Different degrees of loss of function between GEFS+ and SMEI Nav1.1 missense mutants at the same residue induced by rescuable folding defects


Address correspondence to Yoshihiro Sugiura, Department of Neurology, School of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan. E-mail: y-sugiura@umin.ac.jp


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 Nav1.1 sodium channel are responsible for both disorders. We compared the electrophysiologic properties of two mutant Nav1.1 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 β1 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.