A missense mutation of the gene encoding voltage-dependent sodium channel (Nav1.1) confers susceptibility to febrile seizures in rats.
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.
Mashimo
Tomoji
T
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. tmashimo@anim.med.kyoto-u.ac.jp
Ohmori
Iori
I
Ouchida
Mamoru
M
Ohno
Yukihiro
Y
Tsurumi
Toshiko
T
Miki
Takafumi
T
Wakamori
Minoru
M
Ishihara
Shizuka
S
Yoshida
Takashi
T
Takizawa
Akiko
A
Kato
Megumi
M
Hirabayashi
Masumi
M
Sasa
Masashi
M
Mori
Yasuo
Y
Serikawa
Tadao
T
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*
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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