Different degrees of loss of function between GEFS+ and SMEI Nav 1.1 missense mutants at the same residue induced by rescuable folding defects

Abstract

Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy of infancy (SMEI) differ in their clinical severity and prognosis even though mutations of the Na(v) 1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Na(v) 1.1 channels characterized by distinct amino acid substitutions at the same residue position: GEFS+ (A1685V) and SMEI (A1685D). Both the mutants showed complete loss of function when expressed alone. However, the function of A1685V can be partly rescued by the β(1) subunit, consistently with a folding defect, whereas that of A1685D was not rescued. These electrophysiologic differences are consistent with the divergence in clinical severity between GEFS+ and SMEI.