Temperature Sensitive Defects in Paramyotonia Congenita Mutants R1448C and T1313M

The biophysical origins of paramyotonia congenita and its exacerbation in cold temperatures were examined. Human skeletal muscle voltage-gated sodium channels were expressed in Xenopus oocytes and macroscopic currents were recorded from cell-attached patches. Wild-type (hNaV1.4) channels were compared to two mutant channel isoforms, T1313M and R1448C. The voltage dependence and temperature sensitivity of activation, fast-inactivation onset and recovery, and deactivation were studied. Although activation and the onset of fast-inactivation were temperature sensitive in all three isoforms, and although these properties in mutant channels differed from those in wild-type channels, they did not account for cold-exacerbation. Deactivation, however, was disproportionately slower in R1448C, but not in T1313M, than in hNaV1.4. These defects may, at least in part, account for the clinical symptoms of paramyotonia congenita and its exacerbation by cold, and provide a basis for studies into the therapeutic alleviation of these symptoms