Molecular Cell
Volume 10, Issue 1, July 2002, Pages 45-53
Journal home page for Molecular Cell

Article
Loss of the Muscle-Specific Chloride Channel in Type 1 Myotonic Dystrophy Due to Misregulated Alternative Splicing

https://doi.org/10.1016/S1097-2765(02)00572-5Get rights and content
Under an Elsevier user license
open archive

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.

Cited by (0)

4

These authors contributed equally to this work.

5

Present address: Lexicon Genetics Inc., The Woodlands, Texas 77381.

6

Present address: Wilmer Eye Institute, The Johns Hopkins School of Medicine, Baltimore, Maryland 21287.