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.

Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University General University Hospital 121 00 Prague Czech Republic

Department of Pharmacology Ajou University School of Medicine 164 Worldcup ro Yeongtong gu Suwon 16499 Korea

Department of Rheumatology 1st Faculty of Medicine Charles University 121 08 Prague Czech Republic

Faculty of Medicine University Ss Cyril and Methodius 1000 Skopje North Macedonia

Institute of Rheumatology 128 00 Prague Czech Republic

Metabolic Ambulance of Department of Paediatrics and Adolescent Medicine Children's Faculty Hospital 040 11 Košice Slovakia

Research Centre for Genetic Engineering and Biotechnology Georgi D Efremov Macedonian Academy of Sciences and Arts 1000 Skopje North Macedonia

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Bugdayci G., Balaban Y., Sahin O. Causes of Hypouricemia among Outpatients. Lab. Med. 2008;39:550–552. doi: 10.1309/H3TTUVDBE75D6N6P. DOI

Koo B.S., Jeong H.J., Son C.N., Kim S.H., Kim H.J., Kim G.H. Distribution of serum uric acid levels and prevalence of hyper- and hypouricemia in a Korean general population of 172,970. Korean J. Intern. Med. 2021;36((Suppl. S1)):S264–S272. doi: 10.3904/kjim.2020.116. PubMed DOI PMC

Enomoto A., Kimura H., Chairoungdua A., Shigeta Y., Jutabha P., Cha S.H., Endou H. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002;417:447–452. doi: 10.1038/nature742. PubMed DOI

Matsuo H., Chiba T., Nagamori S., Nakayama A., Domoto H., Phetdee K., Shinomiya N. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am. J. Hum. Genet. 2008;83:744–751. doi: 10.1016/j.ajhg.2008.11.001. PubMed DOI PMC

Sugihara S., Hisatome I., Kuwabara M., Niwa K., Maharani N., Kato M., Yamamoto K. Depletion of Uric Acid Due to SLC22A12 (URAT1) Loss-of-Function Mutation Causes Endothelial Dysfunction in Hypouricemia. Circ. J. 2015;79:1125–1132. doi: 10.1253/circj.CJ-14-1267. PubMed DOI

Mancikova A., Krylov V., Hurba O., Sebesta I., Nakamura M., Ichida K., Stiburkova B. Functional analysis of novel allelic variants in URAT1 and GLUT9 causing renal hypouricemia type 1 and 2. Clin. Exp. Nephrol. 2016;20:578–584. doi: 10.1007/s10157-015-1186-z. PubMed DOI

Dinour D., Gray N.K., Campbell S., Shu X., Sawyer L., Richardson W., Holtzman E.J. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J. Am. Soc. Nephrol. 2010;21:64–72. doi: 10.1681/ASN.2009040406. PubMed DOI PMC

Stiburkova B., Taylor J., Marinaki A.M., Sebesta I. Acute kidney injury in two children caused by renal hypouricaemia type 2. Pediatric Nephrol. 2012;27:1411–1415. doi: 10.1007/s00467-012-2174-0. PubMed DOI

Bhasin B., Stiburkova B., De Castro-Pretelt M., Beck N., Bodurtha J.N., Atta M.G. Hereditary renal hypouricemia: A new role for allopurinol? Am. J. Med. 2014;127:e3–e4. doi: 10.1016/j.amjmed.2013.08.025. PubMed DOI

Ichida K., Hosoyamada M., Kamatani N., Kamitsuji S., Hisatome I., Shibasaki T., Hosoya T. Age and origin of the G774A mutation in SLC22A12 causing renal hypouricemia in Japanese. Clin. Genet. 2008;74:243–251. doi: 10.1111/j.1399-0004.2008.01021.x. PubMed DOI

Stiburkova B., Gabrikova D., Cepek P., Simek P., Kristian P., Cordoba-Lanus E., Claverie-Martin F. Prevalence of URAT1 allelic variants in the Roma population. Nucleosides Nucleotides Nucleic Acids. 2016;35:529–535. doi: 10.1080/15257770.2016.1168839. PubMed DOI

Gabrikova D., Bernasovska J., Sokolova J., Stiburkova B. High frequency of SLC22A12 variants causing renal hypouricemia 1 in the Czech and Slovak Roma population; simple and rapid detection method by allele-specific polymerase chain reaction. Urolithiasis. 2015;43:441–445. doi: 10.1007/s00240-015-0790-4. PubMed DOI

Stiburkova B., Ichida K., Sebesta I. Novel homozygous insertion in SLC2A9 gene caused renal hypouricemia. Mol. Genet. Metab. 2011;102:430–435. doi: 10.1016/j.ymgme.2010.12.016. PubMed DOI

Stiburkova B., Sebesta I., Ichida K., Nakamura M., Hulkova H., Krylov V., Jahnova H. Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: Biochemical, genetics and functional analysis. Eur. J. Hum. Genet. 2013;21:1067–1073. doi: 10.1038/ejhg.2013.3. PubMed DOI PMC

Cha D.H., Gee H.Y., Cachau R., Choi J.M., Park D., Jee S.H., Ryu S., Cho S.K. Contribution of SLC22A12 on hypouricemia and its clinical significance for screening purposes. Sci. Rep. 2019;9:14360. doi: 10.1038/s41598-019-50798-6. PubMed DOI PMC

Nakayama A., Matsuo H., Abhishek A., Ichida K., Shinomiya N., Guideline Development Committee of Clinical Practice Guideline for Renal Hypouricaemia First clinical practice guideline for renal hypouricemia: A rare disorder that aided the development of urate-lowering drugs for gout. Rheumatology. 2021;60:3961–3963. doi: 10.1093/rheumatology/keab322. PubMed DOI

Lisyova J., Chandoga J., Jungova P., Repisky M., Knapkova M., Machkova M., Bohmer D. An unusually high frequency of SCAD deficiency caused by two pathogenic variants in the ACADS gene and its relationship to the ethnic structure in Slovakia. BMC Med. Genet. 2018;19:64. doi: 10.1186/s12881-018-0566-0. PubMed DOI PMC

Sebesta I., Stiburkova B., Bartl J., Ichida K., Hosoyamada M., Taylor J., Marinaki A. Diagnostic tests for primary renal hypouricemia. Nucleosides Nucleotides Nucleic Acids. 2011;30:1112–1116. doi: 10.1080/15257770.2011.611483. PubMed DOI

Stiburkova B., Sebesta I. Hypouricemia and hyperuricosuria in a pubescent girl: Answers. Pediatric Nephrol. 2018;33:2277–2279. doi: 10.1007/s00467-018-3934-2. PubMed DOI

Stiburkova B., Sebesta I. Hypouricemia and hyperuricosuria in a pubescent girl: Questions. Pediatric Nephrol. 2018;33:2275. doi: 10.1007/s00467-018-3926-2. PubMed DOI

Claverie-Martin F., Trujillo-Suarez J., Gonzalez-Acosta H., Aparicio C., Roldan M.L.J., Stiburkova B., Garcia-Nieto V.M. URAT1 and GLUT9 mutations in Spanish patients with renal hypouricemia. Clin. Chim. Acta. 2018;481:83–89. doi: 10.1016/j.cca.2018.02.030. PubMed DOI

Morar B., Gresham D., Angelicheva D., Tournev I., Gooding R., Guergueltcheva V., Kalaydjieva L. Mutation history of the roma/gypsies. Am. J. Hum. Genet. 2004;75:596–609. doi: 10.1086/424759. PubMed DOI PMC

Hurba O., Mancikova A., Krylov V., Pavlikova M., Pavelka K., Stiburkova B. Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: No evidence of effect on hyperuricemia and gout. PLoS ONE. 2014;9:e107902. doi: 10.1371/journal.pone.0107902. PubMed DOI PMC

Stiburkova B., Bleyer A.J. Changes in serum urate and urate excretion with age. Adv. Chronic Kidney Disease. 2012;19:372–376. doi: 10.1053/j.ackd.2012.07.010. PubMed DOI

Kolvek G., Rosicova K., Rosenberger J., Podracka L., Stewart R.E., Nagyova I., van Dijk J.P. End-stage renal disease among Roma and non-Roma: Roma are at risk. Int. J. Public Health. 2012;57:751–754. doi: 10.1007/s00038-012-0365-x. PubMed DOI

Rosenberger J., Majernikova M., Jarcuska P., Pella D., Marekova M., Geckova A.M. Higher prevalence of nephropathy in young Roma females compared with non-Roma females. Cent. Eur. J. Public Health. 2014;22:S28–S31. doi: 10.21101/cejph.a3898. PubMed DOI

Pallayova M., Brenisin M., Putrya A., Vrsko M., Drazilova S., Janicko M., Team H. Roma Ethnicity and Sex-Specific Associations of Serum Uric Acid with Cardiometabolic and Hepatorenal Health Factors in Eastern Slovakian Population: The HepaMeta Study. Int. J. Environ. Res. Public Health. 2020;17:7673. doi: 10.3390/ijerph17207673. PubMed DOI PMC

Ichida K., Hosoyamada M., Hisatome I., Enomoto A., Hikita M., Endou H., Hosoya T. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J. Am. Soc. Nephrol. 2004;15:164–173. doi: 10.1097/01.ASN.0000105320.04395.D0. PubMed DOI

Examining the Association of Rare Allelic Variants in Urate Transporters SLC22A11, SLC22A13, and SLC17A1 with Hyperuricemia and Gout

Analysis of Purine Metabolism to Elucidate the Pathogenesis of Acute Kidney Injury in Renal Hypouricemia

Functional Characterization of Rare Variants in OAT1/SLC22A6 and OAT3/SLC22A8 Urate Transporters Identified in a Gout and Hyperuricemia Cohort

Identification of a dysfunctional exon-skipping splice variant in GLUT9/SLC2A9 causal for renal hypouricemia type 2