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J Neurosci 2006 Mar 08;2610:2714-23. doi: 10.1523/JNEUROSCI.2977-05.2006.
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An epilepsy mutation in the sodium channel SCN1A that decreases channel excitability.

Barela AJ , Waddy SP , Lickfett JG , Hunter J , Anido A , Helmers SL , Goldin AL , Escayg A .

Mutations in three voltage-gated sodium channel genes, SCN1A, SCN2A, and SCN1B, and two GABAA receptor subunit genes, GABRG2 and GABRD, have been identified in families with generalized epilepsy with febrile seizures plus (GEFS+). A novel mutation, R859C, in the Nav1.1 sodium channel was identified in a four-generation, 33-member Caucasian family with a clinical presentation consistent with GEFS+. The mutation neutralizes a positively charged arginine in the domain 2 S4 voltage sensor of the Nav1.1 channel alpha subunit. This residue is conserved in mammalian sodium channels as well as in sodium channels from lower organisms. When the mutation was placed in the rat Nav1.1 channel and expressed in Xenopus oocytes, the mutant channel displayed a positive shift in the voltage dependence of sodium channel activation, slower recovery from slow inactivation, and lower levels of current compared with the wild-type channel. Computational analysis suggests that neurons expressing the mutant channel have higher thresholds for firing a single action potential and for firing multiple action potentials, along with decreased repetitive firing. Therefore, this mutation should lead to decreased neuronal excitability, in contrast to most previous GEFS+ sodium channel mutations, which have changes predicted to increase neuronal firing.

PubMed ID: 16525050
PMC ID: PMC6675156
Article link: J Neurosci
Grant support: [+]

Species referenced: Xenopus
Genes referenced: gabarap gabrd gabrg2 nav1 scn1a scn1b scn2a

References [+] :
Abou-Khalil, Partial and generalized epilepsy with febrile seizures plus and a novel SCN1A mutation. 2001, Pubmed