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

FEB4位于染色体5g14-q15上，与标记D5S644连锁，对热性惊厥(FS)具有易感性。传递不平衡检验(TDT)发现标记D5S644、D5S652和D5S2079与FS存在显著连锁不平衡。D5S644、D5S652和D5S2079的共同血统不表明存在或不存在无热性惊厥、复杂热性惊厥或反复热性惊厥。在FEBI(D8S530)、FEB2(D19S1034)、FEB3/GEFS+Type2(D2S1353)和GEFS+TYPEL(D19S224)等核心FS家系中未发现连锁基因。这些发现表明，在日本人群中，这些FS基因座在FS的发生发展中可能不起重要作用。为了确定FS的致病突变(S)，我们筛选了3个基因，即原蛋白转换酶枯草杆菌/可信蛋白1型(PCSK1)、钙调蛋白(CAST)和脂肪细胞衍生的亮氨酸氨基肽酶(A-LAP)，这些基因被定位在标记D5S644的500kb以内。在48名无血缘关系的日本FS患者中，共鉴定出61个多态/变异。我们在48个FS家系中对这些基因多态进行了基因分型和TDT。PCSKI的-103T等位基因和CAST的IVS21-65A等位基因更易传递给FS患者。我们没有证据表明这些多态会导致PCSK1和CAST蛋白的功能改变。我们的数据表明，在PCSK1和CAST之间存在一个FS负责的基因，可能位于D5S644标记附近，尽管D5S644附近还没有已知的基因被定位。

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.