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Hum Mol Genet. 2010 Sep 15;19(18):3614-22. doi: 10.1093/hmg/ddq277. Epub 2010 Jul 5.

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

Author information

1
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

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.

PMID:
20603324
PMCID:
PMC2928132
DOI:
10.1093/hmg/ddq277
[Indexed for MEDLINE]
Free PMC Article

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