DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo

Authors

  • Lindsay M. Wallace BA,

    1. Molecular, Cellular, and Developmental Biology Graduate Program, Ohio State University, Columbus, OH
    2. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Sara E. Garwick BS,

    1. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Wenyan Mei PhD,

    1. Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH
    2. Center for Molecular and Human Genetics, Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Alexandra Belayew PhD,

    1. Laboratory of Molecular Biology, University Academy Wallonie-Bruxelles, University of Mons, Mons, Belgium
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  • Frederique Coppee PhD,

    1. Laboratory of Molecular Biology, University Academy Wallonie-Bruxelles, University of Mons, Mons, Belgium
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  • Katherine J. Ladner PhD,

    1. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH
    2. Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, OH
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  • Denis Guttridge PhD,

    1. Molecular, Cellular, and Developmental Biology Graduate Program, Ohio State University, Columbus, OH
    2. Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH
    3. Arthur G. James Comprehensive Cancer Center, Ohio State University, Columbus, OH
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  • Jing Yang PhD,

    1. Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH
    2. Center for Molecular and Human Genetics, Research Institute at Nationwide Children's Hospital, Columbus, OH
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  • Scott Q. Harper PhD

    Corresponding author
    1. Molecular, Cellular, and Developmental Biology Graduate Program, Ohio State University, Columbus, OH
    2. Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, Columbus, OH
    3. Department of Pediatrics, Ohio State University College of Medicine, Columbus, OH
    • Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Room WA3015, Columbus, OH 43205
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Abstract

Objective:

Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading FSHD pathogenesis models, D4Z4 contractions are proposed to cause epigenetic changes, which ultimately increase expression of genes with myopathic potential. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4-encoded DUX4 gene in FSHD. In this study, our objective was to test the in vivo myopathic potential of DUX4.

Methods:

We delivered DUX4 to zebrafish and mouse muscle by transposon-mediated transgenesis and adeno-associated viral vectors, respectively.

Results:

Overexpression of DUX4, which encodes a transcription factor, caused abnormalities associated with muscular dystrophy in zebrafish and mice. This toxicity required DNA binding, because a DUX4 DNA binding domain mutant produced no abnormalities. Importantly, we found the myopathic effects of DUX4 were p53 dependent, as p53 inhibition mitigated DUX4 toxicity in vitro, and muscles from p53 null mice were resistant to DUX4-induced damage.

Interpretation:

Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53-dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis. Ann Neurol 2010

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