Mutant channels contribute < 50% to Na+ current in paramyotonia congenita muscle

An important question in the pathophysiology of dominantly inherited diseas es, such as channelopathies, is the level of expression of the mutant prote in. In our study, we address this issue by comparing the gating defects of two human muscle Na+ channel mutants (R1448C and R1448P) causing paramyoton ia congenita in native muscle specimens from two patients with those of the same mutant recombinant channels expressed in human embryonic kidney (HEK- 293) cells. Patch-clamp recordings of transfected HEK-293 cells revealed a pronounced slowing of the Na+ current decay, a left-shifted and decreased v oltage dependence of steady-state inactivation, and an increased frequency of channel reopenings for mutant compared with wild-type channels, For R144 8P channels, inactivation was almost six-fold and for R1448C it was three-f old slower than for wildtype channels. The same defects, though less pronou nced, as expected for a disorder with dominant inheritance, were observed f or muscle specimens from paramyotonia congenita patients carrying these mut ations. Quantitative kinetic analysis of Na+ channel inactivation in the pa ramyotonic muscle specimens separating wild-type from mutant channels sugge sted that no more than 38% of the channels in the paramyotonia congenita mu scle specimen were of the mutant type. Our data raise the possibility that variability in the ratio of mutant to wild-type Na+ channels in the muscle membrane has an impact on the clinical severity of the phenotype.