Modulatory Proteins Can Rescue a Trafficking Defective Epileptogenic Nav1.1 Na+Channel Mutant

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Abstract
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 Nav1.1 (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 because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature +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 mutationin vivoand 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 mutantin vivo.