文本框: NOVEL MUTATIONS OF Nav1.1 (SCN1A) FOUND IN INDIVIDUALS WITH FEBRILE SEIZURES (FS) ASSOCIATED WITH AFEBRILE PARTIAL SEIZURES Fukuma G1, Hirose S1, Ito M2, Nagafuji H3, Sugawara T4, Mazaki-Miyazaki E4, Wada K5, Kaneko S5, Yamakawa K4 and Mitsudome A1 1Department of Pediatrics, Fukuoka University, Fukuoka, 2Shiga Medical Center for Children, Moriyama, 3Kitano Hospital, Osaka, 4Brain Science Institute, RIKEN, Wako, 5Hirosaki University, Hirosaki, JAPAN Objective: To identify genetic abnormalities underlying FS associated with afebrile seizures including generalized epilepsy with FS plus (GEFS+), a clinical subset of FS. Mutations of the neuronal voltage-gated Na+ channel b1 (SCN1B) and a1 (Nav1.1 or SCN1A) subunits have been identified as causes of GEFS+I and II, respectively. Methods: Genetic abnormalities of SCN1B and Nav1.1 were sought in genomic DNA obtained from 19 unrelated Japanese families with GEFS+ or FS associated with afebrile seizures. Results: Two heterozygous missense mutations, c.4253T>C:Val1418Ala and c.5024C>T:Ala1675Val were found in five individuals from two families. Their afebrile seizure phenotypes were consistent with partial seizures. Val1418 is located at the pore region of the channel which is extremely conserved among multiple Na+ channel a-subunits. Ala1675Val located in a well conserved transmembrane region was cosegregated with the disease phenotype. The absence of both mutations among 112 control individuals strongly suggested that these mutations were responsible for the disease phenotypes of the affected individuals studied. Conclusions: Our study has generated compelling evidence that mutations in Nav1.1 produce FS associated with afebrile seizures. In addition, Val1418Ala is the first instance of a missense mutation in the pore region of a Na+ channel causing a human disorder. 1937