wilton D. Steve, Laoudj-Chenivesse Dalila, Wattiez Ruddy , Legrand Alexandre , Belayew Alexandra , Coppée Frédérique , ""Antisense strategies targeting DUX4 and DUX4c for the treatment of Facioscapulohumeral muscular dystrophy."" in 5th International Congress of Myology, Lyon, France, 2016

  • Codes CREF : Biologie moléculaire (DI3111), Pathologies particulières (DI3370), Biologie cellulaire (DI311D)
  • Unités de recherche UMONS : Biologie moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)
Texte intégral :

Abstract(s) :

(Anglais) Antisense strategies targeting DUX4 and DUX4c for the treatment of facioscapulohumeral muscular dystrophy (FSHD). Vanderplanck Céline1, Tassin Alexandra1,2, Ansseau Eugénie1, Lancelot Céline1, Derenne Aline1,2, Conotte Stéphanie2, Dudome Virginie1, Leroy Baptiste3, Wilton D. Steve4, Laoudj-Chenivesse Dalila4, Wattiez Ruddy3, Legrand Alexandre2, Belayew Alexandra1, Coppée Frédérique1. 1Laboratory of Molecular Biology, and 2Laboratory of Respiratory physiology, physiopathology and rehabilitation, Research Institute for Health Sciences and Technology, University of Mons, Mons, Belgium; 3Laboratory of Proteomic and Microbiology, Research Institute for Biosciences, University of Mons, Mons, Belgium; 4Centre for Comparative Genomics, Murdoch University, Perth, Australia; 5Laboratory of Physiology and experimental medicine, INSERM U1046, Montpellier, France FSHD affects about 1/17,000 individuals and is characterized by progressive skeletal muscle atrophy. FSHD1 (OMIM #158900) is linked to contractions of the D4Z4 repeat array in 4q35 whereas FSHD2 (OMIM #158901) is associated with mutations in SMCHD1, a chromatin modifier. In both FSHD types (i) D4Z4 DNA is hypomethylated, causing chromatin opening and expression of DUX4 (Double homeobox 4) the FSHD causal gene we have identified in D4Z4 elements; (ii) a 4qA permissive allele provides a polyA addition signal to stabilize DUX4 mRNAs. DUX4 protein is a transcription factor that initiates a large gene deregulation cascade leading to the major FSHD clinical features. The chromatin opening can induce other 4q35 genes such as DUX4c, a DUX4 homologue we have identified that encodes a truncated protein not sharing DUX4 toxicity. FSHD muscle sections reveal small angular atrophic fibers but also hypertrophic fibers and clusters of nuclei. In primary cultures FSHD myoblasts can fuse to myotubes similar to either fiber type: “atrophic” thin and elongated (aFSHD) or large “disorganized” tubes with clusters of nuclei (dFSHD), either type presenting a different proteomic profile. We have shown by gain and loss (siRNA; antisense oligonucleotides) of functions that DUX4 expression induced aFSHD myotubes. DUX4c expression induced differentiation defects involving proteins of the cytoskeleton or the contractile apparatus and nuclear clusters as seen in dFSHD myotubes. This phenotype was only suppressed by antisense agents targeting DUX4c. In aggregate our experiments suggest that besides DUX4, DUX4c should be an additional target of therapeutic approaches against FSHD. For lack of an appropriate transgenic mouse model, we performed naked DNA injection into lower limb muscles in the mouse. Two different lacZ reporter expression levels and patterns were found which could both be relevant for FSHD. DUX4/4c expression vectors are being used to evaluate the specific antisense agents.