文本框: A MISSENSE MUTATION OF THE Na+ CHANNEL a2 SUBUNIT GENE NaV1.2 (SCN2A) CAUSES A HUMAN DISORDER, FEBRILE SEIZURES (FS) ASSOCIATED WITH AFEBRILE SEIZURES
Hirose S1, Fukuma G1, Ito M2, Nagafuji H3, Sugawara T4, Tsurubuchi Y4, Agarwala KL4, Mazaki-Miyazaki E4, Noda M5, Imoto K6, Wada K7, Kaneko S7, Montal M8, Nagata K4, Yamakawa K4 and Mitsudome A1
1Fukuoka University, Fukuoka; 2Shiga Medical Center for Children, Moriyama; 3Kitano Hospital, Osaka; 4Brain Science Institute, RIKEN, Wako; National Institute for 5Basic Biology and 6Physiological Sciences, Okazaki; 7Hirosaki University, Hirosaki, Japan; 8University of California, San Diego, La Jolla, USA

Objective: To examine the involvement of Nav1.2 in pathogenesis of human neurological disorders.  Nav1.2 has been a candidate for causative gene of generalized epilepsy with FS plus (GEFS+), a clinical subset of FS.
Methods: Genetic abnormalities of Nav1.2 were sought in genomic DNA obtained from 19 unrelated Japanese families with GEFS+ and FS associated with afebrile seizures.  The electrophysiological properties of Na+ channels harboring mutations were examined by whole-cell patch clamp recordings on human embryonic kidney (HEK) cells.
Results: A heterozygous missense mutation, c.562C>T:R187W was found in a patient with FS associated with afebrile seizures.  R187W occurring on Arg187, a highly conserved amino acid residue among voltage-gated Na+ channels, was not found in unaffected individuals.  Electrophysiological examination revealed that 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.
Conclusions: These findings strongly suggest the involvement of Nav1.2 in a human disease and propose the R187W mutation as a genetic defect responsible for FS associated with afebrile seizures.
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