Neurology 2004 Dec 28;6312:2371-5. doi: 10.1212/01.wnl.0000148482.40683.88.

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

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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.

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Species referenced: Xenopus laevis
Genes referenced: clcn1