Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy

Authors

  • Minqi Hao,

    1. Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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    • Drs. Hao and Akrami contributed equally to this work.

  • Kevan Akrami,

    1. Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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    • Drs. Hao and Akrami contributed equally to this work.

  • Ke Wei,

    1. Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
    2. Molecular Cellular and Integrative Physiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Carlos De Diego,

    1. Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Nam Che,

    1. Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Jeong-Hee Ku,

    1. Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • James Tidball,

    1. Molecular Cellular and Integrative Physiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Michael C. Graves,

    1. Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Perry B. Shieh,

    1. Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
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  • Fabian Chen

    Corresponding author
    1. Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
    2. Molecular Cellular and Integrative Physiology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
    3. Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
    • David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095-1760
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Abstract

Myotonic dystrophy (DM), the most common adult-onset muscular dystrophy, is caused by CTG or CCTG microsatellite repeat expansions. Expanded DM mRNA microsatellite repeats are thought to accumulate in the nucleus, sequester Muscleblind proteins, and interfere with alternative mRNA splicing. Muscleblind2 (Mbnl2) is a member of the family of Muscleblind RNA binding proteins (that also include Mbnl1 and Mbnl3) that are known to bind CTG/CCTG RNA repeats. Recently, it was demonstrated that Mbnl1-deficient mice have characteristic features of human DM, including myotonia and defective chloride channel expression. Here, we demonstrate that Mbnl2-deficient mice also develop myotonia and have skeletal muscle pathology consistent with human DM. We also find defective expression and mRNA splicing of the chloride channel (Clcn1) in skeletal muscle that likely contributes to the myotonia phenotype. Our results support the hypothesis that Muscleblind proteins and specifically MBNL2 contribute to the pathogenesis of human DM. Developmental Dynamics 237:403–410, 2008. © 2008 Wiley-Liss, Inc.

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