We report the identification of two pathogenic variants in the ABCG2 gene, encoding a urate exporter, in two probands (male and female) with severe familial gouty phenotypes and hyperuricemia. Clinico-genetic analyses identified p.I63YfsTer54 (rs565722112) and p.G74D (rs199976573) as potentially causal mutations; functional analyses demonstrated that these two variants are deficient in plasma membrane localization and functionally null. Our data show that dysfunctional variants in the ABCG2 gene are strong risk factors for hyperuricemia and gout in both males and females.

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

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

Department of Pharmacy The University of Tokyo Hospital Tokyo Japan

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

Institute of Rheumatology Na Slupi 4 128 50 Prague 2 Czech Republic

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Leask MP et al (2024) The pathogenesis of gout: molecular insights from genetic, epigenomic and transcriptomic studies. Nat Rev Rheumatol 20:510–523. https://doi.org/10.1038/s41584-024-01137-1 PubMed DOI

Takada T et al (2024) Regulation of urate homeostasis by membrane transporters. Gout Urate Cryst Depos Dis 2:206–219. https://doi.org/10.3390/gucdd2020016 DOI

Ichida K et al (2012) Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun 3:764. https://doi.org/10.1038/ncomms1756 PubMed DOI

Matsuo H, et al (2009) Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci Transl Med 1:5ra11. https://doi.org/10.1126/scitranslmed.3000237

Toyoda Y et al (2021) Identification of two dysfunctional variants in the ABCG2 urate transporter associated with pediatric-onset of familial hyperuricemia and early-onset gout. Int J Mol Sci 22:1935. https://doi.org/10.3390/ijms22041935 PubMed DOI PMC

Toyoda Y et al (2019) Familial early-onset hyperuricemia and gout associated with a newly identified dysfunctional variant in urate transporter ABCG2. Arthritis Res Ther 21:219. https://doi.org/10.1186/s13075-019-2007-7 PubMed DOI PMC

Toyoda Y et al (2019) Functional characterization of clinically-relevant rare variants in ABCG2 identified in a gout and hyperuricemia cohort. Cells 8:363. https://doi.org/10.3390/cells8040363 PubMed DOI PMC

Higashino T et al (2017) Multiple common and rare variants of ABCG2 cause gout. RMD Open 3:e000464. https://doi.org/10.1136/rmdopen-2017-000464 PubMed DOI PMC

Stiburkova B et al (2016) Novel dysfunctional variant in ABCG2 as a cause of severe tophaceous gout: biochemical, molecular genetics and functional analysis. Rheumatology (Oxford) 55:191–194. https://doi.org/10.1093/rheumatology/kev350 PubMed DOI

Halperin Kuhns VL, Woodward OM (2021) Urate transport in health and disease. Best Pract Res Clin Rheumatol 35:101717. https://doi.org/10.1016/j.berh.2021.101717 PubMed DOI PMC

Wallace SL et al (1977) Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 20:895–900 PubMed

Hasikova L et al (2024) Urinary oxypurinol is a useful tool to assess adherence to allopurinol in clinical practice. Rheumatology (Oxford) 63:e174–e176. https://doi.org/10.1093/rheumatology/keae009 PubMed DOI

Mraz M et al (2015) Modern diagnostic approach to hereditary xanthinuria. Urolithiasis 43:61–67. https://doi.org/10.1007/s00240-014-0734-4 PubMed DOI

Stiburkova B et al (2017) Functional non-synonymous variants of ABCG2 and gout risk. Rheumatology (Oxford) 56:1982–1992. https://doi.org/10.1093/rheumatology/kex295 PubMed DOI

Toyoda Y et al (2023) SVCT2/SLC23A2 is a sodium-dependent urate transporter: functional properties and practical application. J Biol Chem 299:104976. https://doi.org/10.1016/j.jbc.2023.104976 PubMed DOI PMC

Imai Y et al (2002) C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance. Mol Cancer Ther 1:611–616 PubMed

Saison C et al (2012) Null alleles of ABCG2 encoding the breast cancer resistance protein define the new blood group system Junior. Nat Genet 44:174–177. https://doi.org/10.1038/ng.1070 PubMed DOI PMC

Taylor NMI et al (2017) Structure of the human multidrug transporter ABCG2. Nature 546:504–509. https://doi.org/10.1038/nature22345 PubMed DOI

Major TJ et al (2024) A genome-wide association analysis reveals new pathogenic pathways in gout. Nat Genet 56:2392–2406. https://doi.org/10.1038/s41588-024-01921-5 PubMed DOI

Kvasnicka A et al (2023) Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment. Arthritis Res Ther 25:234. https://doi.org/10.1186/s13075-023-03204-6 PubMed DOI PMC