Renal hypouricemia (RHUC) is a rare autosomal recessive disorder characterized by impaired renal tubular uric acid reabsorption and abnormally high uric acid clearance, which may be manifested by reduced serum uric acid (SUA) levels and elevated fractional excretion of uric acid (FE-UA >10%). Most RHUC patients are often asymptomatic or have accidentally decreased SUA levels during health examinations, while others develop kidney stones and exercise-induced acute kidney injury (EIAKI). We now report a case of RHUC complicated with an asymptomatic kidney stone, and we identified a heterozygous mutation of c.269G > A (p.R90H) and a novel heterozygous mutation of c.674C > G (p.T225R) in the SLC22A12 gene in the patient through whole exon gene detection (NGS method). This case offers valuable insights into the mechanisms, clinical management, and prognosis of RHUC and its associated complications.

Renal hypouricemia (RHUC) is a rare hereditary disorder caused by loss-of-function mutations in the SLC22A12 (RHUC type 1) or SLC2A9 (RHUC type 2) genes, encoding urate transporters URAT1 and GLUT9, respectively, that reabsorb urate in the renal proximal tubule. The characteristics of this disorder are low serum urate levels, high renal fractional excretion of urate, and occasional severe complications such as nephrolithiasis and exercise-induced acute renal failure. In this study, we report two Spanish (Caucasian) siblings and a Pakistani boy with clinical characteristics compatible with RHUC. Whole-exome sequencing (WES) analysis identified two homozygous variants: a novel pathogenic SLC22A12 variant, c.1523G>A; p.(S508N), in the two Caucasian siblings and a previously reported SLC2A9 variant, c.646G>A; p.(G216R), in the Pakistani boy. Our findings suggest that these two mutations cause RHUC through loss of urate reabsorption and extend the SLC22A12 mutation spectrum. In addition, this work further emphasizes the importance of WES analysis in clinical settings.

BACKGROUND: The ABCG2, SLC22A12, and ALPK1 genes have been strongly associated with dysfunction of urate metabolism in patients with gout, but it is unknown how these transporters are expressed in patients with acute or chronic gout. Our objectives were to: (a) analyze the gene expression of urate transporters and of inflammation genes in peripheral blood from gout patients and controls; (b) determine whether the metabolic profile of gout patients can influence the gene expression profile and the expression of urate transporters, ABCG2 and SLC22A12, and inflammation molecules, ALPK1 and IL-1β, in peripheral blood leukocytes from gout patients; (c) compare them with their metabolic profile and the gene expression of people without gout and without hyperuricemia.
METHODS: A total of 36 chronic and acute patients and 52 controls were recruited, and ABCG2, SLC22A12, IL-1β, and ALPK1 gene expression was evaluated by quantitative real-time PCR. Correlations of gene expression with clinical and laboratory parameters of patients were also analyzed.
RESULTS: IL-1β was significantly increased in peripheral blood mononuclear cells (PBMCs) of patients compared with their polymorphonuclear leukocytes white blood cells (PMNLs, p < 0.05). A significant increase in ABCG2 and IL-1β was found in PMNLs from patients compared to controls (p < 0.05). Correlations of gene expression in patients were found with levels of serum uric acid (sUA), serum creatinine, C-reactive protein (CRP), triglycerides, body mass index (BMI), kidney disease, hypertension, and metabolic syndrome.
CONCLUSIONS: Our data suggest that leukocytes of patients respond to the presence of hyperuricemia and comorbidities, expressing ABCG2 and IL-1β genes differentially compared to normouricemic and nondisease states. Hyperuricemia, dyslipidemia, and obesity probably stimulate the differential gene expression of peripheral blood leukocytes (neutrophils and monocytes), even in an asymptomatic state.

Hyperuricemia, a lifestyle-related disease characterized by elevated serum urate levels, is the main risk factor for gout; therefore, the serum urate-lowering effects of human diets or dietary ingredients have attracted widespread interest. As Urate transporter 1 (URAT1) governs most urate reabsorption from primary urine into blood, URAT1 inhibition helps decrease serum urate levels by increasing the net renal urate excretion. In this study, we used a cell-based urate transport assay to investigate the URAT1-inhibitory effects of 162 extracts of plant materials consumed by humans. Among these, we focused on Aspalathus linearis, the source of rooibos tea, to explore its active ingredients. Using liquid-liquid extraction with subsequent column chromatography, as well as spectrometric analyses for chemical characterization, we identified quercetin as a URAT1 inhibitor. We also investigated the URAT1-inhibitory activities of 23 dietary ingredients including nine flavanols, two flavanonols, two flavones, two isoflavonoids, eight chalcones, and a coumarin. Among the tested authentic chemicals, fisetin and quercetin showed the strongest and second-strongest URAT1-inhibitory activities, with IC50 values of 7.5 and 12.6 μM, respectively. Although these effects of phytochemicals should be investigated further in human studies, our findings may provide new clues for using nutraceuticals to promote health.

Aims: Gout is a form of inflammatory arthritis characterized by the deposition of monosodium urate crystals. An important risk factor for gout is hyperuricemia. The relationship between SLC22A12 gene variants and the susceptibility to hyperuricemia has been reported, but these findings have been inconsistent. Thus, we aimed to assess the relationship between SLC22A12 gene variants and hyperuricemia susceptibility through a meta-analysis. Methods: The meta-analysis was performed by searching PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) databases. The relationship between hyperuricemia risk and the SLC22A12 rs11602903, rs524023, rs3825018, rs3825016, rs11231825, rs7932775, rs893006, and rs475688 variants was assessed by odds ratios and 95% confidence intervals. Results: In total, 20 eligible publications with 4817 cases and 6819 controls were included in the meta-analysis. Hyperuricemia risk was significantly associated with the SLC22A12 alleles rs3825018, rs7932775, and rs475688 under both the dominant and recessive models and with rs3825016 under the allelic and dominant models. Conclusions: Under the allelic model SLC22A12 rs3825018 and rs3825016 were risk factors for hyperuricemia and gout as was rs7932775 under dominant and recessive models, while the SLC22A12 rs475688 was protective against hyperuricemia under both dominant and recessive models.

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.

Circulation of urate levels is determined by the balance between urate production and excretion, homeostasis regulated by the function of urate transporters in key epithelial tissues and cell types. Our understanding of these physiological processes and identification of the genes encoding the urate transporters has advanced significantly, leading to a greater ability to predict risk for urate-associated diseases and identify new therapeutics that directly target urate transport. Here, we review the identified urate transporters and their organization and function in the renal tubule, the intestinal enterocytes, and other important cell types to provide a fuller understanding of the complicated process of urate homeostasis and its role in human diseases. Furthermore, we review the genetic tools that provide an unbiased catalyst for transporter identification as well as discuss the role of transporters in determining the observed significant gender differences in urate-associated disease risk.

Background: Hyperuricemia is a pathological condition associated with risk factors of cardiovascular disease. In this study, three genetic polymorphisms were genotyped as predisposing factors of hyperuricemia. Methods: A total of 860 Mexicans (129 cases and 731 controls) between 18 and 25 years of age were genotyped for the ABCG2 (Q191K),  SLC22A12 (517G>A), and  XDH (518T>C) polymorphisms, as predisposing factors of hyperuricemia. Biochemical parameters were measured by spectrophotometry, while genetic polymorphisms were analyzed by real-time PCR. An analysis of the risk of hyperuricemia in relation to the variables studied was carried out using a logistic regression. Results: Male sex, being overweight or obese, having hypercholesterolemia or having hypertriglyceridemia were factors associated with hyperuricemia ( p ≤ 0.05). The ABCG2 polymorphism was associated with hyperuricemia (OR = 2.43, 95% CI: 1.41-4.17, p = 0.001) and hypercholesterolemia (OR = 4.89, 95% CI: 1.54-15.48, p = 0.003), employing a dominant model, but only in male participants. Conclusions: The ABCG2 (Q191K) polymorphism increases the risk of hyperuricemia and hypercholesterolemia in young Mexican males.

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.

Renal hypouricemia (RHUC) is a genetic disorder caused by mutations in the SLC22A12 gene, which encodes the major uric acid (UA) transporter, URAT1. The clinical course of related, living donor-derived RHUC in patients undergoing kidney transplantation is poorly understood. Here, we report a case of kidney transplantation from a living relative who had an SLC22A12 mutation. After the transplantation, the recipient\'s fractional excretion of UA (FEUA) decreased, and chimeric tubular epithelium was observed.
A 40-year-old man underwent kidney transplantation. His sister was the kidney donor. Three weeks after the transplantation, he had low serum-UA, 148.7 μmol/L, and elevated FEUA, 20.8% (normal: < 10%). The patient\'s sister had low serum-UA (101.1 μmol/L) and high FEUA (15.8%) before transplant. Suspecting RHUC, we performed next-generation sequencing on a gene panel containing RHUC-associated genes. A heterozygous missense mutation in the SLC22A12 gene was detected in the donor, but not in the recipient. The recipient\'s serum-UA level increased from 148.7 μmol/L to 231.9 μmol/L 3 months after transplantation and was 226.0 μmol/L 1 year after transplantation. His FEUA decreased from 20.8 to 11.7% 3 months after transplantation and was 12.4% 1 year after transplantation. Fluorescence in situ hybridization of allograft biopsies performed 3 months and 1 year after transplantation showed the presence of Y chromosomes in the tubular epithelial cells, suggesting the recipient\'s elevated serum-UA levels were owing to a chimeric tubular epithelium.
We reported on a kidney transplant recipient that developed RHUC owing to his donor possessing a heterozygous mutation in the SLC22A12 (URAT1) gene. Despite this mutation, the clinical course was not problematic. Thus, the presence of donor-recipient chimerism in the tubular epithelium might positively affect the clinical course, at least in the short-term.