Skeletal Muscle Sodium Channel Is Affected by an Epileptogenic β1 Subunit Mutation

Abstract

The syndrome of generalized epilepsy with febrile seizures plus type 1 (GEFS+) has been associated to the gene SCN1B coding for the sodium channel β1 subunit (Wallace, R. H. et al. (1998) Nature Genetics 19, 366–370). In patients, a mutation of the cysteine 121 to trpyptophane (C121W) would cause a lack of modulatory activity of the β1 subunit on sodium channels expressed in the brain, rendering neurons hyperexcitable. We have confirmed that the normal β1-modulation of type-IIA adult brain α subunits (BIIA) expressed in frog oocytes is defective in C121W. We observed that the mixture of wild-type and mutant β1 subunits is less effective than wild-type alone, suggesting that the mutant β1 subunit does bind the α subunit. However, we also observed a similar lack of modulation by C121W of the in adult skeletal muscle α subunit (SkM1). This finding is in contrast with the simple idea that the mutational effect observed in the oocyte expression system is the principal physiopathological correlate of GEFS+, because no skeletal muscle symptoms have been reported in GEFS+ patients. We conclude that the manifestation of the pathological phenotype is conditioned by the presence of susceptibility genes and/or that the frog oocyte expression system is inadequate for the study of the mutant β1 subunit physiopathology.