Molecular analysis of the gene responsible for the hereditary disorders of urate transport with impairment of renal function

最近，从人肾脏中分离出由SLC 22 A12编码的尿酸转运蛋白hURATI（人尿酸转运蛋白1）。在本研究项目中，我们分析了7例血清尿酸水平低于1.0 mg/dl的无亲缘关系的日本肾性低尿酸血症患者及其家庭成员的SLC 22 A12。其中，4名患者在运动后发生急性肾衰竭。我们使用基因组DNA对SLC 22 A12的外显子和外显子-内含子边界进行了直接DNA测序。7例患者中有6例（86%）具有SLC 22 AJ 2突变。在5名患者中，在SLC 22 A12外显子4内的核苷酸774处鉴定出纯合的G至A转换，其将在密码子258（TGG）处形成终止密码子（TGA）（W258 X）。在1例患者中，发现外显子3内的C-至-T转换，其将密码子217处的苏氨酸改变为甲硫氨酸（T217 M），以及W258 X突变（复合杂合子）。因此，在6例患者的12个突变等位基因中，11个为W258 X突变（92%）。具有杂合W258 X突变的家族成员（携带者）显示出相对较低的血清尿酸水平。我们还分析了SLC 22 A12在两个韩国患者肾性低尿酸血症。在1例患者中发现W258 X纯合突变，在另1例患者中发现W258 X/R477 H复合杂合突变。本研究表明，W258 X突变是日本和韩国患者特发性肾性低尿酸血症的主要遗传原因。

Recently, a urate transporter, hURATI (human uric acid transporter 1) encoded by SLC22A12, was isolated from the human kidney. In the present research project, we analyzed SLC22A12 in seven unrelated Japanese patients with renal hypouricemia whose serum level of urate was less than 1.0 mg/dl, and their family members. Among these, four patients developed acute renal failure after exercise. We performed direct DNA sequencing of the exon and exon-intron boundaries of SLC22A12 using genomic DNA. Six of the seven patients (86%) possess mutations in SLC22AJ2. In five patients, a homozygous G-to-A transition at nucleotide 774 within exon 4 of SLC22A12, which will form a stop codon (TGA) at codon 258 (TGG), was identified (W258X). In one patient, the C-to-T transition within exon 3, which will change threonine at codon 217 to methionine (T217M), and the W258X mutation were found (compound heterozygote). Thus, among 12 mutational alleles in 6 patients, 11 were W258X mutation (92 %). Family members with the heterozygous W258X mutation (carriers) show relatively low levels of serum urate. We also analyzed SLC22A12 in two Korean patients with renal hypouricemia. In one patient W258X homozygous mutation was identified, and in the other W258X/R477H compound heterozygous mutation was noted. The present study demonstrates that W258X mutation is the predominant genetic cause of idiopathic renal hypouricemia in Japanese and Korean patients.