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

最近，从人肾脏中分离到了一个由SLC22A12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例血尿酸低于1.0 mg/dl的无血缘关系的日本肾性低尿酸血症患者及其家属的SLC22A12。其中，4名患者在运动后出现急性肾功能衰竭。我们使用基因组DNA对SLC22A12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%)存在SLC22AJ2基因突变。在5例患者中，发现SLC22A12外显子4内774位核苷酸发生纯合子G-A转换，在密码子258(TGG)处形成终止密码子(TGA)(W258X)。在1例患者中，发现外显子3发生C-T转换，将第217位密码子上的苏氨酸转变为蛋氨酸(T217M)，并发现W258X突变(复合杂合子)。因此，在6名患者的12个突变等位基因中，有11个是W258X突变(92%)。W258X杂合突变(携带者)的家庭成员表现出相对较低的血尿酸水平。我们还分析了两名患有肾性低尿酸血症的韩国患者的SLC22A12。其中1例为W258X纯合子突变，另1例为W258X/R477H复合杂合突变。本研究表明，W258X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.