Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus

Abstract

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel beta1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations-D188V, V1353L, and I1656M-were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%.

Figure 1

GEFS+ pedigrees. DNA was not available from those individuals not assigned a letter (X, Y, or Z) or a 0. A, Australian family, with numbering based on figure 1 in the article by Scheffer and Berkovic (1997). B, Ashkenazi family. C, Druze family.

Figure 2

SCN1A mutations. A, Schematic of SCN1A, showing positions of the three mutations identified in this study. B, Sodium-channel amino acid alignments, showing alignment of sodium-channel amino acids surrounding the three SCN1A mutations.