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

5号染色体FEB4区域热性惊厥相关基因的鉴定

基本信息

批准号：
12670727
负责人：
IWASAKI Nobuaki
金额：
$ 2.56万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670727/
关键词：
febrile seizure gene FEB4 linkage analysis Japanese CAST A-LAP PCSK1 分子遺伝学家系分析

项目摘要

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.

FEB 4是染色体5g 14-q15上的遗传位点，与标记D5 S644连锁，赋予对热性惊厥（FS）的易感性。通过传递不平衡检验（TDT），发现标记D5 S644、D5 S652和D5 S2079与FS存在明显的连锁不平衡。D5 S644、D5 S652和D5 S2079时的共同血统同一性并不表明对无热性惊厥、复杂性热性惊厥或复发性热性惊厥的存在或不存在有贡献。在FEB 1（D8 S530）、FEB 2（D19 S1034）、FEB 3/ GEFS+2型（D2 S1353）和GEFS+1型（D19 S224）核FS家系中，未发现FS位点连锁。这些研究结果表明，这些FS位点可能不会发挥重要作用，FS在日本人口的发展。为了鉴定FS的相关突变，我们筛选了三个基因，前蛋白转化酶枯草杆菌蛋白酶/kexin-type 1（PCSK 1）、钙蛋白酶抑制蛋白（CAST）和脂肪细胞来源的亮氨酸氨基肽酶（A-Arg），它们已定位在标记D5 S644的500 kb内。在48例不相关的日本FS患者中共发现61种多态性/变异。我们在48个FS家族中对这些多态性进行了基因分型，并进行了TDT。PCSKI的-103T等位基因和CAST的IVS 21 - 65 A等位基因在FS患者中更易传播。我们没有证据表明这些多态性导致PCSK 1和CAST蛋白的功能改变。我们的数据表明，FS-责任基因之间存在PCSK 1和CAST，可能附近的D5 S644标记，虽然没有已知的基因已被映射到D5 S644。