Search

Uric acid, the end product of purine metabolism in humans, is crucial because of its anti-oxidant activity and a causal relationship with hyperuricemia and gout. Several physiologically important urate transporters regulate this water-soluble metabolite in the human body; however, the existence of latent transporters has been suggested in the literature. We focused on the Escherichia coli urate transporter YgfU, a nucleobase-ascorbate transporter (NAT) family member, to address this issue. Only SLC23A proteins are members of the NAT family in humans. Based on the amino acid sequence similarity to YgfU, we hypothesized that SLC23A1, also known as sodium-dependent vitamin C transporter 1 (SVCT1), might be a urate transporter. First, we identified human SVCT1 and mouse Svct1 as sodium-dependent low-affinity/high-capacity urate transporters using mammalian cell-based transport assays. Next, using the CRISPR-Cas9 system followed by the crossing of mice, we generated Svct1 knockout mice lacking both urate transporter 1 and uricase. In the hyperuricemic mice model, serum urate levels were lower than controls, suggesting that Svct1 disruption could reduce serum urate. Given that Svct1 physiologically functions as a renal vitamin C re-absorber, it could also be involved in urate re-uptake from urine, though additional studies are required to obtain deeper insights into the underlying mechanisms. Our findings regarding the dual-substrate specificity of SVCT1 expand the understanding of urate handling systems and functional evolutionary changes in NAT family proteins.

Objectives Gout, caused by chronic elevation of serum uric acid levels, is the commonest form of inflammatory arthritis. The causative effect of common and rare variants of ATP-binding cassette transporter G2 (ABCG2/BCRP) on gout risk has been studied, but little attention has been paid to the effect of common (rs121907892, p.W258X) and rare variants of urate transporter 1 (URAT1/SLC22A12) on gout, despite dysfunctional variants of URAT1 having been identified as pathophysiological causes of renal hypouricaemia. Methods To address this important but overlooked issue, we investigated the effects of these URAT1 variants on gout susceptibility, using targeted exon sequencing on 480 clinically defined gout cases and 480 controls of Japanese males in combination with a series of functional analyses of newly identified URAT1 variants. Results Our results show that both common and rare dysfunctional variants of URAT1 markedly decrease the risk of gout (OR 0.0338, reciprocal OR 29.6, P = 7.66 × 10−8). Interestingly, we also found that the URAT1-related protective effect on gout eclipsed the ABCG2-related causative effect (OR 2.30–3.32). Our findings reveal only one dysfunctional variant of URAT1 to have a substantial anti-gout effect, even in the presence of causative variants of ABCG2, a ‘gout gene’. Conclusion Our findings provide a better understanding of gout/hyperuricaemia and its aetiology that is highly relevant to personalized health care. The substantial anti-gout effect of common and rare variants of URAT1 identified in the present study support the genetic concept of a ‘Common Disease, Multiple Common and Rare Variant’ model.

Organic anion transporter 10 (OAT10), also known as SLC22A13, has hitherto been identified as a urate transporter by in vitro analyses.1 Despite the reported expression of OAT10 on the apical membrane of the renal proximal tubular cells,1 the physiological impact of OAT10 on urate handling in humans remains to be elucidated. Accumulating evidence suggests that functional variants of already-characterised, physiologically important urate transporters—URAT1/SLC22A12, GLUT9/SLC2A9, BCRP/ABCG2 and NPT1/SLC17A1—affect serum uric acid (SUA) levels and susceptibility of gout,2–6 the most common form of inflammatory arthritis. However, there are no reports on the association between OAT10 gene and either hyperuricaemia or gout. Here, for the first time, we reveal that a dysfunctional variant of OAT10 decreases both gout risk and SUA levels, suggesting OAT10 to be physiologically involved in urate reabsorption in the human kidney, as described below. To explore exonic variants in OAT10 potentially associated with gout susceptibility, we sequenced all exons of OAT10 in 480 gout cases and 480 controls of Japanese male6 and conducted an association analysis (see online supplementary tables S1 and S2), followed by a replication study on 924 gout cases and 2113 controls (see online supplementary figure S1). In two identified OAT10 variants with minor allele frequency (MAF) >0.5%, only rs117371763 (c.1129C>T; p.Arg377Cys [R377C]) was significantly associated with gout susceptibility after Bonferroni correction (p=0.014). The significant association between rs117371763 and gout susceptibility was replicated, and our meta-analysis showed a significant protective effect of rs117371763 on gout susceptibility (OR=0.67; 95% CI 0.53 to 0.85; pmeta …

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.