title: A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction.
abstract: Generalized epilepsy with febrile seizures plus (GEFS+), a clinical subset of febrile seizures (FS), is characterized by frequent episodes beyond 6 years of age (FS+) and various types of subsequent epilepsy. Mutations in beta1 and alpha(I)-subunit genes of voltage-gated Na(+) channels have been associated with GEFS+1 and 2, respectively. Here, we report a mutation resulting in an amino acid exchange (R188W) [corrected] in the gene encoding the alpha-subunit of neuronal voltage-gated Na(+) channel type II (Na(v)1.2) in a patient with FS associated with afebrile seizures. The mutation R188W [corrected] occurring on Arg(187), a highly conserved residue among voltage-gated Na(+) channels, was not found in 224 alleles of unaffected individuals. Whole-cell patch clamp recordings on human embryonic kidney (HEK) cells expressing a rat wild-type (rNa(v)1.2) and the corresponding mutant channels showed that the mutant channel inactivated more slowly than wild-type whereas the Na(+) channel conductance was not affected. Prolonged residence in the open state of the R188W [corrected] mutant channel may augment Na(+) influx and thereby underlie the neuronal hyperexcitability that induces seizure activity. Even though a small pedigree could not show clear cosegregation with the disease phenotype, these findings strongly suggest the involvement of Na(v)1.2 in a human disease and propose the R188W [corrected] mutation as the genetic defect responsible for febrile seizures associated with afebrile seizures.
authors.affiliation: Laboratories for Neurogenetics and Memory and Learning, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sugawara
authors.forename: Y
authors.initials: Y
authors.lastname: Tsurubuchi
authors.forename: K L
authors.initials: KL
authors.lastname: Agarwala
authors.forename: M
authors.initials: M
authors.lastname: Ito
authors.forename: G
authors.initials: G
authors.lastname: Fukuma
authors.forename: E
authors.initials: E
authors.lastname: Mazaki-Miyazaki
authors.forename: H
authors.initials: H
authors.lastname: Nagafuji
authors.forename: M
authors.initials: M
authors.lastname: Noda
authors.forename: K
authors.initials: K
authors.lastname: Imoto
authors.forename: K
authors.initials: K
authors.lastname: Wada
authors.forename: A
authors.initials: A
authors.lastname: Mitsudome
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
authors.forename: M
authors.initials: M
authors.lastname: Montal
authors.forename: K
authors.initials: K
authors.lastname: Nagata
authors.forename: S
authors.initials: S
authors.lastname: Hirose
authors.forename: K
authors.initials: K
authors.lastname: Yamakawa
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D018076:DNA, Complementary; D004594:Electrophysiology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D051381:Rats; D012640:Seizures / Q000235:genetics*; D003294:Seizures, Febrile / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
chemical_list: D018076:DNA, Complementary; D062550:NAV1.1 Voltage-Gated Sodium Channel; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; C568251:SCN2A protein, human; C568250:Scn1a protein, rat; C568253:Scn2A protein, rat; D015222:Sodium Channels