The W258X mutation in SLC22A12 is the predominant cause of Japanese renal hypouricemia

Abstract

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 W258 X 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.

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

“…It had been theorized that loss of URAT1 function in humans would reduce urate reabsorption from glomerular filtrate and decrease the likelihood of urate accumulation and crystallization (Komoda et al, 2004). For example, three SLC22A12 (URAT1) SNPs (R90H, R477H, Trp258STOP) are associated with idiopathic hypouricemia in Japanese patients Iwai et al, 2004b;Komoda et al, 2004).…”

“…For example, three SLC22A12 (URAT1) SNPs (R90H, R477H, Trp258STOP) are associated with idiopathic hypouricemia in Japanese patients Iwai et al, 2004b;Komoda et al, 2004). Even heterozygous carriers of the Trp258STOP mutation exhibit low levels of serum urate (Komoda et al, 2004).…”

A common mutation in an organic anion transporter gene, SLC22A12, is a suppressing factor for the development of gout

“…This mutation is present in exon 4 and leads to the substitution of a stop codon for tryptophan (W258X) (3). The homozygous G774A mutation is the predominant cause of idiopathic renal hypouricemia in Japanese patients (7,8).…”

“…Ten nanograms of genomic DNA was amplified with the forward primer 5Ј-CCGCCTCAGCTCAGCGG-GCAAGCAT-3Ј and the reverse primer 5Ј-CCCCCGGGT-GGAGAGTGGGCAGGAT-3Ј (8). The genotypes were identified by Bsr I restriction endonuclease digestion (New England Biolabs, Beverly, MA), which recognizes its target sequences only when the normal allele is present.…”

Physiology, structure, and regulation of the cloned organic anion transporters

“…To date, over 110 amino acids have been mutated in OATs 1-4 and URAT1 from different species (Feng et al 2001(Feng et al , 2002Wolff et al 2001;Enomoto et al 2002a;Hong et al 2004Hong et al , 2007aIchida et al 2004;Komoda et al 2004;Tanaka et al 2004b, c;Zhou et al 2004aZhou et al , b, 2005Bleasby et al 2005;Erdman et al 2006;). Motivation for the mutations varied, e.g., several studies examined conserved residues most likely directly tied to recognition and transport of organic anions, while other reports examined the role of glycosylation sites (mutating asparagine residues) in protein trafficking (Tanaka et al 2004c;Zhou et al 2005) or cysteine residues that may have been linked to disulfide bonding ).…”