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Am J Physiol Cell Physiol 292: C1291-C1297, 2007. First published November 29, 2006; doi:10.1152/ajpcell.00336.2006
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Chloride channelopathy in myotonic dystrophy resulting from loss of posttranscriptional regulation for CLCN1

John D. Lueck,1,* Codrin Lungu,2,* Ami Mankodi,2 Robert J. Osborne,2 Stephen L. Welle,3 Robert T. Dirksen,1 and Charles A. Thornton2

Departments of 1Pharmacology and Physiology, 2Neurology, and 3Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York

Submitted 19 June 2006 ; accepted in final form 21 November 2006

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.

chloride channel 1; nonsense-mediated decay; alternative splicing; CUG repeats; developmental regulation; muscular dystrophy; ion channel


Address for reprint requests and other correspondence: C. A. Thornton, Dept. of Neurology, Box 673, Rm. 5-5207, 601 Elmwood Ave., Univ. of Rochester Medical Center, Rochester, NY 14642 (e-mail: Charles_Thornton{at}urmc.rochester.edu)




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