Skeletal muscle Na currents in mice heterozygous for Six5 deficiency.
Myotonic dystrophy results from a trinucleotide repeat expansion between the myotonic dystrophy protein kinase gene (Dmpk), which encodes a serine-threonine protein kinase, and the Six5 gene, which encodes a homeodomain protein. The disease is characterized by late bursts of skeletal muscle Na channel openings, and this is recapitulated in Dmpk -/- and Dmpk +/- murine skeletal muscle. To test whether deficiency of the nearby Six5 gene also affected Na channel gating in murine skeletal muscle, we measured Na currents from cell-attached patches in Six5 +/- mice and age-matched wild-type and Dmpk +/- mice. Late bursts of Na channel activity were defined as an opening probability >10% measured from 10 to 110 ms after depolarization. There was no significant difference in the occurrence of late Na channel bursts in wild-type and Six5 +/- muscle, whereas in Dmpk +/- muscle there was greater than fivefold increase in late bursts (P < 0.001). Compared with wild-type mice, Na current amplitude was unchanged in Six5 +/- muscle, whereas in Dmpk +/- muscle it was 36% reduced (P < 0.05). Thus, since Six5 +/- mice do not exhibit the Na channel gating abnormality of Dmpk deficiency, we conclude that Six5 deficiency does not contribute to the Na channel gating abnormality seen in dystrophia myotonica patients.
Mistry
D J
DJ
Cardiovascular Division, Department of Internal Medicine, Cardiovascular Research Center, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Moorman
J R
JR
Reddy
S
S
Mounsey
J P
JP
D000818:Animals; D005838:Genotype; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000502:physiology*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D015222:Sodium Channels / Q000502:physiology*; D013997:Time Factors
C585516:DMPK protein, mouse; D018398:Homeodomain Proteins; C486344:Six5 protein, mouse; D015222:Sodium Channels; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases