Skeletal muscle Na currents in mice heterozygous for Six5 deficiency

Myotonic dystrophy results from a trinucleotide repeat expansion between th e myotonic dystrophy protein kinase gene (Dmpk), which encodes a serine-thr eonine protein kinase, and the Six5 gene, which encodes a homeodomain prote in. The disease is characterized by late bursts of skeletal muscle Na chann el openings, and this is recapitulated in Dmpk -/- and Dmpk +/- murine skel etal muscle. To test whether deficiency of the nearby Six5 gene also affect ed Na channel gating in murine skeletal muscle, we measured Na currents fro m 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 pr obability >10% measured from 10 to 110 ms after depolarization. There was n o significant difference in the occurrence of late Na channel bursts in wil d-type and Six5 +/- muscle, whereas in Dmpk +/- muscle there was greater th an fivefold increase in late bursts (P< 0.001). Compared with wild-type mic e, 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 ex hibit the Na channel gating abnormality of Dmpk deficiency, we conclude tha t Six5 deficiency does not contribute to the Na channel gating abnormality seen in dystrophia myotonica patients.