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Inhibition of nonsense-mediated mRNA decay rescues the phenotype in Ullrich's disease

Authors

  • Fusako Usuki MD,

    Corresponding author
    1. Department of Clinical Medicine, National Institute for Minamata Disease, Hama, Minamata, Japan
    • Department of Clinical Medicine, National Institute for Minamata Disease, 4058-18 Hama, Minamata 867-0008, Japan
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  • Akio Yamashita PhD,

    1. Department of Molecular Biology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan
    Current affiliation:
    1. Department of Biochemistry and Molecular Biology, University of Texas, Houston, TX 77030
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  • Itsuro Higuchi MD,

    1. Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima, Japan
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  • Tetsuo Ohnishi PhD,

    1. Department of Molecular Biology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan
    Current affiliation:
    1. Laboratory for Molecular Psychiatry, Brain Science Institute, RIKEN, WAKO 351-0198, Japan
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  • Tadafumi Shiraishi MD,

    1. Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima, Japan
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  • Mitsuhiro Osame MD,

    1. Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Science, 8-35-1 Sakuragaoka, Kagoshima, Japan
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  • Shigeo Ohno PhD

    1. Department of Molecular Biology, Yokohama City University School of Medicine, Kanazawa-ku, Yokohama, Japan
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Abstract

Nonsense-mediated mRNA decay (NMD) is an mRNA surveillance system that eliminates aberrant mRNAs containing premature translation termination codons (PTCs). We evaluated the role of NMD in of Ullrich's disease. The patient has a frameshift mutation with a PTC in the collagen VI α2 gene causing the loss of collagen VI and functional defects in extracellular matrix (ECM). The pharmacological block of NMD caused upregulation of the mutant collagen VI α2 subunit, resulting in collagen VI assembly and partially functional ECM formation. Our results suggest that NMD inhibitors can be used as a therapeutic tool to rescue some human genetic diseases exacerbated by NMD.

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