In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 98, No. 11 ( 2001-05-22), p. 6384-6389
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 β1 and α 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 (R187W) in the gene encoding the α-subunit of neuronal
voltage-gated Na + channel type II
( Na v 1.2 ) in a patient with FS
associated with afebrile seizures. The mutation R187W 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 R187W 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 R187W mutation as the genetic defect responsible for febrile seizures associated with afebrile seizures.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.111065098
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2001
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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