Sodium channel dysfunction in intractable childhood epilepsy with generalized tonic–clonic seizures

摘要: Mutations in SCN1A, the gene encoding brain voltage-gated sodium channel alpha(1) subunit (Na(V)1.1), are associated with genetic forms of epilepsy, including generalized epilepsy febrile seizures plus (GEFS+ type 2), severe myoclonic infancy (SMEI) and related conditions. Several missense SCN1A mutations have been identified probands affected by syndrome intractable childhood tonic-clonic (ICEGTC), which bears similarity to SMEI. To test whether ICEGTC arises from molecular mechanisms similar those involved SMEI, we characterized eight whole-cell patch clamp recording recombinant human heterologously expressed cultured mammalian cells. Two (G979R T1709I) were non-functional. The remaining alleles (T808S, V983A, N1011I, V1611F, P1632S F1808L) exhibited measurable current, but had heterogeneous biophysical phenotypes. Mutant channels lower (V983A, N1011I F1808L), greater (T808S) or (V1611F P1632S) peak current densities compared wild-type (WT) SCN1A. Three (V1611F, displayed hyperpolarized conductance-voltage relationships, while V983A a strong depolarizing shift voltage dependence activation. All mutants except T808S shifts steady-state availability. persistent ranging approximately 1-3% amplitude that was significantly than WT-SCN1A. impaired slow inactivation, showing most prominent effect. Finally, all functional reduced use-dependent inhibition. In summary, result wide spectrum defects, mild-to-moderate gating impairments, shifted use dependence. constellation abnormalities for some is distinct previously observed GEFS+ suggesting possible, complex, genotype-phenotype correlations.