Genetic variations in urate transporters play a significant role in determining human urate levels and have been implicated in developing hyperuricemia or gout. Polymorphism in the key urate transporters, such as ABCG2, URAT1, or GLUT9 was well-documented in the literature. Therefore in this study, our objective was to determine the frequency and effect of rare nonsynonymous allelic variants of SLC22A11, SLC22A13, and SLC17A1 on urate transport. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined all coding regions and exon-intron boundaries of SLC22A11, SLC22A13, and SLC17A1 using PCR amplification and Sanger sequencing. For comparison, we used a control group consisting of 115 normouricemic subjects. To examine the effects of the rare allelic nonsynonymous variants on the expression, intracellular processing, and urate transporter protein function, we performed a functional characterization using the HEK293A cell line, immunoblotting, fluorescent microscopy, and site directed mutagenesis for preparing variants in vitro. Variants p.V202M (rs201209258), p.R343L (rs75933978), and p.P519L (rs144573306) were identified in the SLC22A11 gene (OAT4 transporter); variants p.R16H (rs72542450), and p.R102H (rs113229654) in the SLC22A13 gene (OAT10 transporter); and the p.W75C variant in the SLC17A1 gene (NPT1 transporter). All variants minimally affected protein levels and cytoplasmic/plasma membrane localization. The functional in vitro assay revealed that contrary to the native proteins, variants p.P519L in OAT4 (p ≤ 0.05), p.R16H in OAT10 (p ≤ 0.05), and p.W75C in the NPT1 transporter (p ≤ 0.01) significantly limited urate transport activity. Our findings contribute to a better understanding of (1) the risk of urate transporter-related hyperuricemia/gout and (2) uric acid handling in the kidneys.

• MeSH
• Gout * genetics   MeSH
• Hyperuricemia * genetics   MeSH
• Sodium-Phosphate Cotransporter Proteins, Type I * genetics   MeSH
• Uric Acid metabolism   MeSH
• Humans MeSH
• Organic Anion Transporters, Sodium-Independent * genetics   MeSH
• Organic Anion Transporters * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Sodium-Phosphate Cotransporter Proteins, Type I * MeSH
• Uric Acid MeSH
• Organic Anion Transporters, Sodium-Independent * MeSH
• Organic Anion Transporters * MeSH
• SLC17A1 protein, human MeSH Browser
• SLC22A11 protein, human MeSH Browser
• SLC22A13 protein, human MeSH Browser
• urate transporter MeSH Browser

Renal hypouricemia is a disease caused by the dysfunction of renal urate transporters. This disease is known to cause exercise-induced acute kidney injury, but its mechanism has not yet been established. To analyze the mechanism by which hypouricemia causes renal failure, we conducted a semi-ischemic forearm exercise stress test to mimic exercise conditions in five healthy subjects, six patients with renal hypouricemia, and one patient with xanthinuria and analyzed the changes in purine metabolites. The results showed that the subjects with renal hypouricemia had significantly lower blood hypoxanthine levels and increased urinary hypoxanthine excretion after exercise than healthy subjects. Oxidative stress markers did not differ between healthy subjects and hypouricemic subjects before and after exercise, and no effect of uric acid as a radical scavenger was observed. As hypoxanthine is a precursor for adenosine triphosphate (ATP) production via the salvage pathway, loss of hypoxanthine after exercise in patients with renal hypouricemia may cause ATP loss in the renal tubules and consequent tissue damage.

• Keywords
• acute kidney injury, hypouricemia, xanthinuria,
• Publication type
• Journal Article MeSH

The OAT1 (SLC22A6) and OAT3 (SLC22A8) urate transporters are located on the basolateral membrane of the proximal renal tubules, where they ensure the uptake of uric acid from the urine back into the body. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined the coding regions of both genes using PCR amplification and Sanger sequencing. Variants p.P104L (rs11568627) and p.A190T (rs146282438) were identified in the gene for solute carrier family 22 member 6 (SLC22A6) and variants p.R149C (rs45566039), p.V448I (rs11568486) and p.R513Q (rs145474422) in the gene solute carrier family 22 member 8 (SLC22A8). We performed a functional study of these rare non-synonymous variants using the HEK293T cell line. We found that only p.R149C significantly reduced uric acid transport in vitro. Our results could deepen the understanding of uric acid handling in the kidneys and the molecular mechanism of uric acid transport by the OAT family of organic ion transporters.

• Keywords
• OAT1, OAT3, gout, hyperuricemia, urate transport,
• MeSH
• Biological Transport MeSH
• Gout * genetics   metabolism   MeSH
• HEK293 Cells MeSH
• Hyperuricemia * genetics   MeSH
• Uric Acid metabolism   MeSH
• Humans MeSH
• Organic Anion Transporters, Sodium-Independent * genetics   MeSH
• Organic Anion Transport Protein 1 * genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Uric Acid MeSH
• organic anion transport protein 3 MeSH Browser
• Organic Anion Transporters, Sodium-Independent * MeSH
• Organic Anion Transport Protein 1 * MeSH

Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon-intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.

• Keywords
• Roma, SLC22A12, URAT1, ethnic specificity, renal hypouricemia,
• Publication type
• Journal Article MeSH

Urate transporters, which are located in the kidneys, significantly affect the level of uric acid in the body. We looked at genetic variants of genes encoding the major reabsorption proteins GLUT9 (SLC2A9) and URAT1 (SLC22A12) and their association with hyperuricemia and gout. In a cohort of 250 individuals with primary hyperuricemia and gout, we used direct sequencing to examine the SLC22A12 and SLC2A9 genes. Identified variants were evaluated in relation to clinical data, biochemical parameters, metabolic syndrome criteria, and our previous analysis of the major secretory urate transporter ABCG2. We detected seven nonsynonymous variants of SLC2A9. There were no nonsynonymous variants of SLC22A12. Eleven variants of SLC2A9 and two variants of SLC22A12 were significantly more common in our cohort than in the European population (p = 0), while variants p.V282I and c.1002+78A>G had a low frequency in our cohort (p = 0). Since the association between variants and the level of uric acid was not demonstrated, the influence of variants on the development of hyperuricemia and gout should be evaluated with caution. However, consistent with the findings of other studies, our data suggest that p.V282I and c.1002+78A>G (SLC2A9) reduce the risk of gout, while p.N82N (SLC22A12) increases the risk.

• Keywords
• SLC22A12, SLC2A9, gout, hyperuricemia, sequencing, urate transporters,
• Publication type
• Journal Article MeSH

• Keywords
• Excretion fraction of uric acid *, Hypouricemia *, SLC22A12 *, URAT1 *, Urate transport *,
• MeSH
• Acute Kidney Injury blood   prevention & control   urine   MeSH
• Allopurinol administration & dosage   MeSH
• Antioxidants administration & dosage   MeSH
• Cystinosis blood   diagnosis   urine   MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Fanconi Syndrome blood   diagnosis   urine   MeSH
• Genetic Testing MeSH
• Uric Acid blood   metabolism   urine   MeSH
• Kidney Tubules metabolism   MeSH
• Humans MeSH
• Urinary Calculi blood   diagnosis   genetics   urine   MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Glucose Transport Proteins, Facilitative genetics   MeSH
• Renal Reabsorption MeSH
• Inappropriate ADH Syndrome blood   diagnosis   urine   MeSH
• Renal Tubular Transport, Inborn Errors blood   diagnosis   genetics   urine   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Allopurinol MeSH
• Antioxidants MeSH
• Uric Acid MeSH
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• Glucose Transport Proteins, Facilitative MeSH
• SLC22A12 protein, human MeSH Browser
• SLC2A9 protein, human MeSH Browser

BACKGROUND: Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport, reabsorption insufficiency and /or acceleration of secretion. The affected individuals are predisposed to nephrolithiasis and recurrent episodes of exercise-induced acute kidney injury. Type 1 is caused by dysfunctional variants in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). To date, more than 150 patients with the loss-of-function mutations for the SLC22A12 gene have been found (compound heterozygotes and/or homozygotes), most of whom are Japanese and Koreans. CASE PRESENTATION: Herein, we report a nine year old Sri Lankan boy with renal hypouricemia (serum uric acid 97 μmol/L, fractional excretion of uric acid 33%).The sequencing analysis of SLC22A12 revealed a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. CONCLUSIONS: This is the first identification of a family with mild renal hypouricemia1 associated to the p.T467 M variant. Detailed investigations of urate blood and urine concentrations in patients with unexplained hypouricemia are needed and renal hypouricemia should also be considered in patients other than those from Japan and/or Korea. Our finding confirms an uneven geographical and ethnic distribution of Romany prevalent SLC22A12 variant that need to be considered in Asian patients (population data Genome Aggregation Database: allele frequency in South Asia 0.007055, in East Asia 0.001330).

• Keywords
• Renal hypouricemia, SLC22A12, URAT1, Uric acid transporters,
• MeSH
• Child MeSH
• Adult MeSH
• Heterozygote * MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Adolescent MeSH
• Urinary Calculi genetics   MeSH
• Child, Preschool MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Sri Lanka MeSH
• Names of Substances
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• SLC22A12 protein, human MeSH Browser