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

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

BACKGROUND: Renal hypouricaemia is a 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 (OMIM #220150), while type 2 is caused by defects in the SLC2A9 gene (OMIM #612076). CASE-DIAGNOSIS/TREATMENT: The cases of two children, a 12- and a 14-year-old boy with acute kidney injury (proband 1: urea 9.4 mmol/l, creatinine 226 μmol/l; proband 2: urea 11.7 mmol/l, creatinine 202 μmol/l) are described. Both are offspring of nonconsanguineous couples in the UK. The concentrations of serum uric acid were consistently below the normal range (0.03 and 0.04 mmol/l) and expressed as an increase in the fractional excretion of uric acid (46 and 93 %). CONCLUSIONS: A sequencing analysis of the coding region of uric acid transporters SLC22A12 and SLC2A9 was performed. Analysis of genomic DNA revealed two unpublished missense transitions, p.G216R and p.N333S in the SLC2A9 gene. No sequence variants in SLC22A12 were found. Our findings suggest that homozygous and/or compound heterozygous loss-of-function mutations p.G216R and p.N333S cause renal hypouricaemia via loss of uric acid absorption and do lead to acute kidney injury.

• MeSH
• akutní poškození ledvin genetika   metabolismus   MeSH
• dítě MeSH
• kyselina močová metabolismus   MeSH
• lidé MeSH
• missense mutace MeSH
• mladiství MeSH
• močové kameny komplikace   genetika   metabolismus   MeSH
• mutační analýza DNA MeSH
• proteiny usnadňující transport glukosy genetika   MeSH
• vrozené poruchy tubulárního transportu komplikace   genetika   metabolismus   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyselina močová MeSH
• proteiny usnadňující transport glukosy MeSH
• SLC2A9 protein, human MeSH Prohlížeč