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

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.