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

Summary 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.