title: Loss of the muscle-specific chloride channel in type 1 myotonic dystrophy due to misregulated alternative splicing.
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.
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-B
authors.forename: Rajesh S
authors.initials: RS
authors.lastname: Savkur
authors.forename: Gopal
authors.initials: G
authors.lastname: Singh
authors.forename: Anne V
authors.initials: AV
authors.lastname: Philips
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grice
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Cooper
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D018118:Chloride Channels / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009223:Myotonic Dystrophy / Q000145:classification / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D012322:RNA Precursors; D012333:RNA, Messenger