Disease relevance of SLC22A12

• CONCLUSION: SLC22A12 is a major gene for hypouricemia but not hyperuricemia in Japanese [1].
• Recent identification of the urate transporter in the kidney (URAT1, encoded by SLC22A12) led to the molecular elucidation of idiopathic renal hypouricemia, which is a predisposition toward exercise-induce acute renal failure [2].
• Among 96 persons, limb-lead RST deviations occurred in all 48 with pericarditis, but only 27 with early repolarization [3].
• In 588 patients with treated and untreated syphilis, the RST results were 91.7% in agreement with the VDRL and RPR results [4].
• A total of 1,020 serum and plasma specimens were tested using the Venereal Disease Research Laboratory (VDRL), Rapid Plasma Reagin (RPR) card, Reagin Screen (RST) and Fluorescent Treponemal Antibody-Absorption (FTA-ABS) tests [4].

High impact information on SLC22A12

• Moreover, we provide evidence that patients with idiopathic renal hypouricaemia (lack of blood uric acid) have defects in SLC22A12 [5].
• Identification of URAT1 should provide insights into the nature of urate homeostasis, as well as lead to the development of better agents against hyperuricaemia, a disadvantage concomitant with human evolution [5].
• The present case-control study was designed to analyze whether hURAT1 might also be a candidate gene for hyperuricemia with primary reduced renal urate excretion [6].
• Taken together, the present study indicates the novel role of PDZK1 in regulating the functional activity of URAT1-mediated urate transport in the apical membrane of renal proximal tubules [7].
• Evidence that the URAT1 transporter was functional was provided by the finding that uptake of (14)C-urate was significantly inhibited in the presence of probenecid, an organic anion transporter inhibitor [8].

Chemical compound and disease context of SLC22A12

• Because genetic background is known to affect serum urate levels, we hypothesized that genetic variations in SLC22A12 may predispose humans to hyperuricemia and gout [9].

Biological context of SLC22A12

• METHODS: We screened for polymorphisms of SLC22A12 and conducted an association study between genetic polymorphisms and urate levels in an epidemiologic cohort representing the general population in Japan. Functional significance of mutations was assessed by oocyte expression analysis [1].
• These results indicate that URAT1 is involved in renal reabsorption of oxypurinol, and the increment of renal clearance of oxypurinol upon concomitant administration of benzbromarone could be due to drug interaction at URAT1 [10].
• Thirty patients had SLC22A12 mutations; 24 homozygotes and compound heterozygotes, and 6 heterozygotes [11].
• The SLC22A12 gene was sequenced in 32 unrelated idiopathic renal hypouricemia patients, and the relationships of serum urate levels, and CUA/creatinine clearance (Ccr) to SLC22A12 genotype were examined [11].
• Mouse renal-specific transporter (RST) cDNA, the amino acid sequence of which has 74% identity with that of human urate transporter 1 (hURAT1), is potentially the mouse homologue of hURAT1, the gene responsible for hereditary renal hypouricemia [12].

Anatomical context of SLC22A12

• This study reports the specific expression of URAT1 on human aortic vascular smooth muscle cells, as assessed by reverse transcription-PCR and Western blot analysis [8].
• Expression of URAT1 was localized to the cell membrane [8].
• Subjects addressed include the role of URAT1-mediated renal proximal tubule epithelial cell urate anion reabsorption in hyperuricemia [13].
• Immunohistochemically, hURAT1 was located at the brush border membrane of renal proximal tubular cells [14].

Associations of SLC22A12 with chemical compounds

• Moreover, benzbromarone inhibited the oxypurinol uptake by URAT1 at concentrations as low as 0.01 microM [10].
• In contrast to healthy subjects, the CUA/Ccr of patients with homozygous and compound heterozygous SLC22A12 mutations was unaffected by pyrazinamide, benzbromarone, and probenecid [11].
• In earlier studies, when the clamped state was induced with an oral ethanol loading dose, the vagaries of gastric emptying and absorption were associated with a 45 min delay (RST: reliable start time) before collection of dependent measurements could be planned with confidence [15].
• Exercise and isoproterenol tend to normalize the RST segment elevation [16].
• The sex hormone testosterone significantly increases promoter activity, suggesting that hormonal regulation of hURAT1 is the root cause of observed differences in urate levels between males and females [17].

Regulatory relationships of SLC22A12

• BACKGROUND: Renal hypouricemia is an autosomal recessive disorder resulting from inactivating mutations in the urate transporter 1 (URAT1) encoded by SLC22A12 [18].

Other interactions of SLC22A12

• Coimmunoprecipitation studies revealed that the wild-type URAT1, but not its mutant lacking the PDZ-motif, directly interacts with PDZK1 [7].
• Recently three proteins, playing central roles in the bidirectional transport of urate in renal proximal tubules, were identified: two members of the organic anion transporter (OAT) family, OAT1 and OAT3, and a protein that designated renal urate-anion exchanger (URAT1) [19].
• The native corresponding proteins of URAT1, OAT1 and OAT3, in human kidney can be recognized by their specific antibodies, respectively, with Western blot analysis and immunohistochemistry [19].

Analytical, diagnostic and therapeutic context of SLC22A12

• Such an interaction requires the PDZ motif of URAT1 in its extreme intracellular C-terminal region and the first, second, and fourth PDZ domains of PDZK1 as identified by yeast two-hybrid assay, in vitro binding assay and surface plasmon resonance analysis (K(D) = 1.97-514 nM) [7].
• However, FST-based estimates are always better than RST when sample sizes are moderate or small (ns </= 10) and the number of loci scored is low (nl < 20) [20].
• METHODS: Eighteen untrained males were randomly assigned to either a resistance-training [RST (N = 9)] or control group [CON (N = 9)] [21].
• Restriction enzyme analysis with HphI was useful to screen the IVS2+1G>A mutation in hURAT1 gene [22].
• (1) extraction by Dormia basket, (2) cystoscopic lithotrity and (3) electronic lithotripsy by Russian-made "URAT 1". Safety and economic advantages to the patients have been discussed [23].

References