Characterization of a new sodium channel mutation at arginine 1448 associated with moderate paramyotonia, congenita in humans

1. Paramyotonia congenita is a temperature-sensitive skeletal muscle disord er caused by missense mutations that occur in the adult skeletal muscle vol tage-gated sodium channel. We report here the identification of a new genet ic mutation in a family with the paramyotonia congenita phenotype. 2. Single-strand conformation polymorphism analysis a,nd DNA sequencing sho wed that the defect was linked to a single nucleotide substitution causing an amino acid change from an arginine to a serine at position 1448 in the h uman sodium channel alpha-subunit. 3. Expression of the altered protein in human embryonic kidney (HEK) 293 ce lls revealed several defects in channel function: (i) the rate of fast inac tivation was slower in the mutant channel compared with wild-type, (ii) ste ady-state fast inactivation was shifted towards hyperpolarizing potentials, (iii) the R1448S channels deactivated much more slowly, and (iv) the mutan t channels recovered from the fast inactivated state more rapidly. 4. By contrast, the activation curve, steady-state slow inactivation and th e rate of onset and recovery from slow inactivation were not altered by the R1448S mutation. 5. These data show that the defects observed in the sodium channel function could well explain the onset of the paramyotonia congenita in this family and emphasize the role of segment S4 of domain IV in sodium channel inactiv ation.