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.

• Klíčová slova
• ABCG2, Gout, Hyperuricemia, Urate transport,
• Publikační typ
• časopisecké články 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.

• Klíčová slova
• ABCG2 genotype, Roma, SUA-lowering therapy, clinico-genetic analysis, ethnic specificity, genetic variations, precision medicine, rare variant, serum uric acid, urate transporter,
• MeSH
• ABC transportér z rodiny G, člen 2 genetika   metabolismus   MeSH
• dítě MeSH
• dna (nemoc) komplikace   genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• HEK293 buňky MeSH
• hyperurikemie krev   komplikace   genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• kyselina močová krev   MeSH
• lidé MeSH
• mutace MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• přenašeče organických aniontů genetika   metabolismus   MeSH
• rodokmen MeSH
• transfekce MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• kyselina močová MeSH
• nádorové proteiny MeSH
• přenašeče organických aniontů MeSH
• urate transporter MeSH Prohlížeč

Gout is an inflammatory arthritis influenced by environmental risk factors and genetic variants. The common dysfunctional p.Q141K allele of the ABCG2 gene affects gout development. We sought after the possible association between the p.Q141K variant and gout risk factors, biochemical, and clinical determinants in hyperuricemic, gouty, and acute gouty arthritis cohorts. Further, we studied the correlation of p.Q141K allele and levels of pro-/anti-inflammatory cytokines. Coding regions of the ABCG2 gene were analyzed in 70 primary hyperuricemic, 182 gout patients, and 132 normouricemic individuals. Their genotypes were compared with demographic and clinical parameters. Plasma levels of 27 cytokines were determined using a human multiplex cytokine assay. The p.Q141K variant was observed in younger hyperuricemic/gout individuals (p = 0.0003), which was associated with earlier disease onset (p = 0.004), trend toward lower BMI (p = 0.056), and C-reactive protein (CRP, p = 0.007) but a higher glomerular filtration rate (GFR, p = 0.035). Levels of 19 cytokines were higher, mainly in patients with acute gouty arthritis (p < 0.001), irrespective of the presence of the p.Q141K variant. The p.Q141K variant influences the age of onset of primary hyperuricemia or gout and other disease-linked risk factors and symptoms. There was no association with cytokine levels in the circulation.

• Klíčová slova
• ABCG2, acute gouty arthritis, cytokines, gout, hyperuricemia, p.Q141K,
• Publikační typ
• časopisecké články MeSH

ATP-binding cassette subfamily G member 2 (ABCG2) is a physiologically important urate transporter. Accumulating evidence demonstrates that congenital dysfunction of ABCG2 is an important genetic risk factor in gout and hyperuricemia; recent studies suggest the clinical significance of both common and rare variants of ABCG2. However, the effects of rare variants of ABCG2 on the risk of such diseases are not fully understood. Here, using a cohort of 250 Czech individuals of European descent (68 primary hyperuricemia patients and 182 primary gout patients), we examined exonic non-synonymous variants of ABCG2. Based on the results of direct sequencing and database information, we experimentally characterized nine rare variants of ABCG2: R147W (rs372192400), T153M (rs753759474), F373C (rs752626614), T421A (rs199854112), T434M (rs769734146), S476P (not annotated), S572R (rs200894058), D620N (rs34783571), and a three-base deletion K360del (rs750972998). Functional analyses of these rare variants revealed a deficiency in the plasma membrane localization of R147W and S572R, lower levels of cellular proteins of T153M and F373C, and null urate uptake function of T434M and S476P. Accordingly, we newly identified six rare variants of ABCG2 that showed lower or null function. Our findings contribute to deepening the understanding of ABCG2-related gout/hyperuricemia risk and the biochemical characteristics of the ABCG2 protein.

• Klíčová slova
• ABCG2/BCRP, European cohort, WGA., common disease, exon sequence, functional study, gout susceptibility, heritability of serum uric acid, multiple rare variant, urate transporter,
• MeSH
• ABC transportér z rodiny G, člen 2 genetika   metabolismus   MeSH
• běloši genetika   MeSH
• biologický transport MeSH
• dítě MeSH
• dna (nemoc) krev   genetika   metabolismus   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• HEK293 buňky MeSH
• hyperurikemie krev   genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• kohortové studie MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• předškolní dítě MeSH
• přenašeče organických aniontů metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• kyselina močová MeSH
• nádorové proteiny MeSH
• přenašeče organických aniontů MeSH
• urate transporter MeSH Prohlížeč

OBJECTIVE: Previous studies have suggested an association between gout susceptibility and common dysfunctional variants in ATP-binding cassette transporter subfamily G member 2/breast cancer resistance protein (ABCG2/BCRP), including rs72552713 (Q126X) and rs2231142 (Q141K). However, the association of rare ABCG2 variants with gout is unknown. Therefore, we investigated the effects of rare ABCG2 variants on gout susceptibility in this study. METHODS: We sequenced the exons of ABCG2 in 480 patients with gout and 480 healthy controls (Japanese males). We also performed functional analyses of non-synonymous variants of ABCG2 and analysed the correlation between urate transport function and scores from the protein prediction algorithms (Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping v2 (PolyPhen-2)). Stratified association analyses and multivariate logistic regression analysis were performed to evaluate the effects of rare and common ABCG2 variants on gout susceptibility. RESULTS: We identified 3 common and 19 rare non-synonymous variants of ABCG2. SIFT scores were significantly correlated with the urate transport function, although some ABCG2 variants showed inconsistent scores. When the effects of common variants were removed by stratified association analysis, the rare variants of ABCG2 were associated with a significantly increased risk of gout (OR=3.2, p=6.4×10-3). Multivariate logistic regression analysis revealed that the size effect of these rare ABCG2 variants (OR=2.7, p=3.0×10-3) was similar to that of the common variants, Q126X (OR=3.4, p=3.2×10-6) and Q141K (OR=2.3, p=2.7×10-16). CONCLUSIONS: This study revealed that multiple common and rare variants of ABCG2 are independently associated with gout. These results could support both the 'Common Disease, Common Variant' and 'Common Disease, Multiple Rare Variant' hypotheses for the association between ABCG2 and gout susceptibility.

• Klíčová slova
• arthritis, epidemiology, gene polymorphism, gout,
• Publikační typ
• časopisecké články MeSH