Journal Article

CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1

Amanda J. Ward, Mendell Rimer, James M. Killian, James J. Dowling and Thomas A. Cooper

in Human Molecular Genetics

Volume 19, issue 18, pages 3614-3622
Published in print September 2010 | ISSN: 0964-6906
Published online July 2010 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddq277
CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1

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The neuromuscular disease myotonic dystrophy type I (DM1) affects multiple organ systems with the major symptoms being severe muscle weakness, progressive muscle wasting and myotonia. The causative mutation in DM1 is a CTG repeat expansion in the 3′-untranslated region of the DM protein kinase (DMPK) gene. RNA transcribed from the expanded allele contains the expanded CUG repeats and leads to the nuclear depletion of Muscleblind-like 1 (MBNL1) and to the increased steady-state levels of CUG-binding protein 1 (CUGBP1). The pathogenic effects of MBNL1 depletion have previously been tested by the generation of MBNL1 knockout mice, but the consequence of CUGBP1 overexpression in adult muscle is not known. In a DM1 mouse model expressing RNA containing 960 CUG repeats in skeletal muscle, CUGBP1 up-regulation is temporally correlated with severe muscle wasting. In this study, we generated transgenic mice with doxycycline-inducible and skeletal muscle-specific expression of CUGBP1. Adult mouse skeletal muscle overexpressing CUGBP1 reproduces molecular and physiological defects of DM1 tissue. The results from this study strongly suggest that CUGBP1 has a major role in DM1 skeletal muscle pathogenesis.

Journal Article.  5148 words.  Illustrated.

Subjects: Genetics and Genomics

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