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Am J Physiol Cell Physiol (November 29, 2006). doi:10.1152/ajpcell.00336.2006
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Submitted on June 19, 2006
Accepted on November 21, 2006

Chloride channelopathy in myotonic dystrophy resulting from loss of post-transcriptional regulation for CLCN1

John D. Lueck1, Codrin Lungu2, Ami Mankodi2, Robert Osborne2, Stephen Welle3, Robert T. Dirksen4, and Charles A Thornton5*

1 Department of Pharmacology and Physiology, University of Rochester, Rochester, New York, United States
2 Department of Neurology, University of Rochester, Rochester, New York, United States
3 Endocrinology Unit, University of Rochester Medical Center, Rochester, New York, United States
4 Department of Pharmacology and Physiology, University of Rochester, United States
5 Neurology, University of Rochester School of Medicine and Dentistry

* To whom correspondence should be addressed. E-mail: charles_thornton{at}urmc.rochester.edu.

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 versus post-transcriptional regulation are unknown. Here we show that alternative splicing of CLCN1 undergoes a physiological splicing transition during the first three weeks 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 post-transcriptional 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.




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