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.
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.
Authors: Zhen Zhi Tang; Viktor Yarotskyy; Lan Wei; Krzysztof Sobczak; Masayuki Nakamori; Katy Eichinger; Richard T Moxley; Robert T Dirksen; Charles A Thornton Journal: Hum Mol Genet Date: 2011-12-02 Impact factor: 6.150
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