Hyperuricemia depends on the balance of endogenous production and renal excretion of uric acid. Transporters for urate are located in the proximal tubule where uric acid is secreted and extensively reabsorbed: secretion is principally ensured by the highly variable ABCG2 gene. Enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) plays a central role in purine metabolism and its deficiency is an X-linked inherited metabolic disorder associated with clinical manifestations of purine overproduction. Here we report the case of a middle-aged man with severe chronic tophaceous gout with a poor response to allopurinol and requiring repeated surgical intervention. We identified the causal mutations in the HPRT1 gene, variant c.481G>T (p.A161S), and in the crucial urate transporter ABCG2, a heterozygous variant c.421C>A (p.Q141K). This case shows the value of an analysis of the genetic background of serum uric acid.

• Klíčová slova
• ABCG2, Gout, Hyperuricemia, Hypoxanthine-guanine phosphoribosyltransferase deficiency, Tophi, Urate transporter,
• MeSH
• ABC transportér z rodiny G, člen 2 genetika   MeSH
• chronická nemoc MeSH
• dna (nemoc) genetika   metabolismus   MeSH
• genetické pozadí * MeSH
• hypoxanthinfosforibosyltransferasa nedostatek   genetika   metabolismus   MeSH
• kyselina močová metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• nádorové proteiny genetika   MeSH
• přenašeče organických aniontů genetika   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• hypoxanthinfosforibosyltransferasa MeSH
• kyselina močová MeSH
• nádorové proteiny MeSH
• přenašeče organických aniontů MeSH
• urate transporter MeSH Prohlížeč

The effect of two days' KC1 administration per os (total amount 11 g, i.e. 140 mEq potassium) on renal uric acid excretion was studied in healthy subjects under conditions of water diuresis. A significant increase in the uric acid excretory fraction (CUA/CCr..100) was found, from 8.04% in the control test to 10.31% under experimental conditions. Elevated renal uric excretion led to a significant drop in the plasma uric acid level from 4.9 mg% to 4.2 mg% after the administration to KC1. The findings suggest that KC1 influences the tubular transport of uric acid, but the mechanism of its action is still obscure.

• MeSH
• chlorid draselný farmakologie   MeSH
• dospělí MeSH
• draslík moč   MeSH
• kyselina močová krev   moč   MeSH
• lidé MeSH
• moč MeSH
• osmolární koncentrace MeSH
• sodík moč   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chlorid draselný MeSH
• draslík MeSH
• kyselina močová MeSH
• sodík MeSH

OBJECTIVE: Uric acid is the end product of purine metabolism in humans, and increased serum uric acid concentrations lead to gout. The objective of the current study was to identify factors that are independently associated with serum uric acid concentrations in a cohort of Czech control individuals. METHODS: The cohort consisted of 589 healthy subjects aged 18-65 years. We studied the associations between the serum uric acid concentration and the following: (i) demographic, anthropometric and other variables previously reported to be associated with serum uric acid concentrations; (ii) the presence of metabolic syndrome and the levels of metabolic syndrome components; and (iii) selected genetic variants of the MTHFR (c.665C>T, c.1286A>C), SLC2A9 (c.844G>A, c.881G>A) and ABCG2 genes (c.421C>A). A backward model selection procedure was used to build two multiple linear regression models; in the second model, the number of metabolic syndrome criteria that were met replaced the metabolic syndrome-related variables. RESULTS: The models had coefficients of determination of 0.59 and 0.53. The serum uric acid concentration strongly correlated with conventional determinants including male sex, and with metabolic syndrome-related variables. In the simplified second model, the serum uric acid concentration positively correlated with the number of metabolic syndrome criteria that were met, and this model retained the explanatory power of the first model. Moderate wine drinking did not increase serum uric acid concentrations, and the urate transporter ABCG2, unlike MTHFR, was a genetic determinant of serum uric acid concentrations. CONCLUSION: Metabolic syndrome, moderate wine drinking and the c.421C>A variant in the ABCG gene are independently associated with the serum uric acid concentration. Our model indicates that uric acid should be clinically monitored in persons with metabolic syndrome.

• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry krev   genetika   MeSH
• dospělí MeSH
• exprese genu MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolický syndrom krev   genetika   patologie   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) krev   genetika   MeSH
• mladiství MeSH
• modely genetické MeSH
• nádorové proteiny krev   genetika   MeSH
• pití alkoholu krev   genetika   patologie   MeSH
• proteiny usnadňující transport glukosy krev   genetika   MeSH
• regresní analýza MeSH
• senioři MeSH
• sexuální faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry MeSH
• ABCG2 protein, human MeSH Prohlížeč
• kyselina močová MeSH
• methylentetrahydrofolátreduktasa (NADPH2) MeSH
• MTHFR protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• proteiny usnadňující transport glukosy MeSH
• SLC2A9 protein, human MeSH Prohlížeč

Uric acid and its oxidation product allantoin are excellent biomarkers of oxidative stress in humans. Currently, there are high requirements not only for tests monitoring oxidative stress but also for screening laboratory tests in general. The highest demand is imposed on the simplest sampling, easy transport of the sample, and the shortest possible analysis time. The possible solution how to fulfil the requirements is sampling by dried blood spot technique with subsequent HPLC-MS/MS analysis. A fast, sensitive, and reliable HPLC-MS/MS method for the simultaneous determination of uric acid and allantoin from dried blood spots using stable isotopically labelled analogs as internal standards was developed. The separation took place in the reversed phase within 3 min, with protein precipitation and extraction in a one-step procedure. The analytical parameters of the method were satisfactory with an excellent linear range. The presented method was used to determine allantoin and uric acid levels in dried blood spot samples from 100 healthy volunteer donors. The median uric acid concentration in the cohort was 239.3 µmol/L and the median allantoin concentration was 5.6 µmol/L. The presented analytical protocol and method are suitable for screening and monitoring allantoin and uric acid levels as biomarkers of oxidative stress in clinical practice.

• Klíčová slova
• Allantoin, Dried blood spot, Liquid chromatography, Oxidative stress, Tandem mass spectrometry, Uric acid,
• MeSH
• alantoin * analýza   MeSH
• biologické markery MeSH
• kyselina močová * MeSH
• lidé MeSH
• oxidační stres MeSH
• tandemová hmotnostní spektrometrie MeSH
• test suché kapky krve MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alantoin * MeSH
• biologické markery MeSH
• kyselina močová * MeSH

Uric acid (UA) levels are associated with many diseases including those related to lifestyle. The aim of this study was to evaluate the influence of clinical and anthropometric parameters on UA and xanthine (X) levels during pregnancy and postpartum in women with physiological pregnancy and pregnancy complicated by gestational diabetes mellitus (GDM), and to evaluate their impact on adverse perinatal outcomes. A total of 143 participants were included. Analyte levels were determined by HPLC with ultraviolet detection (HPLC-UV). Several single-nucleotide polymorphisms (SNPs) in UA transporters were genotyped using commercial assays. UA levels were higher within GDM women with pre-gestational obesity, those in high-risk groups, and those who required insulin during pregnancy. X levels were higher in the GDM group during pregnancy and also postpartum. Positive correlations between UA and X levels with body mass index (BMI) and glycemia levels were found. Gestational age at delivery was negatively correlated with UA and X levels postpartum. Postpartum X levels were significantly higher in women who underwent caesarean sections. Our data support a possible link between increased UA levels and a high-risk GDM subtype. UA levels were higher among women whose glucose tolerance was severely disturbed. Mid-gestational UA and X levels were not linked to adverse perinatal outcomes.

• Klíčová slova
• adverse perinatal outcomes, gestational diabetes mellitus, pregnancy, uric acid, uricemia, xanthine,
• MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• gestační diabetes krev   epidemiologie   MeSH
• kyselina močová krev   MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• těhotenství MeSH
• výsledek těhotenství epidemiologie   MeSH
• xanthin krev   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• kyselina močová MeSH
• xanthin 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

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
• dna (nemoc) * genetika   MeSH
• hyperurikemie * genetika   MeSH
• kotransportní proteiny pro sodík a fosfát - typ I * genetika   MeSH
• kyselina močová metabolismus   MeSH
• lidé MeSH
• přenašeče organických aniontů nezávislé na sodíku * genetika   MeSH
• přenašeče organických aniontů * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kotransportní proteiny pro sodík a fosfát - typ I * MeSH
• kyselina močová MeSH
• přenašeče organických aniontů nezávislé na sodíku * MeSH
• přenašeče organických aniontů * MeSH
• SLC17A1 protein, human MeSH Prohlížeč
• SLC22A11 protein, human MeSH Prohlížeč
• SLC22A13 protein, human MeSH Prohlížeč
• urate transporter MeSH Prohlížeč

The ascomycete fungus Aspergillus nidulans can utilize purines (adenine, guanine, hypoxanthine, xanthine, and uric acid) as sole nitrogen sources [1]. The expression of most structural genes involved in the pathway of purine uptake and catabolism is subject to uric acid induction, mediated by the product of the positive regulatory gene uaY, and to nitrogen metabolite repression, mediated by the product of the general, positive-acting, GATA-like transcription factor, encoded by the areA gene [1].

• MeSH
• Aspergillus nidulans enzymologie   genetika   MeSH
• fungální proteiny * MeSH
• geny hub genetika   MeSH
• membránové transportní proteiny genetika   MeSH
• regulace genové exprese u hub fyziologie   MeSH
• sekvenční homologie aminokyselin MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fungální proteiny * MeSH
• membránové transportní proteiny MeSH
• UAPA protein, Aspergillus nidulans MeSH Prohlížeč

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).

• Klíčová slova
• Renal hypouricemia, SLC22A12, URAT1, Uric acid transporters,
• MeSH
• dítě MeSH
• dospělí MeSH
• heterozygot * MeSH
• lidé MeSH
• missense mutace * MeSH
• mladiství MeSH
• močové kameny genetika   MeSH
• předškolní dítě MeSH
• přenašeče organických aniontů genetika   MeSH
• proteiny přenášející organické kationty genetika   MeSH
• vrozené poruchy tubulárního transportu genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Srí Lanka MeSH
• Názvy látek
• přenašeče organických aniontů MeSH
• proteiny přenášející organické kationty MeSH
• SLC22A12 protein, human MeSH Prohlížeč

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