title: A missense mutation of the gene encoding voltage-dependent sodium channel (Nav1.1) confers susceptibility to febrile seizures in rats.
abstract: Although febrile seizures (FSs) are the most common convulsive syndrome in infants and childhood, the etiology of FSs has remained unclarified. Several missense mutations of the Na(v)1.1 channel (SCN1A), which alter channel properties, have been reported in a familial syndrome of GEFS+ (generalized epilepsy with febrile seizures plus). Here, we generated Scn1a-targeted rats carrying a missense mutation (N1417H) in the third pore region of the sodium channel by gene-driven ENU (N-ethyl-N-nitrosourea) mutagenesis. Despite their normal appearance under ordinary circumstances, Scn1a mutant rats exhibited remarkably high susceptibility to hyperthermia-induced seizures, which involve generalized clonic and/or tonic-clonic convulsions with paroxysmal epileptiform discharges. Whole-cell patch-clamp recordings from HEK cells expressing N1417H mutant channels and from hippocampal GABAergic interneurons of N1417H mutant rats revealed a significant shift of the inactivation curve in the hyperpolarizing direction. In addition, clamp recordings clearly showed the reduction in action potential amplitude in the hippocampal interneurons of these rats. These findings suggest that a missense mutation (N1417H) of the Na(v)1.1 channel confers susceptibility to FS and the impaired biophysical properties of inhibitory GABAergic neurons underlie one of the mechanisms of FS.
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. tmashimo@anim.med.kyoto-u.ac.jp
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.forename: Iori
authors.initials: I
authors.lastname: Ohmori
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ouchida
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohno
authors.forename: Toshiko
authors.initials: T
authors.lastname: Tsurumi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Miki
authors.forename: Minoru
authors.initials: M
authors.lastname: Wakamori
authors.forename: Shizuka
authors.initials: S
authors.lastname: Ishihara
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Akiko
authors.initials: A
authors.lastname: Takizawa
authors.forename: Megumi
authors.initials: M
authors.lastname: Kato
authors.forename: Masumi
authors.initials: M
authors.lastname: Hirabayashi
authors.forename: Masashi
authors.initials: M
authors.lastname: Sasa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D003294:Seizures, Febrile / Q000235:genetics* / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568250:Scn1a protein, rat; D015222:Sodium Channels
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