Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing |
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Authors: | Charlet-B Nicolas Savkur Rajesh S Singh Gopal Philips Anne V Grice Elizabeth A Cooper Thomas A |
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Institution: | Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA. |
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Abstract: | Myotonic dystrophy type 1 (DM1) is a dominant multisystemic disorder caused by a CTG expansion in the 3' untranslated region of the DMPK gene. A predominant characteristic of DM1 is myotonia resulting from skeletal muscle membrane hyperexcitability. Here we demonstrate loss of the muscle-specific chloride channel (ClC-1) mRNA and protein in DM1 skeletal muscle tissue due to aberrant splicing of the ClC-1 pre-mRNA. The splicing regulator, CUG binding protein (CUG-BP), which is elevated in DM1 striated muscle, binds to the ClC-1 pre-mRNA, and overexpression of CUG-BP in normal cells reproduces the aberrant pattern of ClC-1 splicing observed in DM1 skeletal muscle. We propose that disruption of alternative splicing regulation causes a predominant pathological feature of DM1. |
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