OBJECTIVES: IL-37 is an anti-inflammatory cytokine involved in inflammatory and autoimmune diseases. We aimed to investigate the association between IL-37 genetic variants, IL-37 plasma levels, and various clinical phases of gout. METHODS: The study included a control group with no history of primary hyperuricemia/gout, (n = 50), asymptomatic hyperuricemia (n = 74), intercritical gout (n = 200), acute gouty flare (n = 18), and chronic tophaceous gout (n = 30). Plasma IL-37 was analysed using enzyme-linked immunosorbent assay. All coding regions and intron-exon boundaries of IL-37 and exons 1-5 were amplified and sequenced. RESULTS: Plasma levels of IL-37 were significantly higher in asymptomatic hyperuricemic (p = 0.045), intercritical gout (p = 0.001), and chronic tophaceous gout (p = 0.021) cohorts when compared to control group. The levels of IL-37 in patients with acute gouty flare were comparable to control group (p = 0.061). We identified 15 genetic variants of IL-37: eight intron (rs2708959, rs2723170, rs2708958, rs2723169 rs2466448, rs3811045, rs3811048, rs2708944) and seven non-synonymous allelic variants (rs3811046, rs3811047, rs2708943, rs2723183, rs2723187, rs2708947, rs27231927), of which rs2708959 showed an over-presentation in gouty and acute flare cohorts (p = 0.003 and 0.033, respectively) compared to European population (minor allelic frequency MAF = 0.05) but not in control and hyperuricemic cohorts (p/MAF = 0.17/0.08 and 0.71/0.05, respectively).. On the contrary, rs3811045, rs3811046, rs3811047, and rs3811048 were underrepresented among individuals with tophaceous gout (MAF = 0.57) compared to European MAF 0.70-0.71, but not compared to the control cohort (MAF = 0.67). CONCLUSIONS: We demonstrated the up-regulation of IL-37 levels across the clinical phases of gout: asymptomatic hyperuricemia, intercritical, and chronic tophaceous gout compared to control. Moreover, 15 genetic variants of IL-37 were identified and their associations with the clinical variants of gout were evaluated.

• Klíčová slova
• Anti-inflammatory, Gene polymorphism, Gout, IL-1 family, IL-37,
• MeSH
• dna (nemoc) * epidemiologie   MeSH
• dnavá artritida * MeSH
• hyperurikemie * genetika   MeSH
• interleukin-1beta MeSH
• kyselina močová MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• IL37 protein, human MeSH Prohlížeč
• interleukin-1beta MeSH
• kyselina močová MeSH

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.

• Klíčová slova
• acute kidney injury, hypouricemia, xanthinuria,
• Publikační typ
• časopisecké články 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.

• Klíčová slova
• OAT1, OAT3, gout, hyperuricemia, urate transport,
• MeSH
• biologický transport MeSH
• dna (nemoc) * genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• hyperurikemie * genetika   MeSH
• kyselina močová metabolismus   MeSH
• lidé MeSH
• přenašeče organických aniontů nezávislé na sodíku * genetika   MeSH
• protein 1 přenášející organické anionty * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyselina močová MeSH
• organic anion transport protein 3 MeSH Prohlížeč
• přenašeče organických aniontů nezávislé na sodíku * MeSH
• protein 1 přenášející organické anionty * MeSH

BACKGROUND: Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury and nephrolithiasis. Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). METHODS AND RESULTS: In this article we present clinical, biochemical and molecular genetics of two Czech patients. The serum uric acid in the probands was 57 and 98 µmol/l and expressed as an increase in the fractional excretion of uric acid (40 and 18 %). The sequencing analysis of SLC22A12 and SLC2A9 revealed novel variants p.R92C and p.R203C in URAT1 and p.G72D in GLUT9. Functional studies were performed for these novel variants and for previously reported variants p.I118HfsX27, p.G216R and p.N333S in GLUT9 responsible for renal hypouricemia in three probands from Czech Republic and United Kingdom. Functional studies showed significantly decreased urate uptake for all variants. However, urate uptake of GLUT9 variants prepared for both isoforms were not significantly different. CONCLUSIONS: This is the first complex function characterization of non-synonymous allelic variants in patients with renal hypouricemia regarding both GLUT9 isoforms. Our finding of defects in the SLC2A9 and SLC22A12 genes show the following: renal hypouricemia is not restricted to East Asia populations; urate uptake of GLUT9 variants prepared for both isoforms were not significantly different; renal hypouricemia type 2 has more wide clinical variability than type 1; the phenotypic severity of renal hypouricemia is not correlated with results of functional characterizations of URAT1 and GLUT9 variants.

• Klíčová slova
• GLUT9, Renal hypouricemia, SLC22A12, SLC2A9, URAT1, Uric acid transporters,
• MeSH
• dítě MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• močové kameny genetika   MeSH
• mutační analýza DNA MeSH
• přenašeče organických aniontů genetika   MeSH
• proteiny přenášející organické kationty genetika   MeSH
• proteiny usnadňující transport glukosy genetika   MeSH
• vrozené poruchy tubulárního transportu genetika   MeSH
• Xenopus MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• přenašeče organických aniontů MeSH
• proteiny přenášející organické kationty MeSH
• proteiny usnadňující transport glukosy MeSH
• SLC22A12 protein, human MeSH Prohlížeč
• SLC2A9 protein, human MeSH Prohlížeč

Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury (AKI). Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), type 2 in the SLC2A9 gene (GLUT9). This article describes three Czech families with RHUC type 1. The serum UA in the probands was 0.9, 1.1 and 0.5 mg/dl and expressed as an increase in the fractional excretion of UA (48, 43 and 39%). The sequencing analysis of SLC22A12 revealed three novel variants: p.G366R, p.T467M and a deletion p.L415_G417del. A detailed metabolic investigation in proband C for progressive visual failure supported suspicion of neuronal ceroid lipofuscinosis type 7 conditioned by the mutation in the MFSD8 gene. Functional studies showed significantly decreased urate uptake and a mis-localized URAT1 signal in p.G366R, p.L415_G417del and p.T467M. Furthermore, colocalization studies showed accumulation of URAT1 protein in the endoplasmic reticulum. The findings suggest that loss-of-function mutations cause RHUC via loss of UA absorption partly by protein misfolding. However, they do not necessarily lead to AKI and a possible genotype-phenotype correlation was not proposed. Furthermore, results confirm an uneven geographical and ethnic distribution of SLC22A12 variants; the p.L415_G417del mutation predominates in the Roma ethnic group in the Czech Republic.

• MeSH
• absorpce MeSH
• akutní poškození ledvin diagnóza   etiologie   genetika   MeSH
• alely * MeSH
• dítě MeSH
• dospělí MeSH
• endoplazmatické retikulum metabolismus   MeSH
• frekvence genu * MeSH
• heterozygot MeSH
• kyselina močová moč   MeSH
• lidé MeSH
• membránové transportní proteiny genetika   MeSH
• močové kameny komplikace   diagnóza   etnologie   genetika   MeSH
• mutace * MeSH
• neuronální ceroidlipofuscinózy diagnóza   etiologie   genetika   MeSH
• přenašeče organických aniontů genetika   metabolismus   MeSH
• proteiny přenášející organické kationty genetika   metabolismus   MeSH
• rodokmen MeSH
• Romové genetika   MeSH
• vrozené poruchy tubulárního transportu komplikace   diagnóza   etnologie   genetika   MeSH
• Xenopus MeSH
• zvířata MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• kyselina močová MeSH
• membránové transportní proteiny MeSH
• MFSD8 protein, human MeSH Prohlížeč
• přenašeče organických aniontů MeSH
• proteiny přenášející organické kationty MeSH
• SLC22A12 protein, human MeSH Prohlížeč