A NOVEL SODIUM-CHANNEL MUTATION CAUSING A HYPERKALEMIC PARALYTIC AND PARAMYOTONIC SYNDROME WITH VARIABLE CLINICAL EXPRESSIVITY

A point mutation A4078G predicting the amino acid exchange Met1360Val in segment IV/S1 of the human muscle sodium channel alpha-subunit was identified in a family presenting features of hyperkalemic periodic pa ralysis and paramyotonia congenita with sex-related modification of ex pression. In this family, only one male member is clinically affected, presenting episodes of flaccid weakness as well as paradoxical myoton ia and cold-induced weakness. Three female family members who have the same mutation show only myotonic bursts on EMG. We studied the functi onal defect caused by this mutation by investigating recombinant wild type (WT) and mutant; sodium channels expressed ina mammalian cell lin e (HEK293) using the patch-clamp technique. With mutant channels, the decay of the sodium currents was two times slower than with WT, the st eady-state inactivation curve was shifted by -13 mV, and recovery from inactivation was 1.5 times faster. High extracellular potassium (9 mM ) did not affect channel gating. Single-channel measurements revealed prolonged mean open times and an increased number of channel reopening s. The results are remarkable with respect to the lack of complete pen etrance usually seen with sodium channelopathies and the site of mutat ion that was formerly not thought to be involved in channel inactivati on.