Molecular identification of a renal urate–anion exchanger that regulates blood urate levels

Enomoto, Atsushi; Kimura, Hiroaki; Chairoungdua, Arthit; Shigeta, Yasuteru; Jutabha, Promsuk; Ho, Seok; Hosoyamada, Makoto; Takeda, Michio; Sekine, Takashi; Igarashi, Takashi; Matsuo, Hirotaka; Kikuchi, Yasufumi; Oda, Takashi; Ichida, Kimiyoshi; Hosoya, Tatsuo; Shimokata, Kaoru; Niwa, Toshimitsu; Kanai, Yoshikatsu; Endou, Hitoshi

doi:10.1038/nature742

Cited by 1,315 publications

(1,268 citation statements)

References 23 publications

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“…3 Variant p.G366R and p.L415_G417del were present in equivalent positions within the membrane. Variants p.T467M and p.R477H were localized within the putative last extracellular loop.…”

Section: Discussionmentioning

confidence: 95%

“…220150, RHUC1). 3,[5][6][7][8] More than 10 patients with RHUC caused by heterozygous defects in the SLC2A9 gene, coding GLUT9, have been described in Japan (OMIM no. 612076, RHUC2).…”

Section: Introductionmentioning

confidence: 99%

“…Ten exons encode two transcript variants of the URAT1 transporter (332 and 553 amino acids), which are specifically expressed on the apical membrane of the proximal tubules in the kidneys and in human vascular smooth muscle cells. 3 Currently, 34 mutations in the SLC22A12 coding region (28 missense/nonsense, one splicing, two regulatory, one small deletion, one small insertion, one gross deletion) have been described worldwide. Twenty-five mutations are disease causing.…”

Section: Introductionmentioning

confidence: 99%

“…Twenty-five mutations are disease causing. 3,[5][6][7][8][15][16][17][18][19] Five URAT1 variants have been described with a gout phenotype, 20 one variant is associated with increased FE-UA and two variants are associated with reduced FE-UA. 21,22 In this article we present clinical, biochemical, molecular genetics and functional characterization of previously reported p.R477H (CM042475 SNP, source HGMD-PUBLIC 2012.1) and novel p.G366R, p.L415_G417del and p.T467M variants in SLC22A12 gene responsible for RHUC1 in three Czech families.…”

Section: Introductionmentioning

confidence: 99%

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Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

et al. 2013

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Renal hypouricemia (RHUC) is a heterogeneous inherited disorder characterized by impaired tubular uric acid (UA) transport with severe complications, such as acute kidney injury (AKI). Type 1 is caused by a loss-of-function mutation in the SLC22A12 gene (URAT1), type 2 in the SLC2A9 gene (GLUT9). This article describes three Czech families with RHUC type 1. The serum UA in the probands was 0.9, 1.1 and 0.5 mg/dl and expressed as an increase in the fractional excretion of UA (48, 43 and 39%). The sequencing analysis of SLC22A12 revealed three novel variants: p.G366R, p.T467M and a deletion p.L415_G417del. A detailed metabolic investigation in proband C for progressive visual failure supported suspicion of neuronal ceroid lipofuscinosis type 7 conditioned by the mutation in the MFSD8 gene. Functional studies showed significantly decreased urate uptake and a mis-localized URAT1 signal in p.G366R, p.L415_G417del and p.T467M. Furthermore, colocalization studies showed accumulation of URAT1 protein in the endoplasmic reticulum. The findings suggest that loss-of-function mutations cause RHUC via loss of UA absorption partly by protein misfolding. However, they do not necessarily lead to AKI and a possible genotype-phenotype correlation was not proposed. Furthermore, results confirm an uneven geographical and ethnic distribution of SLC22A12 variants; the p.L415_G417del mutation predominates in the Roma ethnic group in the Czech Republic.

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“…3 Variant p.G366R and p.L415_G417del were present in equivalent positions within the membrane. Variants p.T467M and p.R477H were localized within the putative last extracellular loop.…”

Section: Discussionmentioning

confidence: 95%

“…220150, RHUC1). 3,[5][6][7][8] More than 10 patients with RHUC caused by heterozygous defects in the SLC2A9 gene, coding GLUT9, have been described in Japan (OMIM no. 612076, RHUC2).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

et al. 2013

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“…OATs also share substantial identity with OCTs, and thus, perhaps not surprisingly, the organic anion urate was identified as a substrate, demonstrating that RST is actually an organic anion transporter. Thereafter, RST has been referred to as Urat1/ URAT1 [85,86]. In addition to mice, rat and human orthologs have also been identified.…”

Section: Urat1 (Slc22a12)mentioning

confidence: 99%

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

VanWert

Gionfriddo

Sweet

2009

Biopharm & Drug Disp

222

238

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Our understanding of the mechanisms behind inter-and intra-patient variability in drug response is inadequate. Advances in the cytochrome P450 drug metabolizing enzyme field have been remarkable, but those in the drug transporter field have trailed behind. Currently, however, interest in carrier-mediated disposition of pharmacotherapeutics is on a substantial uprise. This is exemplified by the 2006 FDA guidance statement directed to the pharmaceutical industry. The guidance recommended that industry ascertain whether novel drug entities interact with transporters. This suggestion likely stems from the observation that several novel cloned transporters contribute significantly to the disposition of various approved drugs. Many drugs bear anionic functional groups, and thus interact with organic anion transporters (OATs). Collectively, these transporters are nearly ubiquitously expressed in barrier epithelia. Moreover, several reports indicate that OATs are subject to diverse forms of regulation, much like drug metabolizing enzymes and receptors. Thus, critical to furthering our understanding of patient-and condition-specific responses to pharmacotherapy is the complete characterization of OAT interactions with drugs and regulatory factors. This review provides the reader with a comprehensive account of the function and substrate profile of cloned OATs. In addition, a major focus of this review is on the regulation of OATs including the impact of transcriptional and epigenetic factors, phosphorylation, hormones and gender.

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Vitamin C Intake and the Risk of Gout in Men

Choi¹,

Gao²,

Curhan³

2009

Arch Intern Med

174

109

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Background Several metabolic studies and a recent double-blinded placebo-controlled randomized trial have shown that higher vitamin C intake significantly reduces serum uric acid levels. Yet, the relation with the risk of gout is unknown. Methods We prospectively examined over a 20-year period (1986–2006) the relation between vitamin C intake and the risk of incident gout in 46,994 male participants with no history of gout at baseline. We used a supplementary questionnaire to ascertain the American College of Rheumatology criteria for gout. Vitamin C intake was assessed every four years through validated questionnaires. Results During the 20 years of follow-up, we documented 1,317 confirmed incident cases of gout. Compared with men with vitamin C intake < 250mg/day, the multivariate relative risk (RR) of gout was 0.83 (95% confidence interval [CI], 0.71 to 0.97) for total vitamin C intake 500–999 mg/day, 0.66 (0.52 to 0.86) for 1,000–1,499 mg/day, and 0.55 (0.38 to 0.80) for ≥ 1500 mg/day (P for trend < 0.001). The multivariate RR per 500mg increase in total daily vitamin C intake was 0.83 (95% CI, 0.77 to 0.90). Compared with men who did not use supplemental vitamin C, the multivariate RR of gout was 0.66 (95% CI, 0.49 to 0.88) for supplemental vitamin C intake 1,000–1,499 mg/day and 0.55 (0.36 to 0.86) for ≥ 1500 mg/day (P for trend < 0.001). Conclusions Higher vitamin C intake is independently associated with a lower risk of gout. Supplemental vitamin C intake may be beneficial in the prevention of gout.

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Molecular identification of a renal urate–anion exchanger that regulates blood urate levels

Cited by 1,315 publications

References 23 publications

Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

Organic anion transporters: discovery, pharmacology, regulation and roles in pathophysiology

Vitamin C Intake and the Risk of Gout in Men

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