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Blanka Stiburkova - One of the best experts on this subject based on the ideXlab platform.
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Clinical and Functional Characterization of a Novel URAT1 Dysfunctional Variant in a Pediatric Patient with Renal Hypouricemia
Applied Sciences, 2019Co-Authors: Blanka Stiburkova, Jana Bohata, Vladimir Krylov, Andrea Mancikova, Iveta Minarikova, Jiri Vavra, Zdenek DoleželAbstract:Renal hypouricemia (RHUC) is caused by an inherited defect in the main (reabsorptive) renal urate transporters, URAT1 and GLUT9. RHUC is characterized by decreased concentrations of serum uric acid and an increase in its excretion fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report the clinical, biochemical, and genetic findings of a pediatric patient with hypouricemia. Sequencing analysis of the coding region of SLC22A12 and SLC2A9 and a functional study of a novel RHUC1 variant in the Xenopus expression system were performed. The proband showed persistent hypouricemia (67–70 µmol/L; ref. range 120–360 µmol/L) and hyperuricosuria (24–34%; ref. range 7.3 ± 1.3%). The sequencing analysis identified common non-synonymous allelic variants c.73G > A, c.844G > A, c.1049C > T in the SLC2A9 gene and rare variants c.973C > T, c.1300C > T in the SLC22A12 gene. Functional characterization of the novel RHUC associated c.973C > T (p. R325W) variant showed significantly decreased urate uptake, an irregular URAT1 signal on the plasma membrane, and reduced cytoplasmic staining. RHUC is an underdiagnosed disorder and unexplained hypouricemia warrants detailed metabolic and genetic investigations. A greater awareness of URAT1 and GLUT9 deficiency by primary care physicians, nephrologists, and urologists is crucial for identifying the disorder.
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p107 polymorphisms in slc2a9 and SLC22A12 genes are related to hyperuricemia gout and also to hypouricemia
Annals of the Rheumatic Diseases, 2019Co-Authors: K Pavelcova, Jana Bohata, K Pavelka, Blanka StiburkovaAbstract:Career situation of first and presenting author Student for a master or a PhD. Introduction Serum uric acid concentration is significantly influenced by urate transporters, such as ABCG2 (encoded by ABCG2 gene), GLUT9 (SLC2A9 gene) and URAT1 (SLC22A12 gene). The main function of ABCG2 is uric acid secretion, whereas GLU9 and URAT1 also ensure reabsorption. Pathogenic allelic variants in SLC2A9 and SLC22A12 are not only associated with hyperuricemia and gout, but they also lead to rare hereditary renal hypouricemia (type 1 – OMIM #220150 or type 2 – OMIM # 612076). Objectives Previously, we analyzed ABCG2 gene and detected non-synonymous variants that lead to hyperuricemia and early onset of the gout.1 The aim of this study was to find a possible correlation between variants in SLC2A9 and SLC22A12 and hypouricemia, hyperuricemia and gout.2 Methods We recruited a cohort of 232 individuals with primary gout and hyperuricemia. We examined coding regions of SLC2A9 (13 exons) and SLC22A12 (10 exons) by Sanger sequencing. We also analyzed SLC2A9 and SLC22A12 in five patients with suspect hypouricemia. Results In the cohort of 232 individuals, we detected five synonymous variants, 18 intron variants and seven missense variants in SLC2A9: A17T, G25R, T275M, D281H, V282I, R294H, and P350L. In SLC22A12 gene, we found six synonymous variants and seven intron variants. We detected several pathogenic variants in patients with suspect hypouricemia. Intronic variant c.1419+1G>A in SLC2A9 most likely affects the splicing. In SLC22A12, we found rare pathogenic variants T467M and L415_G417del. These variants have according to our previous study high frequency in the Czech and Slovak Roma population.3 Conclusions The uric acid level is determined by a complex mechanism that is not yet fully understood. Disorders of urate transporters can not only lead to hyperuricemia, but in rare cases also to hypouricemia. References Stiburkova B, et al. Rheumatology (Oxford) 2017 November 1;56(11):1982–1992. doi:10.1093/rheumatology/kex295 Hurba O, et al. PLoS One 2014 September 30;9(9):e107902. doi:10.1371/journal.pone.0107902 Gabrikova D, et al. Urolithiasis 2015 October;43(5):441–5. doi:10.1007/s00240-015-0790-4 Acknowledgements This study was supported by the grant from the Czech Republic Ministry of Health AZV 15-26693A. Disclosure of Interest None declared.
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a heterozygous variant in the SLC22A12 gene in a sri lanka family associated with mild renal hypouricemia
BMC Pediatrics, 2018Co-Authors: Dinesha Maduri Vidanapathirana, Subashinie Jayasena, Eresha Jasinge, Blanka StiburkovaAbstract: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. 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. 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).
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URAT1 and GLUT9 mutations in Spanish patients with renal hypouricemia
Clinica Chimica Acta, 2018Co-Authors: Felix Claverie-martin, Jorge Trujillo-suarez, Hilaria González-acosta, Cristina Aparicio, Maria L. Justa Roldan, Blanka Stiburkova, Kimiyoshi Ichida, Maria A. Martín-gomez, Maria Herrero Goñi, Marta Carrasco Hidalgo-barqueroAbstract:Abstract Background Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule, is caused by mutations in SLC22A12 or SLC2A9. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. Methods We report clinical, biochemical and genetics findings of fourteen Spanish patients, six Caucasians and eight of Roma ethnia, diagnosed with idiopathic RHUC. Two of the patients presented exercise-induced acute renal failure and another one had several episodes of nephrolithiasis and four of them had progressive deterioration of renal function, while the rest were asymptomatic. Results Molecular analysis revealed SLC22A12 mutations in ten of the patients, and SLC2A9 mutations in the other four. A new heterozygous SLC22A12 missense mutation, c.1427C>A (p.A476D), was identified in two affected members of the same family. The rest of the patients presented homozygous, heterozygous or compound heterozygous mutations that have been previously identified in patients with RHUC; SLC22A12 p.T467M and p.L415_G417del, and SLC2A9 p.T125M. Expression studies in Xenopus oocytes revealed that c.1427C>A reduced UA transport but did not alter the location of URAT1 protein on the plasma membrane. Conclusions The biochemical and clinical features of our patients together with the genetic analysis results confirmed the diagnosis of RHUC. This is the first report describing SLC22A12 and SLC2A9 mutations in Spanish patients.
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Prevalence of URAT1 allelic variants in the Roma population
Nucleosides Nucleotides & Nucleic Acids, 2016Co-Authors: Blanka Stiburkova, Dana Gabriková, Pavel Cepek, Pavel Simek, Pavol Kristian, Elizabeth Cordoba-lanus, Felix Claverie-martinAbstract:The Roma represents a transnational ethnic group, with a current European population of 8–10 million. The evolutionary process that had the greatest impact on the gene pool of the Roma population is called the founder effect. Renal hypouricemia (RHUC) is a rare heterogenous inherited disorder characterized by impaired renal urate reabsorption. The affected individuals are predisposed to recurrent episodes of exercise-induced nonmyoglobinuric acute kidney injury and nephrolithiasis. To date, more than 150 patients with a loss-of-function mutation for the SLC22A12 (URAT1) gene have been found, most of whom are Asians. However, RHUC 1 patients have been described in a variety of ethnic groups (e.g., Arab Israelis, Iraqi Jews, Caucasians, and Roma) and in geographically noncontiguous countries. This study confirms our previous findings regarding the high frequency of SLC22A12 variants observed. Frequencies of the c.1245_1253del and c.1400C>T variants were found to be 1.92% and 5.56%, respectively, in ...
Hitoshi Endou - One of the best experts on this subject based on the ideXlab platform.
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Apical Voltage-Driven Urate Efflux Transporter NPT4 in Renal Proximal Tubule
Nucleosides Nucleotides & Nucleic Acids, 2011Co-Authors: Promsuk Jutabha, Hitoshi Endou, Naohiko Anzai, Michael F. Wempe, Shin Wakui, Hiroyuki SakuraiAbstract:Uric acid (urate) is the end product of purine metabolism in humans. Human kidneys reabsorb a large proportion of filtered urate. This extensive renal reabsorption, together with the fact that humans do not possess uricase that catalyzes the biotransformation of urate into allantoin, results in a higher plasma urate concentration in humans compared to other mammals. A major determinant of plasma urate concentration is renal excretion as a function of the balance between reabsorption and secretion. We previously identified that renal urate absorption in proximal tubular epithelial cells occurs mainly via apical urate/anion exchanger, URAT1/SLC22A12, and by facilitated diffusion along the trans-membrane potential gradient by the basolateral voltage-driven urate efflux transporter, URATv1/SLC2A9/GLUT9. In contrast, the molecular mechanism by which renal urate secretion occurs remains elusive. Recently, we reported a newly characterized human voltage-driven drug efflux transporter, hNPT4/SLC17A3, which functi...
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Developing Potent Human Uric Acid Transporter 1 (hURAT1) Inhibitors
Journal of Medicinal Chemistry, 2011Co-Authors: Michael F. Wempe, Promsuk Jutabha, Naohiko Anzai, Bettina Quade, Timothy J. Iwen, Morin M. Frick, Ian R. Ross, Peter J. Rice, Hitoshi EndouAbstract:The kidneys are a vital organ in the human body. They serve several purposes including homeostatic functions such as regulating extracellular fluid volume and maintaining acid−base and electrolyte balance and are essential regarding the excretion of metabolic waste. Furthermore, the kidneys play an important role in uric acid secretion/reabsorption. Abnormalities associated with kidney transporters have been associated with various diseases, such as gout. The current study utilized Xenopus oocytes expressing human uric acid transporter 1 (hURAT1; SLC22A12) as an in vitro method to investigate novel compounds and their ability to inhibit 14C-uric acid uptake via hURAT1. We have prepared and tested a series of 2-ethyl-benzofuran compounds and probed the hURAT1 in vitro inhibitor structure−activity relationship. As compared to dimethoxy analogues, monophenols formed on the C ring showed the best in vitro inhibitory potential. Compounds with submicromolar (i.e., IC50 < 1000 nM) inhibitors were prepared by bro...
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Plasma Urate Level Is Directly Regulated by a Voltage-driven Urate Efflux Transporter URATv1 (SLC2A9) in Humans
Journal of Biological Chemistry, 2008Co-Authors: Naohiko Anzai, Kimiyoshi Ichida, Ichiro Hisatome, Promsuk Jutabha, Toru Kimura, Ellappan Babu, Sunena Srivastava, Kenichiro Kitamura, Hitoshi EndouAbstract:Abstract Hyperuricemia is a significant factor in a variety of diseases, including gout and cardiovascular diseases. Although renal excretion largely determines plasma urate concentration, the molecular mechanism of renal urate handling remains elusive. Previously, we identified a major urate reabsorptive transporter, URAT1 (SLC22A12), on the apical side of the renal proximal tubular cells. However, it is not known how urate taken up by URAT1 exits from the tubular cell to the systemic circulation. Here, we report that a sugar transport facilitator family member protein GLUT9 (SLC2A9) functions as an efflux transporter of urate from the tubular cell. GLUT9-expressed Xenopus oocytes mediated saturable urate transport (Km: 365 ± 42 μm). The transport was Na+-independent and enhanced at high concentrations of extracellular potassium favoring negative to positive potential direction. Substrate specificity and pyrazinoate sensitivity of GLUT9 was distinct from those of URAT1. The in vivo role of GLUT9 is supported by the fact that a renal hypouricemia patient without any mutations in SLC22A12 was found to have a missense mutation in SLC2A9, which reduced urate transport activity in vitro. Based on these data, we propose a novel model of transcellular urate transport in the kidney; Remunurate is taken up via apically located URAT1 and exits the cell via basolaterally located GLUT9, which we suggest be renamed URATv1 (voltage-driven urate transporter 1).
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Urate Transport Across the Apical Membrane of Renal Proximal Tubules
Nucleosides Nucleotides & Nucleic Acids, 2008Co-Authors: Hitoshi Endou, Naohiko AnzaiAbstract:Since the molecular cloning of the renal apical urate/anion exchanger URAT1 (SLC22A12), several membrane proteins relevant to urate transport have been identified. In addition, the identification of PDZ (PSD-95, DglA, and ZO-1) domain protein PDZK1 as a binding partner of URAT1, and the emerging role of PDZ scaffold for renal apical transporters have led to a new concept of renal urate transport: urate-transporting multimolecular complex, or “urate transportsome,” that may form an ultimate functional unit at the apical membrane of renal proximal tubules. Elucidation of urate transportsome will lead to the new drug development for hyperuricemia.
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New insights into renal transport of urate.
Current Opinion in Rheumatology, 2007Co-Authors: Naohiko Anzai, Yoshikatsu Kanai, Hitoshi EndouAbstract:Purpose of reviewThis review focuses on recent progress in the understanding of various aspects of renal transport of urate.Recent findingsSince the molecular cloning of the renal apical urate/anion exchanger URAT1 (SLC22A12), several membrane proteins relevant to the transport of urate have been id
Asahi Hishida - One of the best experts on this subject based on the ideXlab platform.
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The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression
Scientific Reports, 2016Co-Authors: Masayuki Sakiyama, Mariko Naito, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Takahiro Nakamura, Akiyoshi Nakayama, Toshihide Higashino, Shino Suma, Asahi HishidaAbstract:The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression
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the effects of urat1 SLC22A12 nonfunctional variants r90h and w258x on serum uric acid levels and gout hyperuricemia progression
Scientific Reports, 2016Co-Authors: Masayuki Sakiyama, Mariko Naito, Hirotaka Matsuo, Seiko Shimizu, Hiroshi Nakashima, Takahiro Nakamura, Akiyoshi Nakayama, Toshihide Higashino, Shino Suma, Asahi HishidaAbstract:The effects of URAT1/SLC22A12 nonfunctional variants,R90H and W258X, on serum uric acid levels and gout/hyperuricemia progression
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Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population
Molecular Genetics and Metabolism, 2011Co-Authors: Nobuyuki Hamajima, Asahi Hishida, Rieko Okada, Kenji Wakai, Emi Morita, Sayo Kawai, Hirotaka Matsuo, Hiroki Inoue, Yuzo TakadaAbstract:Abstract Genome-wide association studies identified that SLC2A9 ( GLUT 9) gene polymorphisms were associated with serum uric acid (SUA) levels. Among the Japanese, a C/T polymorphism in intron 8 (rs11722228) was reported to be highly significant, though the function and strength of association were unknown. This study aimed to confirm the association, estimating the means of SUA according to the genotype, as well as OR of the genotype. Subjects were 5024 health checkup examinees (3413 males and 1611 females) aged 35 to 69 years with creatinine SLC22A12 258X allele and ABCG2 126X allele are known to influence SUA levels strongly, the subjects with SLC22A12 258WW and ABCG2 126QQ (3082 males and 1453 females, in total 4535 subjects) were selected. The genotype frequency of SLC2A9 rs11722228 was 2184 for CC , 1947 for CT , and 404 for TT , being in Hardy–Weinberg equilibrium (p = 0.312). Mean SUA was 6.10 mg/dL for CC , 6.25 mg/dL for CT , and 6.45 mg/dL for TT among males (p = 1.5E-6), and 4.34 mg/dL, 4.59 mg/dL, and 4.87 mg/dL among females (p = 4.6E-11), respectively. Males with SUA less than 5.0 mg/dL were 14.7% for CC , 10.6% for CT , and 7.8% for TT (p = 2.3E-4), and females with SUA less than 4.0 mg/dL were 34.1%, 25.5%, and 15.4% (p = 3.7E-6), respectively. This study was the first report to estimate the impact of SLC2A9 rs11722228 on SUA levels. Since the allele frequency of rs11722228 is similar among different ethnic groups, the impact remains to be examined in other ethnic groups.
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serum uric acid distribution according to SLC22A12 w258x genotype in a cross sectional study of a general japanese population
BMC Medical Genetics, 2011Co-Authors: Nobuyuki Hamajima, Mariko Naito, Asahi Hishida, Rieko Okada, Yatami Asai, Kenji WakaiAbstract:Background Although SLC22A12 258X allele was found among those with hypouricemia, it was unknown that serum uric acid distribution among those with SLC22A12 258X allele. This study examined serum uric acid (SUA) distribution according to SLC22A12 W258X genotype in a general Japanese population.
Tetsuya Inazu - One of the best experts on this subject based on the ideXlab platform.
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Allele-specific real-time polymerase chain reaction as a tool for urate transporter 1 mutation detection.
Methods of Molecular Biology, 2015Co-Authors: Juliet O Makanga, Antonius Christianto, Tetsuya InazuAbstract:Allele-specific polymerase chain reaction (ASPCR) method has long been applied for the detection of nucleotide variations and genotyping, which are detected by the presence or absence of DNA amplification PCR products. Recently, Real-Time PCR genotyping has fast developed and offered a rapid method of detecting mutations without the need of gel electrophoresis as with ASPCR. Here, we describe an easy and rapid touchdown real-time PCR method for the detection of nucleotide variations. Using our method we successfully detect two main mutations in human urate transporter 1 (SLC22A12), W258X and R90H, and validate the results. The method can potentially be applied to genotype of various other nucleotide variations.
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simple and rapid detection method for the mutations in SLC22A12 that cause hypouricemia by allele specific real time polymerase chain reaction
Clinica Chimica Acta, 2013Co-Authors: Shota Takagi, Risa Omae, Juliet O Makanga, Tetsuya Kawahara, Tetsuya InazuAbstract:Abstract Background Hypouricemia is a disorder that serum urate level is less than 2.0 mg/dl, and relatively common in the Japanese population, where the main genetic cause of hypouricemia is W258X and R90H mutations in human urate trasnsporter 1(SLC22A12). Small scale screening has relied on time-consuming traditional ways like polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Therefore, it is beneficial that we have an easy and rapid detection method for these mutations. Methods In this report, we established a touchdown allele-specific real-time polymerase chain reaction (ASPCR) assay for detecting W258X and R90H mutations in SLC22A12, respectively. Results Quantifiable discrimination was successfully achieved by ∆Ct value. Furthermore, we conducted W258X and R90H screening against 120 control genome sets, whereby frequency was 2.92% for W258X, and not detected for R90H, respectively. Conclusions The two mutations, W258X and R90H in SLC22A12 were successfully genotyped by an easy and rapid ASPCR assay.
Kimiyoshi Ichida - One of the best experts on this subject based on the ideXlab platform.
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URAT1 and GLUT9 mutations in Spanish patients with renal hypouricemia
Clinica Chimica Acta, 2018Co-Authors: Felix Claverie-martin, Jorge Trujillo-suarez, Hilaria González-acosta, Cristina Aparicio, Maria L. Justa Roldan, Blanka Stiburkova, Kimiyoshi Ichida, Maria A. Martín-gomez, Maria Herrero Goñi, Marta Carrasco Hidalgo-barqueroAbstract:Abstract Background Renal hypouricemia (RHUC), a rare inherited disorder characterized by impaired uric acid (UA) reabsorption in the proximal tubule, is caused by mutations in SLC22A12 or SLC2A9. Most mutations have been identified in Japanese patients, and only a few have been detected in Europeans. Methods We report clinical, biochemical and genetics findings of fourteen Spanish patients, six Caucasians and eight of Roma ethnia, diagnosed with idiopathic RHUC. Two of the patients presented exercise-induced acute renal failure and another one had several episodes of nephrolithiasis and four of them had progressive deterioration of renal function, while the rest were asymptomatic. Results Molecular analysis revealed SLC22A12 mutations in ten of the patients, and SLC2A9 mutations in the other four. A new heterozygous SLC22A12 missense mutation, c.1427C>A (p.A476D), was identified in two affected members of the same family. The rest of the patients presented homozygous, heterozygous or compound heterozygous mutations that have been previously identified in patients with RHUC; SLC22A12 p.T467M and p.L415_G417del, and SLC2A9 p.T125M. Expression studies in Xenopus oocytes revealed that c.1427C>A reduced UA transport but did not alter the location of URAT1 protein on the plasma membrane. Conclusions The biochemical and clinical features of our patients together with the genetic analysis results confirmed the diagnosis of RHUC. This is the first report describing SLC22A12 and SLC2A9 mutations in Spanish patients.
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a novel compound heterozygous mutation in the SLC22A12 urat1 gene in a japanese patient associated with renal hypouricemia
Clinica Chimica Acta, 2016Co-Authors: Kyoko Fujita, Kimiyoshi IchidaAbstract:A novel compound heterozygous mutation, including c.935_997delinsTGG, in exons 5/6 of SLC22A12 (URAT1) was identified in a patient with renal hypouricemia. This case expands the molecular mechanisms of renal hypouricemia, and suggests a potential relationship with exercise-induced renal failure.
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Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2
Clinical and Experimental Nephrology, 2016Co-Authors: Andrea Mancikova, Kimiyoshi Ichida, I. Sebesta, Makiko Nakamura, Vladimir Krylov, Olha Hurba, Blanka StiburkovaAbstract: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.
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Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2
Clinical and Experimental Nephrology, 2015Co-Authors: Andrea Mancikova, Kimiyoshi Ichida, I. Sebesta, Makiko Nakamura, Krylov, Hurba O, Blanka StiburkovaAbstract: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).
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Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis
European Journal of Human Genetics, 2013Co-Authors: Blanka Stiburkova, Kimiyoshi Ichida, I. Sebesta, Makiko Nakamura, Helena Hulkova, Vladimir Krylov, Lenka Kryspinova, Helena JahnovaAbstract: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.