The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia
The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia
复制标题
DOI：
10.1007/s00467-004-1424-1
复制
发表时间：
2004-07-01
影响因子：
3
通讯作者：
Igarashi, T
中科院分区：
文献类型：
--
作者：
Komoda, F;Sekine, T;Igarashi, T
最近，从人肾中分离出由SLC22A12编码的尿酸转运蛋白hURAT1（人尿酸转运蛋白1）。 hURAT1 被认为在肾小球滤液中尿酸盐的重吸收中发挥着核心作用。在本研究中，我们分析了 7 名无血缘关系的日本肾性低尿酸血症患者及其家庭成员的 SLC22A12，患者的血清尿酸盐水平低于 1.0 mg/dl。我们使用基因组 DNA 对 SLC22A12 的外显子和外显子-内含子边界进行直接 DNA 测序。七名患者中的六名 (86%) 具有 SLC22A12 突变。在 5 名患者中，鉴定出 SLC22A12 外显子 4 内核苷酸 774 处的纯合 G 至 A 转变，该转变在密码子 258 (TGG) 处形成终止密码子 (TGA) (W258X)。在一名患者中，外显子 3 内发生 C 到 T 转变，将密码子 217 处的苏氨酸变为甲硫氨酸 (T217 M)，并发现了 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，11 个是 W258X 突变（92%）。具有 W258X 杂合突变的家庭成员（携带者）的血清尿酸水平相对较低。本研究表明，纯合 W258X 突变是日本患者特发性肾性低尿酸血症的主要遗传原因。
Recently, a urate transporter, hURAT1 (human uric acid transporter 1) encoded by SLC22A12, was isolated from the human kidney. hURAT1 is presumed to play the central role in reabsorption of urate from glomerular filtrate. In the present study, 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. 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 SLC22A12. In five patients, a homozygous G to A transition at nucleotide 774 within exon 4 of SLC22A12, which forms a stop codon (TGA) at codon 258 (TGG), was identified (W258X). In one patient, the C to T transition within exon 3, which changes threonine at codon 217 to methionine (T217 M), and the W258X mutation were found (compound heterozygote). Thus, among 12 mutational alleles in six patients, 11 were the W258X mutation (92%). Family members with the heterozygous W258X mutation (carriers) show relatively low levels of serum urate. The present study demonstrates that homozygous W258X mutation is the predominant genetic cause of idiopathic renal hypouricemia in Japanese patients.