Identification of a febrile seizures-related gene in the FEB4 region on chromosome 5

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FEB4 is a genetic locus on chromosome 5g14-q15, with linkage to the marker D5S644, that confers susceptibility to febrile seizures (FS). Significant linkage disequilibria with FS were observed at the markers D5S644, D5S652 and D5S2079 by the transmission disequilibrium test (TDT). Shared identity-by-descent at D5S644, D5S652 and D5S2079 does not suggest a contribution to the presence or absence of afebrile seizures, complex febrile seizures or recurrent febrile seizures. No linkage was found at the previously identified FS loci in nuclear FS families, including FEBI (D8S530), FEB2 (D19S1034), FEB3 / GEFS+ type2 (D2S1353), and GEFS+ typel (D19S224). These findings indicate that these FS loci may not play an important role in the development of FS in this Japanese population. To identify responsible mutation(s) for FS, we screened three genes, proprotein convertase subtilisin/kexin-type 1 (PCSK1), calpastatin (CAST) and adipocyte-derived leucine aminopeptidase (A-LAP), which have been mapped to within 500kb of marker D5S644. A total of 61 polymorphisms/variants were identified in 48 unrelated Japanese patients with FS. We genotyped these polymorphisms in 48 FS families and performed TDT. The -103T allele of PCSKI and the IVS21-65A allele of CAST were more frequently transmitted to FS patients. We have no evidence that these polymorphisms cause functional alterations in the PCSK1 and CAST proteins. Our data indicate that a FS-responsible gene exists between PCSK1 and CAST, probably near the D5S644 marker, though no known gene has been mapped around D5S644.