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.

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

Department of Pharmacy The University of Tokyo Hospital Tokyo 113 8655 Japan

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

Institute of Rheumatology 128 00 Prague Czech Republic

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Dalbeth N., Choi H.K., Joosten L.A.B., Khanna P.P., Matsuo H., Perez-Ruiz F., Stamp L.K. Gout. Nat. Rev. Dis. Primers. 2019;5:69. doi: 10.1038/s41572-019-0115-y. PubMed DOI

Kawamura Y., Nakaoka H., Nakayama A., Okada Y., Yamamoto K., Higashino T., Sakiyama M., Shimizu T., Ooyama H., Ooyama K., et al. Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout. Ann. Rheum. Dis. 2019;78:1430–1437. doi: 10.1136/annrheumdis-2019-215521. PubMed DOI PMC

Dehlin M., Jacobsson L., Roddy E. Global epidemiology of gout: Prevalence, incidence, treatment patterns and risk factors. Nat. Rev. Rheumatol. 2020;16:380–390. doi: 10.1038/s41584-020-0441-1. PubMed DOI

Kuo C.F., Grainge M.J., See L.C., Yu K.H., Luo S.F., Zhang W., Doherty M. Epidemiology and management of gout in Taiwan: A nationwide population study. Arthritis Res. Ther. 2015;17:13. doi: 10.1186/s13075-015-0522-8. PubMed DOI PMC

Pascart T., Norberciak L., Ea H.K., Guggenbuhl P., Liote F. Patients with early-onset gout and development of earlier severe joint involvement and metabolic comorbid conditions: Results from a cross-sectional epidemiologic survey. Arthritis Care Res. 2019;71:986–992. doi: 10.1002/acr.23706. PubMed DOI

Zhang B., Fang W., Zeng X., Zhang Y., Ma Y., Sheng F., Zhang X. Clinical characteristics of early- and late-onset gout: A cross-sectional observational study from a Chinese gout clinic. Medicine. 2016;95:e5425. doi: 10.1097/MD.0000000000005425. PubMed DOI PMC

Enomoto A., Kimura H., Chairoungdua A., Shigeta Y., Jutabha P., Cha S.H., Hosoyamada M., Takeda M., Sekine T., Igarashi T., et al. 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., Wiriyasermkul P., Kikuchi Y., Oda T., Nishiyama J., et al. 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

Vitart V., Rudan I., Hayward C., Gray N.K., Floyd J., Palmer C.N., Knott S.A., Kolcic I., Polasek O., Graessler J., et al. SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout. Nat. Genet. 2008;40:437–442. doi: 10.1038/ng.106. PubMed DOI

Ichida K., Matsuo H., Takada T., Nakayama A., Murakami K., Shimizu T., Yamanashi Y., Kasuga H., Nakashima H., Nakamura T., et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat. Commun. 2012;3:764. doi: 10.1038/ncomms1756. PubMed DOI PMC

Woodward O.M., Kottgen A., Coresh J., Boerwinkle E., Guggino W.B., Kottgen M. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc. Natl. Acad. Sci. USA. 2009;106:10338–10342. doi: 10.1073/pnas.0901249106. PubMed DOI PMC

Matsuo H., Takada T., Ichida K., Nakamura T., Nakayama A., Ikebuchi Y., Ito K., Kusanagi Y., Chiba T., Tadokoro S., et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: A function-based genetic analysis in a Japanese population. Sci. Transl. Med. 2009;1:5ra11. doi: 10.1126/scitranslmed.3000237. PubMed DOI

Hoque K.M., Dixon E.E., Lewis R.M., Allan J., Gamble G.D., Phipps-Green A.J., Halperin Kuhns V.L., Horne A.M., Stamp L.K., Merriman T.R., et al. The ABCG2 Q141K hyperuricemia and gout associated variant illuminates the physiology of human urate excretion. Nat. Commun. 2020;11:2767. doi: 10.1038/s41467-020-16525-w. PubMed DOI PMC

Major T.J., Dalbeth N., Stahl E.A., Merriman T.R. An update on the genetics of hyperuricaemia and gout. Nat. Rev. Rheumatol. 2018;14:341–353. doi: 10.1038/s41584-018-0004-x. PubMed DOI

Nakayama A., Matsuo H., Nakaoka H., Nakamura T., Nakashima H., Takada Y., Oikawa Y., Takada T., Sakiyama M., Shimizu S., et al. Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors. Sci. Rep. 2014;4:5227. doi: 10.1038/srep05227. PubMed DOI PMC

Vlaming M.L., Lagas J.S., Schinkel A.H. Physiological and pharmacological roles of ABCG2 (BCRP): Recent findings in Abcg2 knockout mice. Adv. Drug Deliv. Rev. 2009;61:14–25. doi: 10.1016/j.addr.2008.08.007. PubMed DOI

Robey R.W., To K.K., Polgar O., Dohse M., Fetsch P., Dean M., Bates S.E. ABCG2: A perspective. Adv. Drug Deliv. Rev. 2009;61:3–13. doi: 10.1016/j.addr.2008.11.003. PubMed DOI PMC

Sarkadi B., Homolya L., Hegedus T. The ABCG2/BCRP transporter and its variants—From structure to pathology. FEBS Lett. 2020;594:4012–4034. doi: 10.1002/1873-3468.13947. PubMed DOI

Allikmets R., Schriml L.M., Hutchinson A., Romano-Spica V., Dean M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. 1998;58:5337–5339. PubMed

Doyle L.A., Yang W., Abruzzo L.V., Krogmann T., Gao Y., Rishi A.K., Ross D.D. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA. 1998;95:15665–15670. doi: 10.1073/pnas.95.26.15665. PubMed DOI PMC

Miyake K., Mickley L., Litman T., Zhan Z., Robey R., Cristensen B., Brangi M., Greenberger L., Dean M., Fojo T., et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: Demonstration of homology to ABC transport genes. Cancer Res. 1999;59:8–13. PubMed

Takada T., Yamamoto T., Matsuo H., Tan J.K., Ooyama K., Sakiyama M., Miyata H., Yamanashi Y., Toyoda Y., Higashino T., et al. Identification of ABCG2 as an exporter of uremic toxin indoxyl sulfate in mice and as a crucial factor influencing CKD progression. Sci. Rep. 2018;8:11147. doi: 10.1038/s41598-018-29208-w. PubMed DOI PMC

Heyes N., Kapoor P., Kerr I.D. Polymorphisms of the multidrug pump ABCG2: A systematic review of their effect on protein expression, function, and drug pharmacokinetics. Drug Metab. Dispos. Biol. Fate Chem. 2018;46:1886–1899. doi: 10.1124/dmd.118.083030. PubMed DOI

Stiburkova B., Pavelcova K., Zavada J., Petru L., Simek P., Cepek P., Pavlikova M., Matsuo H., Merriman T.R., Pavelka K. Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology. 2017;56:1982–1992. doi: 10.1093/rheumatology/kex295. PubMed DOI

Higashino T., Takada T., Nakaoka H., Toyoda Y., Stiburkova B., Miyata H., Ikebuchi Y., Nakashima H., Shimizu S., Kawaguchi M., et al. Multiple common and rare variants of ABCG2 cause gout. RMD Open. 2017;3:e000464. doi: 10.1136/rmdopen-2017-000464. PubMed DOI PMC

Maekawa K., Itoda M., Sai K., Saito Y., Kaniwa N., Shirao K., Hamaguchi T., Kunitoh H., Yamamoto N., Tamura T., et al. Genetic variation and haplotype structure of the ABC transporter gene ABCG2 in a Japanese population. Drug Metab. Pharmacokinet. 2006;21:109–121. doi: 10.2133/dmpk.21.109. PubMed DOI

Matsuo H., Ichida K., Takada T., Nakayama A., Nakashima H., Nakamura T., Kawamura Y., Takada Y., Yamamoto K., Inoue H., et al. Common dysfunctional variants in ABCG2 are a major cause of early-onset gout. Sci. Rep. 2013;3:2014. doi: 10.1038/srep02014. PubMed DOI PMC

Zaidi F., Narang R.K., Phipps-Green A., Gamble G.G., Tausche A.K., So A., Riches P., Andres M., Perez-Ruiz F., Doherty M., et al. Systematic genetic analysis of early-onset gout: ABCG2 is the only associated locus. Rheumatology. 2020;59:2544–2549. doi: 10.1093/rheumatology/kez685. PubMed DOI

Stiburkova B., Pavelcova K., Pavlikova M., Jesina P., Pavelka K. The impact of dysfunctional variants of ABCG2 on hyperuricemia and gout in pediatric-onset patients. Arthritis Res. Ther. 2019;21:77. doi: 10.1186/s13075-019-1860-8. 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

Pavelcova K., Bohata J., Pavlikova M., Bubenikova E., Pavelka K., Stiburkova B. Evaluation of the influence of genetic variants of SLC2A9 (GLUT9) and SLC22A12 (URAT1) on the development of hyperuricemia and gout. J. Clin. Med. 2020;9:2510. doi: 10.3390/jcm9082510. PubMed DOI PMC

Toyoda Y., Pavelcova K., Klein M., Suzuki H., Takada T., Stiburkova B. Familial early-onset hyperuricemia and gout associated with a newly identified dysfunctional variant in urate transporter ABCG2. Arthritis Res. Ther. 2019;21:219. doi: 10.1186/s13075-019-2007-7. PubMed DOI PMC

Stiburkova B., Sebesta I., Ichida K., Nakamura M., Hulkova H., Krylov V., Kryspinova L., 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

Toyoda Y., Takada T., Suzuki H. Inhibitors of human ABCG2: From technical background to recent updates with clinical implications. Front. Pharmacol. 2019;10:208. doi: 10.3389/fphar.2019.00208. PubMed DOI PMC

Miyata H., Takada T., Toyoda Y., Matsuo H., Ichida K., Suzuki H. Identification of febuxostat as a new strong ABCG2 inhibitor: Potential applications and risks in clinical situations. Front. Pharmacol. 2016;7:518. doi: 10.3389/fphar.2016.00518. PubMed DOI PMC

Toyoda Y., Mancikova A., Krylov V., Morimoto K., Pavelcova K., Bohata J., Pavelka K., Pavlikova M., Suzuki H., Matsuo H., et al. Functional characterization of clinically-relevant rare variants in ABCG2 identified in a gout and hyperuricemia cohort. Cells. 2019;8:363. doi: 10.3390/cells8040363. PubMed DOI PMC

Manolaridis I., Jackson S.M., Taylor N.M.I., Kowal J., Stahlberg H., Locher K.P. Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states. Nature. 2018;563:426–430. doi: 10.1038/s41586-018-0680-3. PubMed DOI PMC

Nakagawa H., Toyoda Y., Wakabayashi-Nakao K., Tamaki H., Osumi M., Ishikawa T. Ubiquitin-mediated proteasomal degradation of ABC transporters: A new aspect of genetic polymorphisms and clinical impacts. J. Pharm. Sci. 2011;100:3602–3619. doi: 10.1002/jps.22615. PubMed DOI

Eckenstaler R., Benndorf R.A. 3D structure of the transporter ABCG2-What’s new? Br. J. Pharmacol. 2020;177:1485–1496. doi: 10.1111/bph.14991. PubMed DOI PMC

Toyoda Y., Takada T., Miyata H., Ishikawa T., Suzuki H. Regulation of the axillary osmidrosis-associated ABCC11 protein stability by N-linked glycosylation: Effect of glucose condition. PLoS ONE. 2016;11:e0157172. doi: 10.1371/journal.pone.0157172. PubMed DOI PMC

Morar B., Gresham D., Angelicheva D., Tournev I., Gooding R., Guergueltcheva V., Schmidt C., Abicht A., Lochmuller H., Tordai A., et al. Mutation history of the Roma/Gypsies. Am. J. Hum. Genet. 2004;75:596–609. doi: 10.1086/424759. PubMed DOI PMC

Kalaydjieva L., Morar B., Chaix R., Tang H. A newly discovered founder population: The Roma/Gypsies. Bioessays. 2005;27:1084–1094. doi: 10.1002/bies.20287. PubMed DOI

Roberts R.L., Wallace M.C., Phipps-Green A.J., Topless R., Drake J.M., Tan P., Dalbeth N., Merriman T.R., Stamp L.K. ABCG2 loss-of-function polymorphism predicts poor response to allopurinol in patients with gout. Pharm. J. 2017;17:201–203. doi: 10.1038/tpj.2015.101. PubMed DOI

Wen C.C., Yee S.W., Liang X., Hoffmann T.J., Kvale M.N., Banda Y., Jorgenson E., Schaefer C., Risch N., Giacomini K.M. Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin. Pharmacol. Ther. 2015;97:518–525. doi: 10.1002/cpt.89. PubMed DOI PMC

Horvathova V., Bohata J., Pavlikova M., Pavelcova K., Pavelka K., Senolt L., Stiburkova B. Interaction of the p.Q141K variant of the ABCG2 gene with clinical data and cytokine levels in primary hyperuricemia and gout. J. Clin. Med. 2019;8:1965. doi: 10.3390/jcm8111965. PubMed DOI PMC

Lehtisalo M., Keskitalo J.E., Tornio A., Lapatto-Reiniluoto O., Deng F., Jaatinen T., Viinamaki J., Neuvonen M., Backman J.T., Niemi M. Febuxostat, but not allopurinol, markedly raises the plasma concentrations of the breast cancer resistance protein substrate rosuvastatin. Clin. Transl. Sci. 2020;13:1236–1243. doi: 10.1111/cts.12809. PubMed DOI PMC

Mackenzie I.S., Ford I., Nuki G., Hallas J., Hawkey C.J., Webster J., Ralston S.H., Walters M., Robertson M., De Caterina R., et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): A multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396:1745–1757. doi: 10.1016/S0140-6736(20)32234-0. PubMed DOI

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

Higashino T., Morimoto K., Nakaoka H., Toyoda Y., Kawamura Y., Shimizu S., Nakamura T., Hosomichi K., Nakayama A., Ooyama K., et al. Dysfunctional missense variant of OAT10/SLC22A13 decreases gout risk and serum uric acid levels. Ann. Rheum. Dis. 2020;79:164–166. doi: 10.1136/annrheumdis-2019-216044. PubMed DOI PMC

Wallace S.L., Robinson H., Masi A.T., Decker J.L., McCarty D.J., Yu T.F. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20:895–900. doi: 10.1002/art.1780200320. PubMed DOI

Mraz M., Hurba O., Bartl J., Dolezel Z., Marinaki A., Fairbanks L., Stiburkova B. Modern diagnostic approach to hereditary xanthinuria. Urolithiasis. 2015;43:61–67. doi: 10.1007/s00240-014-0734-4. 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., 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

Khunweeraphong N., Szollosi D., Stockner T., Kuchler K. The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid. Nat. Commun. 2019;10:5433. doi: 10.1038/s41467-019-13302-2. PubMed DOI PMC

Orban T.I., Seres L., Ozvegy-Laczka C., Elkind N.B., Sarkadi B., Homolya L. Combined localization and real-time functional studies using a GFP-tagged ABCG2 multidrug transporter. Biochem. Biophys. Res. Commun. 2008;367:667–673. doi: 10.1016/j.bbrc.2007.12.172. PubMed DOI

Takada T., Suzuki H., Sugiyama Y. Characterization of polarized expression of point- or deletion-mutated human BCRP/ABCG2 in LLC-PK1 cells. Pharm. Res. 2005;22:458–464. doi: 10.1007/s11095-004-1884-9. PubMed DOI

Stiburkova B., Miyata H., Zavada J., Tomcik M., Pavelka K., Storkanova G., Toyoda Y., Takada T., Suzuki H. Novel dysfunctional variant in ABCG2 as a cause of severe tophaceous gout: Biochemical, molecular genetics and functional analysis. Rheumatology. 2016;55:191–194. doi: 10.1093/rheumatology/kev350. PubMed DOI

Toyoda Y., Sakurai A., Mitani Y., Nakashima M., Yoshiura K., Nakagawa H., Sakai Y., Ota I., Lezhava A., Hayashizaki Y., et al. Earwax, osmidrosis, and breast cancer: Why does one SNP (538G>A) in the human ABC transporter ABCC11 gene determine earwax type? FASEB J. 2009;23:2001–2013. doi: 10.1096/fj.09-129098. PubMed DOI

Nakagawa H., Wakabayashi-Nakao K., Tamura A., Toyoda Y., Koshiba S., Ishikawa T. Disruption of N-linked glycosylation enhances ubiquitin-mediated proteasomal degradation of the human ATP-binding cassette transporter ABCG2. FEBS J. 2009;276:7237–7252. doi: 10.1111/j.1742-4658.2009.07423.x. PubMed DOI

Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment