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Truncated ClC-1 mRNA in myotonic dystrophy exerts a dominant-negative effect on the Cl current

From the Department of Neurobiology (J. Berg), Harvard Medical School, Boston, MA; Department of Neurology (Drs. Jiang and Thornton), University of Rochester Medical Center, NY; and Department of Neurology (Dr. Cannon), UT Southwestern Medical Center, Dallas, TX.

Address correspondence and reprint requests to Dr. Stephen Cannon, Department of Neurology, 5323 Harry Hines Boulevard, UT Southwestern Medical Center, Dallas, TX 75390-9039; e-mail: steve.cannon{at}utsouthwestern.edu

Background: Muscle fiber degeneration and myotonic discharges are the hallmarks of myotonic dystrophy (DM). The molecular basis for the myotonia was recently tied to abnormal splicing of the chloride channel (ClC-1) pre-mRNA, often resulting in UAG premature termination, which leads to decreased channel protein and therefore a reduced resting chloride conductance.

Methods: The authors assessed the functional properties of two commonly occurring DM mRNA splice variants by expression in oocytes.

Results: Neither splice variant coded for a functional Cl^– channel. Co-injection of alternative splice variants with wild-type ClC-1 cRNA reduced the current density and accelerated channel closure upon repolarization of the membrane.

Conclusions: These data show that the aberrantly spliced chloride channel message exerts a dominant negative effect that may contribute to the development of myotonia.

Received December 31, 2003. Accepted in final form September 3, 2004.

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