[PDF][PDF] Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing

N Charlet-B, RS Savkur, G Singh, AV Philips, EA Grice… - Molecular cell, 2002 - cell.com
N Charlet-B, RS Savkur, G Singh, AV Philips, EA Grice, TA Cooper
Molecular cell, 2002cell.com
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 …
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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