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.
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Authors | T Sugawara, Y Tsurubuchi, K L Agarwala, M Ito, G Fukuma, E Mazaki-Miyazaki, H Nagafuji, M Noda, K Imoto, K Wada, A Mitsudome, S Kaneko, M Montal, K Nagata, S Hirose, K Yamakawa |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 98
Issue 11
Pg. 6384-9
(May 22 2001)
ISSN: 0027-8424 [Print] United States |
PMID | 11371648
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- DNA, Complementary
- NAV1.1 Voltage-Gated Sodium Channel
- NAV1.2 Voltage-Gated Sodium Channel
- Nerve Tissue Proteins
- SCN1A protein, human
- SCN2A protein, human
- Scn1a protein, rat
- Scn2A protein, rat
- Sodium Channels
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Topics |
- Amino Acid Substitution
- Animals
- Base Sequence
- Cell Line
- Child
- DNA, Complementary
- Electrophysiology
- Humans
- Male
- Molecular Sequence Data
- Mutation, Missense
- NAV1.1 Voltage-Gated Sodium Channel
- NAV1.2 Voltage-Gated Sodium Channel
- Nerve Tissue Proteins
(genetics, physiology)
- Rats
- Seizures
(genetics)
- Seizures, Febrile
(genetics)
- Sodium Channels
(genetics, physiology)
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