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

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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.