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Identification of urate transporter, genetic analysis of renal hypouricemia and the development of anti-hyperuricemia drug

尿酸转运蛋白的鉴定、肾性低尿酸血症的基因分析及抗高尿酸血症药物的开发

基本信息

批准号：
14370318
负责人：
NIWA Toshimitsu
金额：
$ 8.96万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

We have succeeded in cloning of urate transporter (URAT1) that is involved in the reabsorption of urate in the tubules of human kidneys, and demonstrated that the transcript protein shows the function of urate transport (Nature 417(6887):447-452,2002). We produced antibody against the protein, and demonstrated that the protein is expressed in the renal tubules. Patients with renal hypouricemia showed homo mutation in the gene of URAT1,and thus URAT1 is a gene responsible for renal hypouricemia. This gene is a target molecule for the development of anti-hyperuricemia drugs.We studied the association between single nucleotide polymorphism(SNP) mutation of URAT1 and the serum levels of urate. We analyzed mutations of URAT1 [Ex3(C217;Thr→Met) (C→T)とEx4(G258A;Trp→stop)(G→A)] by using Light-Cycler in 164 healthy subjects who had taken health checkup at our hospital. We found that for Ex3 mutation(C217;Thr→Met)(C→T), one subject showed hetero mutation, and none showed homo mutation, and that for Ex4(G258A;Trp→stop)(G→A), 3 subjects showed hetero mutation, and none showed homo mutation. The serum levels of urate in the subjects with hetero mutation were 4.1 mg/dl for Ex3 mutation, and 5.3 mg/dl, 4.2 mg/dl, and 4.5 mg/dl for E4 mutation. Thus, the hetero mutation of URAT1 was not associated with hypouricemia.

我们成功克隆了参与人肾小管尿酸重吸收的尿酸转运蛋白（URAT1），并证明转录蛋白具有尿酸转运功能（Nature 417（6887）：447-452，2002）。我们产生了针对该蛋白质的抗体，并证明该蛋白质在肾小管中表达。肾性低尿酸血症患者URAT1基因存在同源突变,因此URAT1是肾性低尿酸血症的致病基因。该基因是开发抗高尿酸血症药物的靶分子。我们研究了URAT1的单核苷酸多态性(SNP)突变与血清尿酸盐水平的关系。我们使用 Light-Cycler 对在我院进行健康检查的 164 名健康受试者进行了 URAT1 [Ex3(C217;Thr→Met) (C→T)とEx4(G258A;Trp→stop)(G→A)] 突变分析。我们发现，对于Ex3突变（C217；Thr→Met）（C→T），1名受试者出现异质突变，无同源突变；对于Ex4（G258A；Trp→stop）（G→A），3名受试者出现异质突变，无同源突变。异种突变受试者的血清尿酸盐水平，Ex3突变为4.1 mg/dl，E4突变为5.3 mg/dl、4.2 mg/dl和4.5 mg/dl。因此，URAT1的异质突变与低尿酸血症无关。