Dysfunctional missense variant of<i>OAT10/SLC22A13</i>decreases gout risk and serum uric acid levels

Higashino, Toshihide; Morimoto, Keito; Nakaoka, Hirofumi; Toyoda, Yu; Kawamura, Yusuke; Shimizu, Seiko; Nakamura, Takahiro; Hosomichi, Kazuyoshi; Nakayama, Akiyoshi; Ooyama, Keiko; Oda, Hiroshi; Shimizu, Toru; Ueno, Miki; Ito, Tsuyoshi; Tamura, Takashi; Naito, Mariko; Nakashima, Hiroshi; Kikuchi, Makoto; Mitsui, Takao; Kawai, Yosuke; Osada, Naoki; Ichida, Kimiyoshi; Yamamoto, Ken; Suzuki, Hiroshi; Shinomiya, Nariyoshi; Inoue, Ituro; Takada, Tappei

doi:10.1136/annrheumdis-2019-216044

Cited by 28 publications

(31 citation statements)

References 6 publications

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“…The urate transporters URAT1 and OAT10, co-expressed in the apical membrane of renal proximal tubule cells ( Bahn et al, 2008 ), reabsorb urate in exchange with intracellular nicotinate, pyrazinoate (PZA), or related monocarboxylates ( Enomoto et al, 2002 ; Mandal et al, 2017 ) ; the sodium monocarboxylate transporters SMCT1 and SMCT2 facilitate intracellular accumulation of these anions, resulting in “trans-activation” of apical exchange with urate ( Figure 1A ; Mandal and Mount, 2015 ; Mandal et al, 2017 ). Dysfunctional variants of URAT1 ( Enomoto et al, 2002 ) and OAT10 ( Higashino et al, 2020 ) are associated with decreased SU levels, underscoring the importance of these apical transporters in urate re-absorption. GLUT9 (expressed as two isoforms, GLUT9a and GLUT9b) is a membrane-potential driven, high-capacity urate transporter ( Anzai et al, 2008 ; Caulfield et al, 2008 ; Vitart et al, 2008 ; Witkowska et al, 2012 ; Mandal et al, 2017 ), functioning as the sole transporter for exclusive exit of reabsorbed urate from proximal tubule into blood.…”

Section: Introductionmentioning

confidence: 99%

Genetic and Physiological Effects of Insulin on Human Urate Homeostasis

et al. 2021

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Insulin and hyperinsulinemia reduce renal fractional excretion of urate (FeU) and play a key role in the genesis of hyperuricemia and gout, via uncharacterized mechanisms. To explore this association further we studied the effects of genetic variation in insulin-associated pathways on serum urate (SU) levels and the physiological effects of insulin on urate transporters. We found that urate-associated variants in the human insulin (INS), insulin receptor (INSR), and insulin receptor substrate-1 (IRS1) loci associate with the expression of the insulin-like growth factor 2, IRS1, INSR, and ZNF358 genes; additionally, we found genetic interaction between SLC2A9 and the three loci, most evident in women. We also found that insulin stimulates the expression of GLUT9 and increases [14C]-urate uptake in human proximal tubular cells (PTC-05) and HEK293T cells, transport activity that was effectively abrogated by uricosurics or inhibitors of protein tyrosine kinase (PTK), PI3 kinase, MEK/ERK, or p38 MAPK. Heterologous expression of individual urate transporters in Xenopus oocytes revealed that the [14C]-urate transport activities of GLUT9a, GLUT9b, OAT10, OAT3, OAT1, NPT1 and ABCG2 are directly activated by insulin signaling, through PI3 kinase (PI3K)/Akt, MEK/ERK and/or p38 MAPK. Given that the high-capacity urate transporter GLUT9a is the exclusive basolateral exit pathway for reabsorbed urate from the renal proximal tubule into the blood, that insulin stimulates both GLUT9 expression and urate transport activity more than other urate transporters, and that SLC2A9 shows genetic interaction with urate-associated insulin-signaling loci, we postulate that the anti-uricosuric effect of insulin is primarily due to the enhanced expression and activation of GLUT9.

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Section: Introductionmentioning

confidence: 99%

Genetic and Physiological Effects of Insulin on Human Urate Homeostasis

et al. 2021

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“…Thus, we can assume the presence of latent mechanisms causing the decreased (<5%) FE-UA levels observed in our patients. Although there is little information available regarding this, a possible factor could be increased renal urate reabsorption, which can be mediated by up-regulation of renal urate re-absorbers, including URAT1/SLC22A12, GLUT9 / SLC2A9 , and organic anion transporter 10 (known as SLC22A13 ) [ 49 ]. In this context, genetic variations affecting the expression of such genes will be the targets of future studies.…”

Section: Discussionmentioning

confidence: 99%

Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout

Toyoda

Pavelcová

Bohatá

et al. 2021

IJMS

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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.

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“…Nonetheless, given that the interaction of free FAs with cellular membranes occurs within minutes [21] and usually requires biochemical conversion of FAs into phospholipids, the experimental period we used in this study, 20 s incubation for urate uptake, was so short that the tested FAs must have had a negligible effect on the plasma membranes during the assay. Finally, the effects of FAs on other physiologically important urate transporters-GLUT9/SLC2A9 [29,30], OAT10/SLC22A13 [31], and ABCG2/BCRP [32][33][34]-remain to be elucidated. Since such urate transporters, including URAT1, coordinately regulate the behavior of urate in the human body, comprehensive understanding of the latent interaction between FAs and these transporters should be addressed in the future.…”

Section: Discussionmentioning

confidence: 99%

Omega-3 Polyunsaturated Fatty Acids Inhibit the Function of Human URAT1, a Renal Urate Re-Absorber

et al. 2020

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The beneficial effects of fatty acids (FAs) on human health have attracted widespread interest. However, little is known about the impact of FAs on the handling of urate, the end-product of human purine metabolism, in the body. Increased serum urate levels occur in hyperuricemia, a disease that can lead to gout. In humans, urate filtered by the glomerulus of the kidney is majorly re-absorbed from primary urine into the blood via the urate transporter 1 (URAT1)-mediated pathway. URAT1 inhibition, thus, contributes to decreasing serum urate concentration by increasing net renal urate excretion. Here, we investigated the URAT1-inhibitory effects of 25 FAs that are commonly contained in foods or produced in the body. For this purpose, we conducted an in vitro transport assay using cells transiently expressing URAT1. Our results showed that unsaturated FAs, especially long-chain unsaturated FAs, inhibited URAT1 more strongly than saturated FAs. Among the tested unsaturated FAs, eicosapentaenoic acid, α-linolenic acid, and docosahexaenoic acid exhibited substantial URAT1-inhibitory activities, with half maximal inhibitory concentration values of 6.0, 14.2, and 15.2 μM, respectively. Although further studies are required to investigate whether the ω-3 polyunsaturated FAs can be employed as uricosuric agents, our findings further confirm FAs as nutritionally important substances influencing human health.

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Dysfunctional missense variant ofOAT10/SLC22A13decreases gout risk and serum uric acid levels

Cited by 28 publications

References 6 publications

Genetic and Physiological Effects of Insulin on Human Urate Homeostasis

Genetic and Physiological Effects of Insulin on Human Urate Homeostasis

Identification of Two Dysfunctional Variants in the ABCG2 Urate Transporter Associated with Pediatric-Onset of Familial Hyperuricemia and Early-Onset Gout

Omega-3 Polyunsaturated Fatty Acids Inhibit the Function of Human URAT1, a Renal Urate Re-Absorber

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