The FSHD atrophic myotube phenotype is caused by DUX4 expression

B.P. Chadwick; C. Vanderplanck; E. Ansseau; S. Charron; N. Stricwant; A. Tassin; D. Laoudj-Chenivesse; S.D. Wilton; F. Coppée; A. Belayew

doi:10.1371/journal.pone.0026820

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The FSHD atrophic myotube phenotype is caused by DUX4 expression

Journal article

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The FSHD atrophic myotube phenotype is caused by DUX4 expression

B.P. Chadwick, C. Vanderplanck, E. Ansseau, S. Charron, N. Stricwant, A. Tassin, D. Laoudj-Chenivesse, S.D. Wilton, F. Coppée and A. Belayew

PLoS ONE, Vol.6(10), e26820

2011

DOI: https://doi.org/10.1371/journal.pone.0026820

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Abstract

Background: Facioscapulohumeral muscular dystrophy (FSHD) is linked to deletions in 4q35 within the D4Z4 repeat array in which we identified the double homeobox 4 (DUX4) gene. We found stable DUX4 mRNAs only derived from the most distal D4Z4 unit and unexpectedly extended to the flanking pLAM region that provided an intron and a polyadenylation signal. DUX4 encodes a transcription factor expressed in FSHD but not control primary myoblasts or muscle biopsies. The DUX4 protein initiates a large transcription deregulation cascade leading to muscle atrophy and oxidative stress, which are FSHD key features. Methodology/Principal Findings: We now show that transfection of myoblasts with a DUX4 expression vector leads to atrophic myotube formation associated with the induction of E3 ubiquitin ligases (MuRF1 and Atrogin1/MAFbx) typical of muscle atrophy. DUX4 induces expression of downstream targets deregulated in FSHD such as mu-crystallin and TP53. We developed specific siRNAs and antisense oligonucleotides (AOs) targeting the DUX4 mRNA. Addition of these antisense agents to primary FSHD myoblast cultures suppressed DUX4 protein expression and affected expression of the abovementioned markers. Conclusions/Significance: These results constitute a proof of concept for the development of therapeutic approaches for FSHD targeting DUX4 expression.

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Title: The FSHD atrophic myotube phenotype is caused by DUX4 expression
Authors/Creators: B.P. Chadwick (Author/Creator)
C. Vanderplanck (Author/Creator) - University of Mons
E. Ansseau (Author/Creator) - University of Mons
S. Charron (Author/Creator) - University of Mons
N. Stricwant (Author/Creator) - University of Mons
A. Tassin (Author/Creator) - University of Mons
D. Laoudj-Chenivesse (Author/Creator) - Hôpital Arnaud de Villeneuve
S.D. Wilton (Author/Creator) - The University of Western Australia
F. Coppée (Author/Creator) - University of Mons
A. Belayew (Author/Creator) - University of Mons
Publication Details: PLoS ONE, Vol.6(10), e26820
Publisher: Public Library of Science
Identifiers: 991005539588907891
Copyright: 2011 Vanderplanck et al.
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.255 Musculoskeletal Disorders; 1.255.628 Duchenne Muscular Dystrophy
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics