Paramyotonia congenita: the R1448P Na+ channel mutation in adult human skeletal muscle.

Twitch force and Na+ currents were investigated in a muscle biopsy specimen from a patient with paramyotonia congenita carrying the dominant Arg-1448-Pro mutation in the skeletal muscle sodium channel. Cooling of the muscle fibers caused sustained membrane depolarization that resulted in reduced twitch force. Membrane repolarization, produced by a K+ channel opener, partly prevented and antagonized the drop in twitch force. Patch-clamp recordings on sarcolemmal blebs revealed a distinctly slower Na+ current decay on paramyotonia congenita muscle compared to control muscle. In addition, patches with mutant Na+ channels showed a significantly higher frequency of steady-state openings, which increased with cooling. Activation of mutant channels was not affected, whereas the steady-state inactivation curve was shifted by -5 mV and showed less voltage dependence. We suggest that the weakness of cooled muscle can be explained by a combination of the increased steady-state Na+ current and the left-shifted inactivation curve.