title: Chloride channelopathy in myotonic dystrophy resulting from loss of posttranscriptional regulation for CLCN1.
abstract: Transmembrane chloride ion conductance in skeletal muscle increases during early postnatal development. A transgenic mouse model of myotonic dystrophy type 1 (DM1) displays decreased sarcolemmal chloride conductance. Both effects result from modulation of chloride channel 1 (CLCN1) expression, but the respective contributions of transcriptional vs. posttranscriptional regulation are unknown. Here we show that alternative splicing of CLCN1 undergoes a physiological splicing transition during the first 3 wk of postnatal life in mice. During this interval, there is a switch to production of CLCN1 splice products having an intact reading frame, an upregulation of CLCN1 mRNA encoding full-length channel protein, and an increase of CLCN1 function, as determined by patch-clamp analysis of single muscle fibers. In a transgenic mouse model of DM1, however, the splicing transition does not occur, CLCN1 channel function remains low throughout the postnatal interval, and muscle fibers display myotonic discharges. Thus alternative splicing is a posttranscriptional mechanism regulating chloride conductance during muscle development, and the chloride channelopathy in a transgenic mouse model of DM1 results from a failure to execute a splicing transition for CLCN1.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Lueck
authors.forename: Codrin
authors.initials: C
authors.lastname: Lungu
authors.forename: Ami
authors.initials: A
authors.lastname: Mankodi
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Osborne
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Welle
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dirksen
authors.forename: Charles A
authors.initials: CA
authors.lastname: Thornton
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D053447:Channelopathies / Q000235:genetics / Q000378:metabolism*; D018118:Chloride Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D051379:Mice; D008822:Mice, Transgenic; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism*; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000096:biosynthesis; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: C086321:CLC-1 channel; D018118:Chloride Channels; D020033:Protein Isoforms; D012333:RNA, Messenger