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Abstract
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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