Modulatory proteins can rescue a trafficking defective epileptogenic Nav1.1 (SCN1A) Na+ channel mutant

Familial epilepsies are often caused by mutations of voltage-gated Na ⁺ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na_v1.1 (SCN1A) Na⁺ channel α subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function becausewhenexpressed alone, the current was no greater than background. Function was restored by incubation at temperature <30°C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na⁺ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo. Copyright © 2007 Society for Neuroscience.