UNLABELLED: Xanthinurias are rare inherited disorders of purine metabolism. Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. Here, we described five Roma patients from four unrelated families with hypouricemia, accumulation of xanthine/hypoxanthine, deficiency of xanthine oxidase activity, variable age of diagnosis, and only asymptomatic or mild clinical course. Whole exome sequencing was performed on all probands, aged 3 to 43 years, due to lack of genetic confirmation for xanthinuria types I and II. The causality of the putative pathogenic variant was confirmed by analysis of sulfite and related metabolites and in vitro functional characterization of metal-binding pterin (MPT) synthesis and protein complex formation. Considering the rarity of the condition and recessive inheritance, 34 candidate variants were identified after filtering out allele frequency threshold in non-Finnish Europeans. An ultra-rare MOCS2 variant rs776441627 in two overlapping reading frames (c.244A > T (NM_176806.4; p.Ile82Phe) = c.57A > T (NM_004531.5; p.Leu19Phe)) segregated with the disease in all five patients (four homozygotes, one compound heterozygote). The variant has an allele frequency of 3.6% in a Roma population control group. Functional characterization revealed the significantly decreased MPT synthesis activity and confirmed the causality of rs776441627 in MoCD. CONCLUSION: The rs776441627 is a functional variant for MoCD with a mild to asymptomatic clinical phenotype and fully penetrant biochemical phenotype. Hypouricemia should be considered in the differential diagnostic algorithm of pediatric and adult patients with neurological symptoms, and MOCS2 should be considered in gene panels for xanthinuria screening. WHAT IS KNOWN: • Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. • The majority of patients with xanthinuria III present with classical early-onset MoCD due to autosomal recessive variants in the MOCS1 gene, manifesting severe progressive neurological complications during the first postnatal days. • To date, approximately 40 patients with MoCD due to pathogenic MOCS2 variants have been reported; most were diagnosed during the neonatal period with intractable seizures and feeding disorders. WHAT IS NEW: • A novel ultra-rare variant, rs776441627, located in two overlapping reading frames of the MOCS2, was identified in five Roma patients presenting a mild to asymptomatic clinical MoCD phenotype and a fully penetrant biochemical phenotype. • Functional studies of p.Ile82Phe (small MOCS2A subunit) and p.Leu19Phe (large MOCS2B subunit) demonstrate a strong reduction in molydopterin synthase complex formation and activity, consistent with the changes in biomarkers of MoCD observed in affected individuals. • The rs776441627 variant shows significantly elevated frequency among the Roma population, highlighting the importance of considering ethnic background in the differential diagnosis of MoCD. • Hypouricemia may provide an initial, generally available biochemical key marker indicator of molybdenum cofactor deficiency.

• Keywords
• Genetic screening test, MOCS, MoCD, Sulfite, Uric acid, Xanthinuria,
• MeSH
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Molybdenum Cofactors MeSH
• Child, Preschool MeSH
• Pedigree MeSH
• Roma * genetics   MeSH
• Exome Sequencing MeSH
• Sulfurtransferases * genetics   MeSH
• Metal Metabolism, Inborn Errors * genetics   ethnology   diagnosis   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Molybdenum Cofactors MeSH
• Sulfurtransferases * 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.

• Keywords
• acute kidney injury, hypouricemia, xanthinuria,
• Publication type
• Journal Article MeSH

Renal hypouricemia (RHUC) is a pathological condition characterized by extremely low serum urate and overexcretion of urate in the kidney; this inheritable disorder is classified into type 1 and type 2 based on causative genes encoding physiologically-important urate transporters, URAT1 and GLUT9, respectively; however, research on RHUC type 2 is still behind type 1. We herein describe a typical familial case of RHUC type 2 found in a Slovak family with severe hypouricemia and hyperuricosuria. Via clinico-genetic analyses including whole exome sequencing and in vitro functional assays, we identified an intronic GLUT9 variant, c.1419+1G>A, as the causal mutation that could lead the expression of p.Gly431GlufsTer28, a functionally-null variant resulting from exon 11 skipping. The causal relationship was also confirmed in another unrelated Macedonian family with mild hypouricemia. Accordingly, non-coding regions should be also kept in mind during genetic diagnosis for hypouricemia. Our findings provide a better pathogenic understanding of RHUC and pathophysiological importance of GLUT9.

• Keywords
• RHUC, genetic disorder, renal urate handling, splicing variant, urate,
• Publication type
• Journal Article MeSH

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.

• Keywords
• Roma, SLC22A12, URAT1, ethnic specificity, renal hypouricemia,
• Publication type
• Journal Article MeSH

The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K-a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type-has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 μmol/L for men or 360 μmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397-405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations-c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history.

• Keywords
• ABCG2 genotype, Roma, SUA-lowering therapy, clinico-genetic analysis, ethnic specificity, genetic variations, precision medicine, rare variant, serum uric acid, urate transporter,
• MeSH
• ATP Binding Cassette Transporter, Subfamily G, Member 2 genetics   metabolism   MeSH
• Child MeSH
• Gout complications   genetics   MeSH
• Adult MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• HEK293 Cells MeSH
• Hyperuricemia blood   complications   genetics   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Uric Acid blood   MeSH
• Humans MeSH
• Mutation MeSH
• Neoplasm Proteins genetics   metabolism   MeSH
• Organic Anion Transporters genetics   metabolism   MeSH
• Pedigree MeSH
• Transfection MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• ATP Binding Cassette Transporter, Subfamily G, Member 2 MeSH
• ABCG2 protein, human MeSH Browser
• Uric Acid MeSH
• Neoplasm Proteins MeSH
• Organic Anion Transporters MeSH
• urate transporter MeSH Browser

• Keywords
• Excretion fraction of uric acid *, Hypouricemia *, SLC22A12 *, URAT1 *, Urate transport *,
• MeSH
• Acute Kidney Injury blood   prevention & control   urine   MeSH
• Allopurinol administration & dosage   MeSH
• Antioxidants administration & dosage   MeSH
• Cystinosis blood   diagnosis   urine   MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Fanconi Syndrome blood   diagnosis   urine   MeSH
• Genetic Testing MeSH
• Uric Acid blood   metabolism   urine   MeSH
• Kidney Tubules metabolism   MeSH
• Humans MeSH
• Urinary Calculi blood   diagnosis   genetics   urine   MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Glucose Transport Proteins, Facilitative genetics   MeSH
• Renal Reabsorption MeSH
• Inappropriate ADH Syndrome blood   diagnosis   urine   MeSH
• Renal Tubular Transport, Inborn Errors blood   diagnosis   genetics   urine   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Allopurinol MeSH
• Antioxidants MeSH
• Uric Acid MeSH
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• Glucose Transport Proteins, Facilitative MeSH
• SLC22A12 protein, human MeSH Browser
• SLC2A9 protein, human MeSH Browser

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).

• Keywords
• Renal hypouricemia, SLC22A12, URAT1, Uric acid transporters,
• MeSH
• Child MeSH
• Adult MeSH
• Heterozygote * MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Adolescent MeSH
• Urinary Calculi genetics   MeSH
• Child, Preschool MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Sri Lanka MeSH
• Names of Substances
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• SLC22A12 protein, human MeSH Browser

BACKGROUND: Uric acid is the metabolic end product of purine metabolism in humans. Altered serum and urine uric acid level (both above and below the reference ranges) is an indispensable marker in detecting rare inborn errors of metabolism. We describe different case scenarios of 4 Sri Lankan patients related to abnormal uric acid levels in blood and urine. CASE 1: A one-and-half-year-old boy was investigated for haematuria and a calculus in the bladder. Xanthine crystals were seen in microscopic examination of urine sediment. Low uric acid concentrations in serum and low urinary fractional excretion of uric acid associated with high urinary excretion of xanthine and hypoxanthine were compatible with xanthine oxidase deficiency. CASE 2: An 8-month-old boy presented with intractable seizures, feeding difficulties, screaming episodes, microcephaly, facial dysmorphism and severe neuro developmental delay. Low uric acid level in serum, low fractional excretion of uric acid and radiological findings were consistent with possible molybdenum cofactor deficiency. Diagnosis was confirmed by elevated levels of xanthine, hypoxanthine and sulfocysteine levels in urine. CASE 3: A 3-year-10-month-old boy presented with global developmental delay, failure to thrive, dystonia and self-destructive behaviour. High uric acid levels in serum, increased fractional excretion of uric acid and absent hypoxanthine-guanine phosphoribosyltransferase enzyme level confirmed the diagnosis of Lesch-Nyhan syndrome. CASE 4: A 9-year-old boy was investigated for lower abdominal pain, gross haematuria and right renal calculus. Low uric acid level in serum and increased fractional excretion of uric acid pointed towards hereditary renal hypouricaemia which was confirmed by genetic studies. CONCLUSION: Abnormal uric acid level in blood and urine is a valuable tool in screening for clinical conditions related to derangement of the nucleic acid metabolic pathway.

• Keywords
• Hyperuricaemic hyperuricosuria, Hypouricaemic hyperuricosuria, Hypouricaemic hypouricosuria, Purine, Uric acid,
• MeSH
• Child MeSH
• Infant MeSH
• Uric Acid blood   MeSH
• Humans MeSH
• Metabolic Networks and Pathways MeSH
• Mass Screening * MeSH
• Child, Preschool MeSH
• Purines metabolism   MeSH
• Metabolism, Inborn Errors blood   diagnosis   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Uric Acid MeSH
• Purines 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.

• Keywords
• GLUT9, Renal hypouricemia, SLC22A12, SLC2A9, URAT1, Uric acid transporters,
• MeSH
• Child MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Urinary Calculi genetics   MeSH
• DNA Mutational Analysis MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Glucose Transport Proteins, Facilitative genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Xenopus MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• Glucose Transport Proteins, Facilitative MeSH
• SLC22A12 protein, human MeSH Browser
• SLC2A9 protein, human MeSH Browser

Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport with severe complications, such as acute kidney injury. Type 1 and 2 are caused by loss-of-function mutations in the SLC22A12 and SLC2A9 gene, respectively. A cohort of 881 randomly chosen ethnic Roma from two regions in Eastern Slovakia and two regions in the Czech Republic participated. Genomic DNA was isolated from buccal swabs and/or from blood samples. The c.1245_1253del and c.1400C>T genotypes were determined using polymerase chain reaction with allele-specific primers in a multiplex arrangement and/or direct sequencing of exon 7 and 9. Allele frequencies and genotypes were tested for Hardy-Weinberg equilibrium using the Chi-square test. 25 subjects were heterozygous and three were homozygous for the c.1245_1253del, while 92 subjects were heterozygous and two were homozygous for the c.1400C>T. Moreover, two participants were compound heterozygotes. Frequencies of the c.1245_1253del and c.1400C>T variants were 1.87 and 5.56 %, respectively. Our finding confirms an uneven geographical and ethnic distribution of SLC22A12 mutant variants. We found that the c.1245_1253del and c.1400C>T variants were present in the Czech and Slovak Roma population at unexpectedly high frequencies. Renal hypouricemia should be kept in mind during differential diagnostic on Roma patients with low serum uric acid concentrations.

• Keywords
• Acute kidney injury, Renal hypouricemia, SLC22A12, URAT1,
• MeSH
• Genetic Testing methods   MeSH
• Humans MeSH
• Urinary Calculi genetics   MeSH
• Polymerase Chain Reaction methods   MeSH
• Organic Anion Transporters genetics   MeSH
• Organic Cation Transport Proteins genetics   MeSH
• Retrospective Studies MeSH
• Roma genetics   MeSH
• Renal Tubular Transport, Inborn Errors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH
• Slovakia MeSH
• Names of Substances
• Organic Anion Transporters MeSH
• Organic Cation Transport Proteins MeSH
• SLC22A12 protein, human MeSH Browser