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Human Molecular Genetics, 2000, Vol. 9, No. 15 2313-2320
© 2000 Oxford University Press

Skeletal muscle sodium channel gating in mice deficient in myotonic dystrophy protein kinase

J. Paul Mounsey1,3,+, Dilaawar J. Mistry1, Cui Wei Ai4, Sita Reddy4 and J. Randall Moorman1,2,3

1Department of Internal Medicine (Cardiovascular Division), 2Department of Molecular Physiology and Biological Physics and 3The Cardiovascular Research Center University of Virginia Health System, Charlottesville, VA 22908, USA and 4Institute for Genetic Medicine, University of Southern California, School of Medicine, Los Angeles, CA 90033, USA

Myotonic dystrophy, a progressive autosomal dominant disorder, is associated with an expansion of a CTG repeat tract located in the 3'-untranslated region of a serine/threonine protein kinase, DMPK. DMPK modulates skeletal muscle Na channels in vitro, and thus we hypothesized that mice deficient in DMPK would have altered muscle Na channel gating. We measured macroscopic and single channel Na currents from cell-attached patches of skeletal myocytes from mice heterozygous (DMPK+/–) and homozygous (DMPK–/–) for DMPK loss. In DMPK–/– myocytes, Na current amplitude was reduced because of reduced channel number. Single channel recordings revealed Na channel reopenings, similar to the gating abnormality of human myotonic muscular dystrophy (DM), which resulted in a plateau of Na current. The gating abnormality deteriorated with increasing age. In DMPK+/– muscle there was reduced Na current amplitude and increased Na channel reopenings identical to those in DMPK–/– muscle. Thus, these mouse models of complete and partial DMPK deficiency reproduce the Na channel abnormality of the human disease, providing direct evidence that DMPK deficiency underlies the Na channel abnormality in DM.

+ To whom correspondence should be addressed at: University of Virginia Health System, Box 801395, MR4 Building, Charlottesville, VA 22908, USA. Tel: +1 804 982 3367; Fax: +1 804 982 3162: Email: pmounsey@ virginia.edu


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