期刊
JOURNAL OF NEUROSCIENCE
卷 27, 期 41, 页码 11037-11046出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3515-07.2007
关键词
sodium; current; epilepsy; excitability; trafficking; GEFS; SMEI; seizure; SCN1A
Familial epilepsies are often caused by mutations of voltage-gated Na+ channels, but correlation genotype-phenotype is not yet clear. In particular, the cause of phenotypic variability observed in some epileptic families is unclear. We studied Na(v)1.1 (SCN1A) Na+ channel alpha subunit M1841T mutation, identified in a family characterized by a particularly large phenotypic spectrum. The mutant is a loss of function because when expressed alone, the current was no greater than background. Function was restored by incubation at temperature <30 degrees C, showing that the mutant is trafficking defective, thus far the first case among neuronal Na+ channels. Importantly, also molecular interactions with modulatory proteins or drugs were able to rescue the mutant. Protein-protein interactions may modulate the effect of the mutation in vivo and thus phenotype; variability in their strength may be one of the causes of phenotypic variability in familial epilepsy. Interacting drugs may be used to rescue the mutant in vivo.
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