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      Identification of GLUT12/SLC2A12 as a urate transporter that regulates the blood urate level in hyperuricemia model mice

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          Abstract

          Recent genome-wide association studies have revealed some genetic loci associated with serum uric acid levels and susceptibility to gout/hyperuricemia which contain potential candidates of physiologically important urate transporters. One of these novel loci is located upstream of SGK1 and SLC2A12, suggesting that variations in these genes increase the risks of hyperuricemia and gout. We herein focused on SLC2A12 encoding a transporter, GLUT12, the physiological function of which remains unclear. As GLUT12 belongs to the same protein family as a well-recognized urate transporter GLUT9, we hypothesized that GLUT12 mediates membrane transport of urate. Therefore, we conducted functional assays and analyzed Glut12 knockout hyperuricemia model mice, generated using the CRISPR-Cas9 system. Our results revealed that GLUT12 acts as a physiological urate transporter and its dysfunction elevates the blood urate concentration. This study provides insights into the deeper understanding of the urate regulatory system in the body, which is also important for pathophysiology of gout/hyperuricemia.

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          Most cited references 11

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          Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia.

          Renal hypouricemia is an inherited disorder characterized by impaired renal urate (uric acid) reabsorption and subsequent low serum urate levels, with severe complications such as exercise-induced acute renal failure and nephrolithiasis. We previously identified SLC22A12, also known as URAT1, as a causative gene of renal hypouricemia. However, hypouricemic patients without URAT1 mutations, as well as genome-wide association studies between urate and SLC2A9 (also called GLUT9), imply that GLUT9 could be another causative gene of renal hypouricemia. With a large human database, we identified two loss-of-function heterozygous mutations in GLUT9, which occur in the highly conserved "sugar transport proteins signatures 1/2." Both mutations result in loss of positive charges, one of which is reported to be an important membrane topology determinant. The oocyte expression study revealed that both GLUT9 isoforms showed high urate transport activities, whereas the mutated GLUT9 isoforms markedly reduced them. Our findings, together with previous reports on GLUT9 localization, suggest that these GLUT9 mutations cause renal hypouricemia by their decreased urate reabsorption on both sides of the renal proximal tubules. These findings also enable us to propose a physiological model of the renal urate reabsorption in which GLUT9 regulates serum urate levels in humans and can be a promising therapeutic target for gout and related cardiovascular diseases.
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            Hyperuricemia and urate nephropathy in urate oxidase-deficient mice.

            Urate oxidase, or uricase (EC 1.7.3.3), is a purine metabolic enzyme that catalyzes the conversion of uric acid to allantoin in most mammals except humans and certain other primates. The loss of urate oxidase in the human during primate evolution predisposes man to hyperuricemia, a metabolic disturbance that can lead to gouty arthritis and renal stones. To create a mouse model for hyperuricemia and gout, and to address the question of whether urate oxidase is essential in lower mammalian species, we have disrupted the urate oxidase gene in the mouse by homologous recombination in embryonic stem cells. Unlike the human situation, urate oxidase deficiency in mice causes pronounced hyperuricemia and urate nephropathy. More than half of the mutant mice died before 4 weeks of age, indicating that urate oxidase is essential in mice. These mutant mice may also serve as animal models for hyperuricemia and its related nephropathy in humans.
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              Genome-wide association study for serum urate concentrations and gout among African Americans identifies genomic risk loci and a novel URAT1 loss-of-function allele.

              Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using (14)C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P< 5.0 × 10(-8)): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P= 1.0 × 10(-9)), and two loci previously identified in EA participants, SLC2A9 (P= 3.8 × 10(-32)) and SLC22A12 (P= 2.1 × 10(-10)). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta -1.19 mg/dl, P= 2.7 × 10(-16)). (14)C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                4 August 2020
                20 July 2020
                20 July 2020
                : 117
                : 31
                : 18175-18177
                Affiliations
                aDepartment of Pharmacy, The University of Tokyo Hospital , Bunkyo-ku, 113-8655 Tokyo, Japan;
                bDepartment of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College , Tokorozawa, 359-8513 Saitama, Japan;
                cLaboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo , Bunkyo-ku, 113-0033 Tokyo, Japan;
                dDivision of Public Health Informatics, Department of Integrative Health Science, Nagoya University Graduate School of Medicine , 461-8673 Nagoya, Japan;
                eDepartment of Pathophysiology, Tokyo University of Pharmacy and Life Sciences , Hachioji, 192-0392 Tokyo, Japan;
                fDepartment of Human Physiology and Pathology, Faculty of Pharma-Sciences, Teikyo University , Itabashi-ku, 173-8605 Tokyo, Japan
                Author notes
                2To whom correspondence may be addressed. Email: tappei-tky@ 123456umin.ac.jp .

                Edited by Francisco Bezanilla, The University of Chicago, Chicago, IL, and approved June 29, 2020 (received for review April 14, 2020)

                Author contributions: Y.T., T.T., and H. Miyata designed research; Y.T. and H. Miyata performed research; Y.T., H. Miyata, H.K., K.N., M.H., and A.A. contributed new reagents/analytic tools; Y.T., T.T., H. Miyata, H. Matsuo, M.N., Y.K., S.S., N.S., and K.I. analyzed data; and Y.T., T.T., and H.S. wrote the paper.

                1Y.T., T.T., and H. Miyata contributed equally to this work.

                Article
                202006958
                10.1073/pnas.2006958117
                7414087
                32690690
                Copyright © 2020 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                Page count
                Pages: 3
                Product
                Funding
                Funded by: MEXT | Japan Society for the Promotion of Science (JSPS) 501100001691
                Award ID: 16H01808
                Award Recipient : Tappei Takada
                Funded by: MEXT | Japan Society for the Promotion of Science (JSPS) 501100001691
                Award ID: 20H00568
                Award Recipient : Tappei Takada
                Funded by: Gout and uric acid foundation of Japan
                Award ID: N/A
                Award Recipient : Tappei Takada
                Funded by: Takeda Science Foundation 100007449
                Award ID: N/A
                Award Recipient : Tappei Takada
                Funded by: Suzuken Memorial Foundation 100007434
                Award ID: N/A
                Award Recipient : Tappei Takada
                Funded by: Mochida Memorial Foundation for Medical and Pharmaceutical Research 501100005865
                Award ID: N/A
                Award Recipient : Tappei Takada
                Categories
                524
                Biological Sciences
                Physiology
                Brief Report

                gout, gwas, hyperuricemia, serum uric acid, urate handling

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