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¹ Department of Physiology and Pharmacology, University of Rochester, Rochester, NY 14642
² Department of Neurology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642
³ Department of Molecular Genetics and Microbiology and the Genetic Institute, Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL 32610

Correspondence to Robert T. Dirksen: Robert_Dirksen{at}URMC.Rochester.edu

Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Transgenic mice engineered to express mRNA with expanded (CUG)₂₅₀ repeats (HSA^LR mice) exhibit prominent myotonia and altered splicing of muscle chloride channel gene (Clcn1) transcripts. We used whole-cell patch clamp recordings and nonstationary noise analysis to compare and biophysically characterize the magnitude, kinetics, voltage dependence, and single channel properties of the skeletal muscle chloride channel (ClC-1) in individual flexor digitorum brevis (FDB) muscle fibers isolated from 1–3-wk-old wild-type and HSA^LR mice. The results indicate that peak ClC-1 current density at –140 mV is reduced >70% (–48.5 ± 3.6 and –14.0 ± 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18–20- d-old HSA^LR mice. Nonstationary noise analysis revealed that the reduction in ClC-1 current density in HSA^LR FDB fibers results from a large reduction in ClC-1 channel density (170 ± 21 and 58 ± 11 channels/pF in control and HSA^LR fibers, respectively) and a modest decrease in maximal channel open probability(0.91 ± 0.01 and 0.75 ± 0.03, respectively). Qualitatively similar results were observed for ClC-1 channel activity in knockout mice for muscleblind-like 1 (Mbnl1^E3/E3), a second murine model of DM1 that exhibits prominent myotonia and altered Clcn1 splicing (Kanadia et al., 2003). These results support a molecular mechanism for myotonia in DM1 in which a reduction in both the number of functional sarcolemmal ClC-1 and maximal channel open probability, as well as an acceleration in the kinetics of channel deactivation, results from CUG repeat–containing mRNA molecules sequestering Mbnl1 proteins required for proper CLCN1 pre-mRNA splicing and chloride channel function.

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				G. Zifarelli and M. Pusch The Muscle Chloride Channel ClC-1 Is Not Directly Regulated by Intracellular ATP J. Gen. Physiol., February 1, 2008; 131(2): 109 - 116. [Abstract] [Full Text] [PDF]

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