{"gene":"SLC2A9","run_date":"2026-06-10T07:46:33","timeline":{"discoveries":[{"year":2008,"finding":"SLC2A9 (GLUT9) mediates high-capacity urate transport in Xenopus laevis oocytes, with urate transported at rates 45- to 60-fold faster than glucose. Glucose and fructose facilitate SLC2A9-mediated urate transport, and the uricosuric drug benzbromarone inhibits transport dose-dependently (Ki = 27 µM). siRNA knockdown of SLC2A9 in a mammalian cell line diminished urate transport, confirming specificity.","method":"Xenopus laevis oocyte expression system, HEK cell overexpression, siRNA knockdown, radiolabeled urate flux assay","journal":"PLoS medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted urate transport in oocytes and mammalian cells, confirmed by siRNA knockdown, multiple orthogonal methods, replicated across labs","pmids":["18842065"],"is_preprint":false},{"year":2008,"finding":"SLC2A9 (GLUT9/URATv1) functions as a voltage-driven efflux transporter of urate on the basolateral side of renal proximal tubular cells. Transport in Xenopus oocytes is Na+-independent, saturable (Km ~365 µM), and enhanced by high extracellular potassium (negative-to-positive potential direction). A missense mutation in SLC2A9 found in a renal hypouricemia patient reduced urate transport in vitro, supporting the in vivo role.","method":"Xenopus laevis oocyte expression system, two-electrode voltage clamp, radiolabeled urate uptake, patient mutation functional assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with electrophysiology and flux assay, patient mutation validation, multiple orthogonal methods","pmids":["18701466"],"is_preprint":false},{"year":2008,"finding":"SLC2A9 exhibits strong uric acid transport activity in Xenopus laevis oocytes. This established SLC2A9, previously known only as a fructose transporter, as a urate transporter influencing serum uric acid concentration and fractional excretion of uric acid.","method":"Xenopus laevis oocyte expression system, urate transport assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct transport assay in oocytes, replicated across multiple independent labs in the same year","pmids":["18327257"],"is_preprint":false},{"year":2008,"finding":"Loss-of-function mutations in SLC2A9 (GLUT9) cause renal hypouricemia. Two heterozygous mutations in the 'sugar transport proteins signatures 1/2' region markedly reduced urate transport activity of both GLUT9 isoforms in Xenopus oocytes. The localization of GLUT9 on both sides of the renal proximal tubules suggests it regulates urate reabsorption on apical and basolateral membranes.","method":"Xenopus oocyte expression system, mutant transporter functional assay, sequencing of patient samples","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro functional assay of patient mutations in oocytes, replicated in subsequent studies","pmids":["19026395"],"is_preprint":false},{"year":2009,"finding":"Homozygous SLC2A9 mutations (L75R missense and a 36-kb deletion causing truncated protein) cause severe renal hypouricemia with fractional excretion of uric acid >150%. The L75R mutation dramatically impaired uric acid transport in vitro, establishing GLUT9 as essential for renal uric acid reabsorption.","method":"In vitro transport assay (patient mutation), genome-wide homozygosity screen, sequencing","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro mutation functional assay with clear loss-of-function phenotype, confirmed by homozygosity mapping","pmids":["19926891"],"is_preprint":false},{"year":2014,"finding":"SLC2A9 has two isoforms with distinct subcellular localizations in the kidney: SLC2A9-L (540 aa) localizes to the basolateral membrane of proximal tubules, while SLC2A9-S (512 aa) localizes to the apical membrane of collecting duct cells. In MDCK cells, SLC2A9-L is restricted to the basolateral membrane and SLC2A9-S is at both apical and basolateral membranes. N-terminal amino acids play a role in protein stability and trafficking. The unique N-terminus of SLC2A9-L (>30 aa deletion leads to mislocalization and lysosomal targeting) determines basolateral sorting.","method":"Isoform-specific antibody staining of human kidney sections, GFP-fusion protein expression in MDCK cells, N-terminal deletion/substitution mutagenesis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by isoform-specific antibody in human tissue plus mutagenesis in polarized epithelial cells, multiple orthogonal methods","pmids":["24409316"],"is_preprint":false},{"year":2014,"finding":"SLC2A9 is a direct transcriptional target of p53. Oxidative stress induces SLC2A9 expression in a p53-dependent manner. SLC2A9 reduces intracellular reactive oxygen species (ROS) by transporting uric acid (an antioxidant) into cells, and its inhibition (by siRNA or probenecid) increases ROS levels and sensitizes cancer cells to chemotherapeutic drugs. Expression of SLC2A9 protected against DNA damage and cell death.","method":"siRNA knockdown, reporter assay, p53-dependent gene expression analysis, ROS measurement, drug treatment (probenecid)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (siRNA, reporter assay, ROS assay) in single lab; p53-binding to promoter not shown by ChIP in abstract","pmids":["24858040"],"is_preprint":false},{"year":2014,"finding":"The nuclear receptor HNF4α binds a site in the promoter of SLC2A9 isoform 1 and transcriptionally activates SLC2A9 expression. Mutation of the HNF4α binding site diminished promoter activation; HNF4α overexpression induced endogenous SLC2A9 expression in vitro; chromatin immunoprecipitation confirmed HNF4α binding at the SLC2A9 promoter in vivo.","method":"In silico promoter analysis, reporter gene assay, site-directed mutagenesis, HNF4α overexpression, ChIP assay, RT-qPCR in human kidney samples","journal":"American journal of physiology. Renal physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reporter assay with mutagenesis, ChIP in vivo, overexpression with endogenous mRNA validation; multiple orthogonal methods in single lab","pmids":["25209865"],"is_preprint":false},{"year":2011,"finding":"Kidney-specific transgenic overexpression of URATv1 (SLC2A9) in mice decreased urate excretion compared to wild-type mice, indicating that increased SLC2A9 activity in the kidney enhances urate reabsorption. Plasma urate concentrations were not significantly different, suggesting compensatory mechanisms exist.","method":"Kidney-specific transgenic mouse model (URAT1 promoter-driven SLC2A9), plasma and urine urate measurement","journal":"Nucleosides, nucleotides & nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo transgenic mouse model with urate measurements, single lab, single method approach","pmids":["22132990"],"is_preprint":false},{"year":2018,"finding":"SLC2A9 mediates urate reabsorption in the mouse kidney in vivo. Inducible kidney-specific deletion of GLUT9 (kiKO mice) caused a major increase in urinary urate excretion and fractional excretion of urate within 4 days, without spontaneous kidney stones. kiKO mice also displayed lower blood pressure with increased heart rate.","method":"Tetracycline-inducible kidney-specific knockout mouse (Cre-lox), urate/creatinine ratio measurement, 24-hour urine collection, blood pressure monitoring","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO mouse with well-defined renal phenotype, multiple physiological readouts, clear loss-of-function result","pmids":["30105595"],"is_preprint":false},{"year":2014,"finding":"Intestinal (enterocyte) SLC2A9/GLUT9 regulates whole-body uric acid clearance and metabolism. Glut9-deficient mice developed impaired enterocyte uric acid transport kinetics, hyperuricemia, hyperuricosuria, spontaneous hypertension, dyslipidemia, and elevated body fat. Treatment with allopurinol (xanthine oxidase inhibitor) reversed the hypertension and hypercholesterolemia, indicating these metabolic effects are mediated by elevated uric acid.","method":"Whole-body SLC2A9 knockout mouse model, urate transport kinetics assay, allopurinol pharmacological rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple metabolic phenotypes and pharmacological rescue by allopurinol, multi-readout study","pmids":["25100214"],"is_preprint":false},{"year":2008,"finding":"A missense mutation (C188F) in the SLC2A9 gene, along with promoter mutations reducing expression of one isoform, causes hyperuricosuria and hyperuricemia in Dalmatian dogs and other dog breeds. This demonstrates SLC2A9 mediates uric acid transport in the liver and renal proximal tubules across mammalian species.","method":"Positional cloning, linkage mapping, sequence and expression analysis, breed-specific mutation verification","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — positional cloning with genetic and expression evidence in multiple breeds; no in vitro transport assay reported in abstract","pmids":["18989453"],"is_preprint":false},{"year":2018,"finding":"Systematic functional analysis of human SLC2A9 (Glut9) disease-causing variants using 14C-urate uptake assay and two-electrode voltage clamp (TEVC) in Xenopus oocytes showed that most variants decreased urate transport. No variant permitted glucose transport. Two categories of dysfunction were identified: reduced cell-surface expression causing low activity, and full surface expression with decreased intrinsic activity. Residue N333S showed decreased urate affinity, suggesting it contributes to the urate binding pocket. C210F displayed lower transport ability.","method":"Xenopus oocyte expression, 14C-urate uptake flux assay, two-electrode voltage clamp, immunostaining, cell-surface biotinylation","journal":"Frontiers in physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic in vitro reconstitution with multiple orthogonal methods (flux, electrophysiology, surface expression), multiple mutants analyzed","pmids":["29967582"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of human SLC2A9 were determined in apo (3.3 Å) and urate-bound (4.1 Å) forms, both captured in inward-open conformation. Modeling of the outward-facing conformation revealed alternative salt bridge pairs on the cytoplasmic side that may balance energetics of the alternating access mechanism. The structures elucidate the molecular basis for urate selectivity and the locations of disease-causing mutations within the transporter.","method":"Cryo-EM structural determination, molecular modeling of outward-facing conformation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures at near-atomic resolution with disease mutation mapping; single lab but highest-quality method","pmids":["39937868"],"is_preprint":false},{"year":2011,"finding":"Two novel homozygous SLC2A9 missense mutations (R171C and T125M) dramatically reduced urate transport activity in Xenopus laevis oocytes. Molecular modeling showed both mutations are located within the inner channel that transports urate between cytoplasmic and extracellular regions, providing a structural basis for loss of function.","method":"Xenopus oocyte transport assay, molecular modeling","journal":"Nephrology, dialysis, transplantation","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro transport assay in oocytes with molecular modeling, single lab, limited structural validation","pmids":["21810765"],"is_preprint":false},{"year":2021,"finding":"The SLC2A9 variant p.Met126Val (in the short isoform; p.Met155Val in long isoform) significantly reduced uric acid transport in Xenopus oocytes without affecting protein expression level. Molecular dynamics simulation predicted the mutation hinders uric acid transport by disrupting the outward open geometry of the transporter.","method":"Xenopus oocyte expression and urate transport assay, molecular dynamics simulation, whole-exome sequencing","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro oocyte transport assay with molecular dynamics modeling, single lab, single method for functional assay","pmids":["34572357"],"is_preprint":false},{"year":2023,"finding":"An intronic SLC2A9 variant (c.1419+1G>A) causes exon 11 skipping, producing a functionally null frameshift variant (p.Gly431GlufsTer28), confirmed as causal for renal hypouricemia type 2 by in vitro functional assays and identification in a second unrelated family.","method":"Whole exome sequencing, in vitro functional assay, mini-gene splicing assay, family segregation analysis","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro splicing and functional assay, confirmed in two unrelated families","pmids":["36733941"],"is_preprint":false},{"year":2016,"finding":"GLUT9/SLC2A9 protein (immunoreactive) was detected in ependymal cells, neurons, and brain capillaries of mouse brain by immunostaining and in situ hybridization, suggesting urate transport by SLC2A9 occurs in the murine brain, potentially providing neuroprotection.","method":"Immunostaining, highly-sensitive in situ hybridization","journal":"Fluids and barriers of the CNS","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization only by immunostaining and ISH, no functional consequence demonstrated in this study","pmids":["27955673"],"is_preprint":false},{"year":2024,"finding":"SLC2A9 rs16890979 (V282I missense) reduces uric acid absorption in kidney organoids derived from gene-edited human embryonic stem cells. SLC2A9 overexpression increased urate absorption and SLC2A9 knockdown decreased it in the same system. Additionally, urate treatment of organoids with SLC2A9 overexpression induced epithelial-mesenchymal transition (EMT), suggesting a mechanism for hyperuricosuria-related renal injury.","method":"Human ESC-derived kidney organoids with CRISPR gene editing, SLC2A9 overexpression and shRNA knockdown, urate absorption assay, histopathological analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human organoid model with gene editing and knockdown controls, multiple readouts, single lab","pmids":["38269090"],"is_preprint":false},{"year":2000,"finding":"SLC2A9 (GLUT9) was identified as a novel member of the facilitative glucose transporter family encoding a predicted 540 amino acid protein with 12 transmembrane domains. Northern analysis revealed expression primarily in kidney and liver. The gene was localized to chromosome 4p15.3-p16.","method":"cDNA cloning, Northern blot analysis, hydropathic analysis, somatic cell hybrid mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — initial molecular cloning with expression analysis; no functional transport assay performed in this paper","pmids":["10860667"],"is_preprint":false}],"current_model":"SLC2A9 (GLUT9/URATv1) is a voltage-driven, high-capacity facilitative urate transporter with two isoforms: SLC2A9-L localizes to the basolateral membrane of renal proximal tubules (mediating urate efflux back to plasma) and SLC2A9-S localizes to the apical membrane of collecting duct cells; together these mediate transcellular urate reabsorption in the kidney, with transport being Na+-independent, electrogenic, and inhibitable by uricosuric drugs such as benzbromarone and probenecid. Cryo-EM structures captured in the inward-open conformation reveal the urate binding pocket and disease-mutation locations, and indicate an alternating-access mechanism. SLC2A9 is also expressed in enterocytes (regulating intestinal urate clearance) and in the liver; its transcription is regulated by HNF4α and p53, and p53-induced SLC2A9 expression reduces intracellular ROS by facilitating urate import as an antioxidant. Loss-of-function mutations in SLC2A9 cause renal hypouricemia type 2 in humans and hyperuricosuria in dogs."},"narrative":{"mechanistic_narrative":"SLC2A9 (GLUT9/URATv1) is a Na+-independent, voltage-driven, high-capacity facilitative urate transporter that mediates transcellular urate reabsorption in the kidney and regulates whole-body uric acid handling [PMID:18842065, PMID:18701466, PMID:30105595]. Originally cloned as a facilitative glucose transporter family member with 12 predicted transmembrane domains and kidney/liver expression [PMID:10860667], it was reclassified when reconstitution in Xenopus oocytes showed urate is transported 45- to 60-fold faster than glucose, with transport that is saturable, electrogenic, enhanced by extracellular potassium, and dose-dependently inhibited by the uricosuric drug benzbromarone [PMID:18842065, PMID:18701466, PMID:18327257]. Two isoforms partition the transport task across renal epithelia: the long isoform (SLC2A9-L) sorts to the basolateral membrane of proximal tubule cells via its unique N-terminus, while the short isoform (SLC2A9-S) localizes to the apical membrane of collecting duct cells [PMID:24409316]. In vivo, inducible kidney-specific deletion sharply increases urinary urate excretion, establishing SLC2A9 as the principal mediator of renal urate reabsorption, while intestinal/enterocyte SLC2A9 governs whole-body urate clearance, with its loss producing hyperuricemia, hypertension, and dyslipidemia that are reversed by xanthine oxidase inhibition [PMID:30105595, PMID:25100214]. Transcription is activated by the nuclear receptor HNF4α binding the isoform-1 promoter and is induced by p53 under oxidative stress, where urate import lowers intracellular ROS, linking SLC2A9 to antioxidant defense and chemoresistance [PMID:24858040, PMID:25209865]. Cryo-EM structures in apo and urate-bound inward-open states define the urate selectivity pocket and an alternating-access mechanism, and map the loss-of-function disease mutations onto the transport pathway [PMID:39937868, PMID:29967582]. Loss-of-function mutations in SLC2A9 cause renal hypouricemia type 2 in humans and analogous hyperuricosuria in dogs [PMID:19926891, PMID:36733941, PMID:18989453].","teleology":[{"year":2000,"claim":"Establishing the molecular identity of SLC2A9 as a facilitative transporter family member set the structural and expression baseline before any transport function was known.","evidence":"cDNA cloning, Northern blot, hydropathy analysis, chromosomal mapping","pmids":["10860667"],"confidence":"Medium","gaps":["No transport substrate identified in this study","Annotated as a glucose transporter, which proved misleading"]},{"year":2008,"claim":"The central question of what SLC2A9 transports was answered by reconstitution showing it is a high-capacity, Na+-independent, electrogenic urate transporter rather than a glucose transporter, redefining its physiological role.","evidence":"Xenopus oocyte expression, two-electrode voltage clamp, radiolabeled urate flux, siRNA knockdown, benzbromarone inhibition","pmids":["18842065","18701466","18327257"],"confidence":"High","gaps":["Isoform-specific subcellular localization not resolved","Directionality (efflux vs reabsorption) in intact epithelium not directly shown"]},{"year":2008,"claim":"Linking SLC2A9 loss-of-function to human renal hypouricemia connected the transport activity to a defined disease, demonstrating its essential role in renal urate reabsorption.","evidence":"Patient sequencing plus mutant transporter functional assays in oocytes; positional cloning in Dalmatian dogs","pmids":["19026395","18989453"],"confidence":"Medium","gaps":["Apical vs basolateral contribution to reabsorption not dissected","Dog study lacked direct in vitro transport assay"]},{"year":2009,"claim":"Homozygous null and missense mutations producing extreme fractional urate excretion confirmed GLUT9 as essential and non-redundant for renal urate reabsorption.","evidence":"Homozygosity mapping, sequencing, in vitro transport assay of L75R mutant","pmids":["19926891"],"confidence":"High","gaps":["Mechanism of compensatory transport in heterozygotes unaddressed"]},{"year":2011,"claim":"In vivo kidney overexpression and additional patient mutations refined the model that renal SLC2A9 activity scales urate reabsorption and that disease mutations map to the urate-conducting channel.","evidence":"Kidney-specific transgenic mouse; oocyte transport assay with molecular modeling of R171C/T125M","pmids":["22132990","21810765"],"confidence":"Medium","gaps":["Plasma urate unchanged in transgenic mice implies unquantified compensation","Channel model based on homology modeling, not experimental structure"]},{"year":2014,"claim":"Resolving the two isoforms' distinct polarized localizations explained how a single gene executes transcellular urate movement across different nephron segments.","evidence":"Isoform-specific antibody staining of human kidney, GFP-fusion in MDCK cells, N-terminal mutagenesis","pmids":["24409316"],"confidence":"High","gaps":["Quantitative contribution of each isoform to net reabsorption not measured","Trafficking machinery recognizing the N-terminal sorting signal not identified"]},{"year":2014,"claim":"Identifying HNF4α and p53 as transcriptional regulators placed SLC2A9 within gene-regulatory networks controlling renal expression and oxidative-stress responses, the latter via urate's antioxidant import.","evidence":"Reporter assays, ChIP, HNF4α overexpression (renal promoter); siRNA, reporter assay, ROS measurement, probenecid (p53/oxidative stress)","pmids":["25209865","24858040"],"confidence":"Medium","gaps":["p53 promoter occupancy by ChIP not demonstrated","Crosstalk between HNF4α and p53 regulation unexplored"]},{"year":2014,"claim":"Extending function beyond the kidney, intestinal SLC2A9 was shown to govern whole-body urate clearance, linking transport loss to hyperuricemia-driven metabolic and cardiovascular phenotypes.","evidence":"Whole-body knockout mouse, enterocyte urate transport kinetics, allopurinol pharmacological rescue","pmids":["25100214"],"confidence":"High","gaps":["Relative renal vs intestinal contribution to systemic urate not quantified","Molecular link between urate and hypertension/dyslipidemia not defined"]},{"year":2018,"claim":"Inducible kidney-specific knockout established in vivo that renal SLC2A9 directly mediates urate reabsorption, while systematic variant analysis classified disease mutations into surface-expression versus intrinsic-activity defects and implicated specific residues in the binding pocket.","evidence":"Tetracycline-inducible kidney KO mouse with urate/creatinine and blood pressure readouts; oocyte 14C-urate uptake, TEVC, surface biotinylation across multiple variants","pmids":["30105595","29967582"],"confidence":"High","gaps":["No urate variant conferred glucose transport, leaving substrate-switch determinants undefined at the time","Cause of blood-pressure phenotype in kiKO mice not mechanistically resolved"]},{"year":2025,"claim":"Cryo-EM structures in apo and urate-bound inward-open states defined the urate selectivity pocket and an alternating-access mechanism, providing the structural framework onto which disease mutations are mapped.","evidence":"Cryo-EM (3.3 Å apo, 4.1 Å urate-bound), modeling of outward-facing conformation; corroborated by oocyte/organoid variant studies and molecular dynamics","pmids":["39937868","34572357","38269090","36733941"],"confidence":"High","gaps":["Outward-open state captured only by modeling, not experimentally","Structural basis for voltage dependence and potassium enhancement not resolved"]},{"year":null,"claim":"How SLC2A9 activity is dynamically regulated across tissues (brain, liver, intestine) and how its antioxidant urate-import role integrates with its bulk reabsorptive function in disease remain open.","evidence":"","pmids":[],"confidence":"Low","gaps":["Functional role of brain SLC2A9 shown only by localization, not activity","Post-translational and trafficking regulation in vivo undefined","Mechanism linking urate transport to EMT/renal injury not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,9,12]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,9,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[10]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["HNF4A","TP53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NRM0","full_name":"Solute carrier family 2, facilitated glucose transporter member 9","aliases":["Glucose transporter type 9","GLUT-9","Urate transporter"],"length_aa":540,"mass_kda":58.7,"function":"High-capacity urate transporter, which may play a role in the urate reabsorption by proximal tubules (PubMed:18327257, PubMed:18701466, PubMed:22647630, PubMed:28083649, PubMed:36749388). May have a residual high-affinity, low-capacity glucose and fructose transporter activity (PubMed:18327257, PubMed:18701466, PubMed:18842065). Transports urate at rates 45- to 60-fold faster than glucose (PubMed:18842065). Does not transport galactose (PubMed:28083649). May mediate small uptake of adenine but not of other nucleobases (PubMed:22647630)","subcellular_location":"Cell membrane; Apical cell membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NRM0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC2A9","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC2A9","total_profiled":1310},"omim":[{"mim_id":"612076","title":"HYPOURICEMIA, RENAL, 2; RHUC2","url":"https://www.omim.org/entry/612076"},{"mim_id":"606142","title":"SOLUTE CARRIER FAMILY 2 (FACILITATED GLUCOSE TRANSPORTER), MEMBER 9; SLC2A9","url":"https://www.omim.org/entry/606142"},{"mim_id":"220150","title":"HYPOURICEMIA, RENAL, 1; RHUC1","url":"https://www.omim.org/entry/220150"},{"mim_id":"138900","title":"URIC ACID CONCENTRATION, SERUM, QUANTITATIVE TRAIT LOCUS 1; UAQTL1","url":"https://www.omim.org/entry/138900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":27.3},{"tissue":"liver","ntpm":20.0}],"url":"https://www.proteinatlas.org/search/SLC2A9"},"hgnc":{"alias_symbol":["Glut9","GLUTX","URATv1"],"prev_symbol":[]},"alphafold":{"accession":"Q9NRM0","domains":[{"cath_id":"1.20.1250.20","chopping":"53-253","consensus_level":"medium","plddt":91.7971,"start":53,"end":253},{"cath_id":"1.20.1250.20","chopping":"303-521","consensus_level":"medium","plddt":88.7484,"start":303,"end":521},{"cath_id":"1.10.286","chopping":"255-299","consensus_level":"medium","plddt":88.4411,"start":255,"end":299}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRM0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRM0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRM0-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC2A9","jax_strain_url":"https://www.jax.org/strain/search?query=SLC2A9"},"sequence":{"accession":"Q9NRM0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRM0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRM0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRM0"}},"corpus_meta":[{"pmid":"18327257","id":"PMC_18327257","title":"SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18327257","citation_count":614,"is_preprint":false},{"pmid":"18327256","id":"PMC_18327256","title":"SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18327256","citation_count":332,"is_preprint":false},{"pmid":"19026395","id":"PMC_19026395","title":"Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19026395","citation_count":303,"is_preprint":false},{"pmid":"18842065","id":"PMC_18842065","title":"SLC2A9 is a high-capacity urate transporter in humans.","date":"2008","source":"PLoS medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18842065","citation_count":290,"is_preprint":false},{"pmid":"18701466","id":"PMC_18701466","title":"Plasma urate level is directly regulated by a voltage-driven urate efflux transporter URATv1 (SLC2A9) in humans.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18701466","citation_count":290,"is_preprint":false},{"pmid":"19926891","id":"PMC_19926891","title":"Homozygous SLC2A9 mutations cause severe renal hypouricemia.","date":"2009","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19926891","citation_count":178,"is_preprint":false},{"pmid":"10860667","id":"PMC_10860667","title":"Cloning and expression analysis of a novel member of the facilitative glucose transporter family, SLC2A9 (GLUT9).","date":"2000","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10860667","citation_count":165,"is_preprint":false},{"pmid":"25100214","id":"PMC_25100214","title":"Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25100214","citation_count":159,"is_preprint":false},{"pmid":"18989453","id":"PMC_18989453","title":"Mutations in the SLC2A9 gene cause hyperuricosuria and hyperuricemia in the dog.","date":"2008","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18989453","citation_count":88,"is_preprint":false},{"pmid":"19877038","id":"PMC_19877038","title":"Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case-control sample sets.","date":"2009","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/19877038","citation_count":87,"is_preprint":false},{"pmid":"18487473","id":"PMC_18487473","title":"Sex-specific association of the putative fructose transporter SLC2A9 variants with uric acid levels is modified by BMI.","date":"2008","source":"Diabetes care","url":"https://pubmed.ncbi.nlm.nih.gov/18487473","citation_count":83,"is_preprint":false},{"pmid":"24026676","id":"PMC_24026676","title":"Sugar-sweetened beverage consumption: a risk factor for prevalent gout with SLC2A9 genotype-specific effects on serum urate and risk of gout.","date":"2013","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/24026676","citation_count":80,"is_preprint":false},{"pmid":"24858040","id":"PMC_24858040","title":"The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24858040","citation_count":76,"is_preprint":false},{"pmid":"24409316","id":"PMC_24409316","title":"Expression of SLC2A9 isoforms in the kidney and their localization in polarized epithelial cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24409316","citation_count":69,"is_preprint":false},{"pmid":"23349133","id":"PMC_23349133","title":"Population-specific influence of SLC2A9 genotype on the acute hyperuricaemic response to a fructose load.","date":"2013","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/23349133","citation_count":58,"is_preprint":false},{"pmid":"29967582","id":"PMC_29967582","title":"Human Mutations in SLC2A9 (Glut9) Affect Transport Capacity for Urate.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29967582","citation_count":56,"is_preprint":false},{"pmid":"19723617","id":"PMC_19723617","title":"Associations of a non-synonymous variant in SLC2A9 with gouty arthritis and uric acid levels in Han Chinese subjects and Solomon Islanders.","date":"2009","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19723617","citation_count":51,"is_preprint":false},{"pmid":"21256783","id":"PMC_21256783","title":"Novel homozygous insertion in SLC2A9 gene caused renal hypouricemia.","date":"2011","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21256783","citation_count":45,"is_preprint":false},{"pmid":"21810765","id":"PMC_21810765","title":"Two novel homozygous SLC2A9 mutations cause renal hypouricemia type 2.","date":"2011","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/21810765","citation_count":43,"is_preprint":false},{"pmid":"20589538","id":"PMC_20589538","title":"Variation in the uric acid transporter gene SLC2A9 and its association with AAO of Parkinson's disease.","date":"2010","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/20589538","citation_count":41,"is_preprint":false},{"pmid":"30105595","id":"PMC_30105595","title":"SLC2A9 (GLUT9) mediates urate reabsorption in the mouse kidney.","date":"2018","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30105595","citation_count":40,"is_preprint":false},{"pmid":"25268603","id":"PMC_25268603","title":"Complex analysis of urate transporters SLC2A9, SLC22A12 and functional characterization of non-synonymous allelic variants of GLUT9 in the Czech population: no evidence of effect on hyperuricemia and gout.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25268603","citation_count":36,"is_preprint":false},{"pmid":"20348110","id":"PMC_20348110","title":"Bayesian methods for instrumental variable analysis with genetic instruments ('Mendelian randomization'): example with urate transporter SLC2A9 as an instrumental variable for effect of urate levels on metabolic syndrome.","date":"2010","source":"International journal of epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/20348110","citation_count":36,"is_preprint":false},{"pmid":"27116386","id":"PMC_27116386","title":"A Novel Homozygous SLC2A9 Mutation Associated with Renal-Induced Hypouricemia.","date":"2016","source":"American journal of nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/27116386","citation_count":30,"is_preprint":false},{"pmid":"24379826","id":"PMC_24379826","title":"Genome-wide association analysis confirms and extends the association of SLC2A9 with serum uric acid levels to Mexican Americans.","date":"2013","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24379826","citation_count":30,"is_preprint":false},{"pmid":"20197412","id":"PMC_20197412","title":"Variation in the uric acid transporter gene (SLC2A9) and memory performance.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20197412","citation_count":29,"is_preprint":false},{"pmid":"24628802","id":"PMC_24628802","title":"Recurrent exercise-induced acute kidney injury by idiopathic renal hypouricemia with a novel mutation in the SLC2A9 gene and literature review.","date":"2014","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/24628802","citation_count":28,"is_preprint":false},{"pmid":"21536615","id":"PMC_21536615","title":"Recurrent EIARF and PRES with severe renal hypouricemia by compound heterozygous SLC2A9 mutation.","date":"2011","source":"Pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/21536615","citation_count":27,"is_preprint":false},{"pmid":"21186168","id":"PMC_21186168","title":"Association between SLC2A9 transporter gene variants and uric acid phenotypes in African American and white families.","date":"2010","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21186168","citation_count":25,"is_preprint":false},{"pmid":"24301058","id":"PMC_24301058","title":"Replication of the effect of SLC2A9 genetic variation on serum uric acid levels in American Indians.","date":"2013","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24301058","citation_count":23,"is_preprint":false},{"pmid":"24397858","id":"PMC_24397858","title":"Recurrent exercise-induced acute renal failure in a young Pakistani man with severe renal hypouricemia and SLC2A9 compound heterozygosity.","date":"2014","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24397858","citation_count":23,"is_preprint":false},{"pmid":"24821702","id":"PMC_24821702","title":"Abundant local interactions in the 4p16.1 region suggest functional mechanisms underlying SLC2A9 associations with human serum uric acid.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24821702","citation_count":23,"is_preprint":false},{"pmid":"34887389","id":"PMC_34887389","title":"Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34887389","citation_count":20,"is_preprint":false},{"pmid":"21511506","id":"PMC_21511506","title":"Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population.","date":"2011","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21511506","citation_count":20,"is_preprint":false},{"pmid":"26552468","id":"PMC_26552468","title":"Genetic analysis of ABCG2 and SLC2A9 gene polymorphisms in gouty arthritis in a Korean population.","date":"2015","source":"The Korean journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26552468","citation_count":19,"is_preprint":false},{"pmid":"25209865","id":"PMC_25209865","title":"Transcriptional regulation of urate transportosome member SLC2A9 by nuclear receptor HNF4α.","date":"2014","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25209865","citation_count":19,"is_preprint":false},{"pmid":"21584282","id":"PMC_21584282","title":"The rs1014290 polymorphism of the SLC2A9 gene is associated with type 2 diabetes mellitus in Han Chinese.","date":"2011","source":"Experimental diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/21584282","citation_count":18,"is_preprint":false},{"pmid":"20972595","id":"PMC_20972595","title":"Association of an intronic SNP of SLC2A9 gene with serum uric acid levels in the Chinese male Han population by high-resolution melting method.","date":"2010","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/20972595","citation_count":18,"is_preprint":false},{"pmid":"27255295","id":"PMC_27255295","title":"Association between SLC2A9 (GLUT9) gene polymorphisms and gout susceptibility: an updated meta-analysis.","date":"2016","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/27255295","citation_count":16,"is_preprint":false},{"pmid":"27955673","id":"PMC_27955673","title":"Immunohistochemical and in situ hybridization study of urate transporters GLUT9/URATv1, ABCG2, and URAT1 in the murine brain.","date":"2016","source":"Fluids and barriers of the CNS","url":"https://pubmed.ncbi.nlm.nih.gov/27955673","citation_count":15,"is_preprint":false},{"pmid":"20162745","id":"PMC_20162745","title":"Association of nephrolithiasis and gene for glucose transporter type 9 (SLC2A9): study of 145 patients.","date":"2010","source":"Croatian medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/20162745","citation_count":15,"is_preprint":false},{"pmid":"27225847","id":"PMC_27225847","title":"Additive composite ABCG2, SLC2A9 and SLC22A12 scores of high-risk alleles with alcohol use modulate gout risk.","date":"2016","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27225847","citation_count":15,"is_preprint":false},{"pmid":"26528330","id":"PMC_26528330","title":"Association of SLC2A9 genotype with phenotypic variability of serum urate in pre-menopausal women.","date":"2015","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26528330","citation_count":15,"is_preprint":false},{"pmid":"22393348","id":"PMC_22393348","title":"Polymorphisms in the presumptive promoter region of the SLC2A9 gene are associated with gout in a Chinese male population.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22393348","citation_count":15,"is_preprint":false},{"pmid":"25007794","id":"PMC_25007794","title":"Copy number polymorphisms near SLC2A9 are associated with serum uric acid concentrations.","date":"2014","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25007794","citation_count":13,"is_preprint":false},{"pmid":"22132990","id":"PMC_22132990","title":"Increased expression of SLC2A9 decreases urate excretion from the kidney.","date":"2011","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/22132990","citation_count":12,"is_preprint":false},{"pmid":"25606423","id":"PMC_25606423","title":"Four pairs of gene-gene interactions associated with increased risk for type 2 diabetes (CDKN2BAS-KCNJ11), obesity (SLC2A9-IGF2BP2, FTO-APOA5), and hypertension (MC4R-IGF2BP2) in Chinese women.","date":"2014","source":"Meta gene","url":"https://pubmed.ncbi.nlm.nih.gov/25606423","citation_count":12,"is_preprint":false},{"pmid":"23422251","id":"PMC_23422251","title":"Short communication: genetic variations of SLC2A9 in relation to Parkinson's disease.","date":"2013","source":"Translational neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/23422251","citation_count":11,"is_preprint":false},{"pmid":"34210831","id":"PMC_34210831","title":"Aotearoa New Zealand Māori and Pacific Population-amplified Gout Risk Variants: CLNK Is a Separate Risk Gene at the SLC2A9 Locus.","date":"2021","source":"The Journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/34210831","citation_count":11,"is_preprint":false},{"pmid":"38269090","id":"PMC_38269090","title":"SLC2A9 rs16890979 reduces uric acid absorption by kidney organoids.","date":"2024","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38269090","citation_count":10,"is_preprint":false},{"pmid":"20162744","id":"PMC_20162744","title":"Interactions between genetic variants in glucose transporter type 9 (SLC2A9) and dietary habits in serum uric acid regulation.","date":"2010","source":"Croatian medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/20162744","citation_count":10,"is_preprint":false},{"pmid":"22212408","id":"PMC_22212408","title":"Effects of SLC2A9 variants on uric acid levels in a Korean population.","date":"2012","source":"Rheumatology international","url":"https://pubmed.ncbi.nlm.nih.gov/22212408","citation_count":10,"is_preprint":false},{"pmid":"31131560","id":"PMC_31131560","title":"Amplicon targeted resequencing for SLC2A9 and SLC22A12 identified novel mutations in hypouricemia subjects.","date":"2019","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31131560","citation_count":9,"is_preprint":false},{"pmid":"39607832","id":"PMC_39607832","title":"Triglyceride-glucose index and its additive interaction with ABCG2/SLC2A9 polygenic risk score on hyperuricemia in middle age and older adults: findings from the DLCC and BHMC study.","date":"2024","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39607832","citation_count":9,"is_preprint":false},{"pmid":"36733941","id":"PMC_36733941","title":"Identification of a dysfunctional exon-skipping splice variant in GLUT9/SLC2A9 causal for renal hypouricemia type 2.","date":"2023","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36733941","citation_count":9,"is_preprint":false},{"pmid":"24940677","id":"PMC_24940677","title":"Identification of a hypouricemia patient with SLC2A9 R380W, a pathogenic mutation for renal hypouricemia type 2.","date":"2014","source":"Nucleosides, nucleotides & nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/24940677","citation_count":9,"is_preprint":false},{"pmid":"27052299","id":"PMC_27052299","title":"Associations between SLC2A9 polymorphisms and gout susceptibility : A meta-analysis.","date":"2017","source":"Zeitschrift fur Rheumatologie","url":"https://pubmed.ncbi.nlm.nih.gov/27052299","citation_count":8,"is_preprint":false},{"pmid":"37176161","id":"PMC_37176161","title":"Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M).","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37176161","citation_count":8,"is_preprint":false},{"pmid":"29523220","id":"PMC_29523220","title":"Overexpression of Uric Acid Transporter SLC2A9 Inhibits Proliferation of Hepatocellular Carcinoma Cells.","date":"2018","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/29523220","citation_count":8,"is_preprint":false},{"pmid":"25476142","id":"PMC_25476142","title":"Association of an Exon SNP of SLC2A9 Gene with Hyperuricemia Complicated with Type 2 Diabetes Mellitus in the Chinese Male Han Population.","date":"2015","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/25476142","citation_count":7,"is_preprint":false},{"pmid":"26098909","id":"PMC_26098909","title":"Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26098909","citation_count":7,"is_preprint":false},{"pmid":"26345926","id":"PMC_26345926","title":"SLC2A9 and ZNF518B polymorphisms correlate with gout-related metabolic indices in Chinese Tibetan populations.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26345926","citation_count":6,"is_preprint":false},{"pmid":"23272134","id":"PMC_23272134","title":"Changes in uric acid levels following bariatric surgery are not associated with SLC2A9 variants in the Swedish Obese Subjects Study.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23272134","citation_count":6,"is_preprint":false},{"pmid":"30087870","id":"PMC_30087870","title":"An Intron Variant of SLC2A9 Increases the Risk for Type 2 Diabetes Mellitus Complicated with Hyperuricemia in Chinese Male Population.","date":"2018","source":"Iranian journal of public health","url":"https://pubmed.ncbi.nlm.nih.gov/30087870","citation_count":6,"is_preprint":false},{"pmid":"30189835","id":"PMC_30189835","title":"Long-term effects of the SLC2A9 G844A and SLC22A12 C246T variants on serum uric acid concentrations in children.","date":"2018","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/30189835","citation_count":6,"is_preprint":false},{"pmid":"29158942","id":"PMC_29158942","title":"The Single Nucleotide Polymorphism rs1014290 of the SLC2A9 Gene Is Associated with Uric Acid Metabolism in Parkinson's Disease.","date":"2017","source":"Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/29158942","citation_count":5,"is_preprint":false},{"pmid":"34572357","id":"PMC_34572357","title":"Characterization of a Compound Heterozygous SLC2A9 Mutation That Causes Hypouricemia.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/34572357","citation_count":4,"is_preprint":false},{"pmid":"39937868","id":"PMC_39937868","title":"Structural basis of disease mutation and substrate recognition by the human SLC2A9 transporter.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/39937868","citation_count":4,"is_preprint":false},{"pmid":"39828898","id":"PMC_39828898","title":"Red blood cell urate levels are linked to hemolysis in vitro and post-transfusion as a function of donor sex, population and genetic polymorphisms in SLC2A9 and ABCG2.","date":"2025","source":"Transfusion","url":"https://pubmed.ncbi.nlm.nih.gov/39828898","citation_count":4,"is_preprint":false},{"pmid":"34603806","id":"PMC_34603806","title":"Mutation in the SLC2A9 Gene: A New Family with Familial Renal Hypouricemia Type 2.","date":"2021","source":"Case reports in nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/34603806","citation_count":4,"is_preprint":false},{"pmid":"26538670","id":"PMC_26538670","title":"Primary portal vein hypoplasia and SLC2A9 mutation associated with urate urolithiasis in a Spanish water dog.","date":"2015","source":"The Canadian veterinary journal = La revue veterinaire canadienne","url":"https://pubmed.ncbi.nlm.nih.gov/26538670","citation_count":4,"is_preprint":false},{"pmid":"38689651","id":"PMC_38689651","title":"Polymorphism rs3733591 of the SLC2A9 gene and metabolic syndrome affect gout risk in Taiwan Biobank subjects.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38689651","citation_count":3,"is_preprint":false},{"pmid":"36557230","id":"PMC_36557230","title":"Gene Dose-Dependent and Additive Effects of ABCG2 rs2231142 and SLC2A9 rs3733591 Genetic Polymorphisms on Serum Uric Acid Levels.","date":"2022","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/36557230","citation_count":3,"is_preprint":false},{"pmid":"27119840","id":"PMC_27119840","title":"[ROLE OF SLC2A9 AND ABCG2 GENE POLYMORPHISMS IN ORIGIN OF HYPERURICEMIA AND GOUT].","date":"2016","source":"Georgian medical news","url":"https://pubmed.ncbi.nlm.nih.gov/27119840","citation_count":3,"is_preprint":false},{"pmid":"39698087","id":"PMC_39698087","title":"Mechanism of intestinal flora affecting SLC2A9 transport function to promote the formation of hyperuricemia.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39698087","citation_count":3,"is_preprint":false},{"pmid":"30350810","id":"PMC_30350810","title":"Association of solute carrier family 2, member 9 (SLC2A9) genetic variant rs3733591 with gout in a Malay sample set.","date":"2018","source":"The Medical journal of Malaysia","url":"https://pubmed.ncbi.nlm.nih.gov/30350810","citation_count":3,"is_preprint":false},{"pmid":"39421323","id":"PMC_39421323","title":"Renal hypouricemia type 2 with SLC2A9 compound heterozygous variants: a case report of recurrent acute kidney injury triggered by low-intensity exercise.","date":"2024","source":"Frontiers in nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/39421323","citation_count":3,"is_preprint":false},{"pmid":"34499869","id":"PMC_34499869","title":"Identification of two novel heterozygous SLC2A9 mutations in a Chinese woman and review of literature.","date":"2021","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34499869","citation_count":2,"is_preprint":false},{"pmid":"40373704","id":"PMC_40373704","title":"Single Nucleotide Variants of the SLC2A9 Gene Are Associated with Hyperuricemia in Mexican Patients with Type 2 Diabetes.","date":"2025","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/40373704","citation_count":2,"is_preprint":false},{"pmid":"40765230","id":"PMC_40765230","title":"PCR-based detection of hereditary mutations in SLC2A9, BTBD17, and NECAP1 among native Korean dog breeds.","date":"2025","source":"Journal of veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/40765230","citation_count":1,"is_preprint":false},{"pmid":"40779481","id":"PMC_40779481","title":"Diagnostic Significance of SLC2A9 Gene Polymorphisms and Serum Biomarkers in Gout and Hyperuricemia.","date":"2025","source":"Clinical laboratory","url":"https://pubmed.ncbi.nlm.nih.gov/40779481","citation_count":0,"is_preprint":false},{"pmid":"41837832","id":"PMC_41837832","title":"Mendelian Randomization Identified SLC2A9 as a Novel cis-eQTL-Mediated Susceptibility Gene in Suppressing Renal Cancer and Its Related Metabolic Mechanisms.","date":"2026","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/41837832","citation_count":0,"is_preprint":false},{"pmid":"40996129","id":"PMC_40996129","title":"Prevalence of the SOD1, PRCD and SLC2A9 gene mutations responsible for degenerative myelopathy, progressive rod-cone degeneration, and hyperuricosuria in Polish population of Labrador Retriever dogs.","date":"2025","source":"Polish journal of veterinary sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40996129","citation_count":0,"is_preprint":false},{"pmid":"29615104","id":"PMC_29615104","title":"Genetic analysis for rs2280205 (A>G) and rs2276961 (T>C) in SLC2A9 polymorphism for the susceptibility of gout in Cameroonians: a pilot study.","date":"2018","source":"BMC research notes","url":"https://pubmed.ncbi.nlm.nih.gov/29615104","citation_count":0,"is_preprint":false},{"pmid":"41826282","id":"PMC_41826282","title":"A potential association of SLC2A9 variant rs7442295 with uric acid at baseline and in interaction with iloperidone.","date":"2026","source":"The pharmacogenomics journal","url":"https://pubmed.ncbi.nlm.nih.gov/41826282","citation_count":0,"is_preprint":false},{"pmid":"39173651","id":"PMC_39173651","title":"[First detection of the SLC2A9:p.C188F gene defect in a German Hunting Terrier with ammonium urate urolithiasis].","date":"2024","source":"Tierarztliche Praxis. Ausgabe K, Kleintiere/Heimtiere","url":"https://pubmed.ncbi.nlm.nih.gov/39173651","citation_count":0,"is_preprint":false},{"pmid":"42235823","id":"PMC_42235823","title":"Associations between dietary micronutrient intake and serum urate concentrations are dependent on SLC2A9 polymorphism rs12498742: A UK Biobank cohort study.","date":"2026","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/42235823","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47099,"output_tokens":5165,"usd":0.109386,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13491,"output_tokens":3601,"usd":0.07874,"stage2_stop_reason":"end_turn"},"total_usd":0.188126,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"SLC2A9 (GLUT9) mediates high-capacity urate transport in Xenopus laevis oocytes, with urate transported at rates 45- to 60-fold faster than glucose. Glucose and fructose facilitate SLC2A9-mediated urate transport, and the uricosuric drug benzbromarone inhibits transport dose-dependently (Ki = 27 µM). siRNA knockdown of SLC2A9 in a mammalian cell line diminished urate transport, confirming specificity.\",\n      \"method\": \"Xenopus laevis oocyte expression system, HEK cell overexpression, siRNA knockdown, radiolabeled urate flux assay\",\n      \"journal\": \"PLoS medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted urate transport in oocytes and mammalian cells, confirmed by siRNA knockdown, multiple orthogonal methods, replicated across labs\",\n      \"pmids\": [\"18842065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SLC2A9 (GLUT9/URATv1) functions as a voltage-driven efflux transporter of urate on the basolateral side of renal proximal tubular cells. Transport in Xenopus oocytes is Na+-independent, saturable (Km ~365 µM), and enhanced by high extracellular potassium (negative-to-positive potential direction). A missense mutation in SLC2A9 found in a renal hypouricemia patient reduced urate transport in vitro, supporting the in vivo role.\",\n      \"method\": \"Xenopus laevis oocyte expression system, two-electrode voltage clamp, radiolabeled urate uptake, patient mutation functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with electrophysiology and flux assay, patient mutation validation, multiple orthogonal methods\",\n      \"pmids\": [\"18701466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SLC2A9 exhibits strong uric acid transport activity in Xenopus laevis oocytes. This established SLC2A9, previously known only as a fructose transporter, as a urate transporter influencing serum uric acid concentration and fractional excretion of uric acid.\",\n      \"method\": \"Xenopus laevis oocyte expression system, urate transport assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct transport assay in oocytes, replicated across multiple independent labs in the same year\",\n      \"pmids\": [\"18327257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss-of-function mutations in SLC2A9 (GLUT9) cause renal hypouricemia. Two heterozygous mutations in the 'sugar transport proteins signatures 1/2' region markedly reduced urate transport activity of both GLUT9 isoforms in Xenopus oocytes. The localization of GLUT9 on both sides of the renal proximal tubules suggests it regulates urate reabsorption on apical and basolateral membranes.\",\n      \"method\": \"Xenopus oocyte expression system, mutant transporter functional assay, sequencing of patient samples\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro functional assay of patient mutations in oocytes, replicated in subsequent studies\",\n      \"pmids\": [\"19026395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Homozygous SLC2A9 mutations (L75R missense and a 36-kb deletion causing truncated protein) cause severe renal hypouricemia with fractional excretion of uric acid >150%. The L75R mutation dramatically impaired uric acid transport in vitro, establishing GLUT9 as essential for renal uric acid reabsorption.\",\n      \"method\": \"In vitro transport assay (patient mutation), genome-wide homozygosity screen, sequencing\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro mutation functional assay with clear loss-of-function phenotype, confirmed by homozygosity mapping\",\n      \"pmids\": [\"19926891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC2A9 has two isoforms with distinct subcellular localizations in the kidney: SLC2A9-L (540 aa) localizes to the basolateral membrane of proximal tubules, while SLC2A9-S (512 aa) localizes to the apical membrane of collecting duct cells. In MDCK cells, SLC2A9-L is restricted to the basolateral membrane and SLC2A9-S is at both apical and basolateral membranes. N-terminal amino acids play a role in protein stability and trafficking. The unique N-terminus of SLC2A9-L (>30 aa deletion leads to mislocalization and lysosomal targeting) determines basolateral sorting.\",\n      \"method\": \"Isoform-specific antibody staining of human kidney sections, GFP-fusion protein expression in MDCK cells, N-terminal deletion/substitution mutagenesis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by isoform-specific antibody in human tissue plus mutagenesis in polarized epithelial cells, multiple orthogonal methods\",\n      \"pmids\": [\"24409316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC2A9 is a direct transcriptional target of p53. Oxidative stress induces SLC2A9 expression in a p53-dependent manner. SLC2A9 reduces intracellular reactive oxygen species (ROS) by transporting uric acid (an antioxidant) into cells, and its inhibition (by siRNA or probenecid) increases ROS levels and sensitizes cancer cells to chemotherapeutic drugs. Expression of SLC2A9 protected against DNA damage and cell death.\",\n      \"method\": \"siRNA knockdown, reporter assay, p53-dependent gene expression analysis, ROS measurement, drug treatment (probenecid)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (siRNA, reporter assay, ROS assay) in single lab; p53-binding to promoter not shown by ChIP in abstract\",\n      \"pmids\": [\"24858040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The nuclear receptor HNF4α binds a site in the promoter of SLC2A9 isoform 1 and transcriptionally activates SLC2A9 expression. Mutation of the HNF4α binding site diminished promoter activation; HNF4α overexpression induced endogenous SLC2A9 expression in vitro; chromatin immunoprecipitation confirmed HNF4α binding at the SLC2A9 promoter in vivo.\",\n      \"method\": \"In silico promoter analysis, reporter gene assay, site-directed mutagenesis, HNF4α overexpression, ChIP assay, RT-qPCR in human kidney samples\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reporter assay with mutagenesis, ChIP in vivo, overexpression with endogenous mRNA validation; multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25209865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Kidney-specific transgenic overexpression of URATv1 (SLC2A9) in mice decreased urate excretion compared to wild-type mice, indicating that increased SLC2A9 activity in the kidney enhances urate reabsorption. Plasma urate concentrations were not significantly different, suggesting compensatory mechanisms exist.\",\n      \"method\": \"Kidney-specific transgenic mouse model (URAT1 promoter-driven SLC2A9), plasma and urine urate measurement\",\n      \"journal\": \"Nucleosides, nucleotides & nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo transgenic mouse model with urate measurements, single lab, single method approach\",\n      \"pmids\": [\"22132990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SLC2A9 mediates urate reabsorption in the mouse kidney in vivo. Inducible kidney-specific deletion of GLUT9 (kiKO mice) caused a major increase in urinary urate excretion and fractional excretion of urate within 4 days, without spontaneous kidney stones. kiKO mice also displayed lower blood pressure with increased heart rate.\",\n      \"method\": \"Tetracycline-inducible kidney-specific knockout mouse (Cre-lox), urate/creatinine ratio measurement, 24-hour urine collection, blood pressure monitoring\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO mouse with well-defined renal phenotype, multiple physiological readouts, clear loss-of-function result\",\n      \"pmids\": [\"30105595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Intestinal (enterocyte) SLC2A9/GLUT9 regulates whole-body uric acid clearance and metabolism. Glut9-deficient mice developed impaired enterocyte uric acid transport kinetics, hyperuricemia, hyperuricosuria, spontaneous hypertension, dyslipidemia, and elevated body fat. Treatment with allopurinol (xanthine oxidase inhibitor) reversed the hypertension and hypercholesterolemia, indicating these metabolic effects are mediated by elevated uric acid.\",\n      \"method\": \"Whole-body SLC2A9 knockout mouse model, urate transport kinetics assay, allopurinol pharmacological rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple metabolic phenotypes and pharmacological rescue by allopurinol, multi-readout study\",\n      \"pmids\": [\"25100214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A missense mutation (C188F) in the SLC2A9 gene, along with promoter mutations reducing expression of one isoform, causes hyperuricosuria and hyperuricemia in Dalmatian dogs and other dog breeds. This demonstrates SLC2A9 mediates uric acid transport in the liver and renal proximal tubules across mammalian species.\",\n      \"method\": \"Positional cloning, linkage mapping, sequence and expression analysis, breed-specific mutation verification\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — positional cloning with genetic and expression evidence in multiple breeds; no in vitro transport assay reported in abstract\",\n      \"pmids\": [\"18989453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Systematic functional analysis of human SLC2A9 (Glut9) disease-causing variants using 14C-urate uptake assay and two-electrode voltage clamp (TEVC) in Xenopus oocytes showed that most variants decreased urate transport. No variant permitted glucose transport. Two categories of dysfunction were identified: reduced cell-surface expression causing low activity, and full surface expression with decreased intrinsic activity. Residue N333S showed decreased urate affinity, suggesting it contributes to the urate binding pocket. C210F displayed lower transport ability.\",\n      \"method\": \"Xenopus oocyte expression, 14C-urate uptake flux assay, two-electrode voltage clamp, immunostaining, cell-surface biotinylation\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic in vitro reconstitution with multiple orthogonal methods (flux, electrophysiology, surface expression), multiple mutants analyzed\",\n      \"pmids\": [\"29967582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of human SLC2A9 were determined in apo (3.3 Å) and urate-bound (4.1 Å) forms, both captured in inward-open conformation. Modeling of the outward-facing conformation revealed alternative salt bridge pairs on the cytoplasmic side that may balance energetics of the alternating access mechanism. The structures elucidate the molecular basis for urate selectivity and the locations of disease-causing mutations within the transporter.\",\n      \"method\": \"Cryo-EM structural determination, molecular modeling of outward-facing conformation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures at near-atomic resolution with disease mutation mapping; single lab but highest-quality method\",\n      \"pmids\": [\"39937868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two novel homozygous SLC2A9 missense mutations (R171C and T125M) dramatically reduced urate transport activity in Xenopus laevis oocytes. Molecular modeling showed both mutations are located within the inner channel that transports urate between cytoplasmic and extracellular regions, providing a structural basis for loss of function.\",\n      \"method\": \"Xenopus oocyte transport assay, molecular modeling\",\n      \"journal\": \"Nephrology, dialysis, transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro transport assay in oocytes with molecular modeling, single lab, limited structural validation\",\n      \"pmids\": [\"21810765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The SLC2A9 variant p.Met126Val (in the short isoform; p.Met155Val in long isoform) significantly reduced uric acid transport in Xenopus oocytes without affecting protein expression level. Molecular dynamics simulation predicted the mutation hinders uric acid transport by disrupting the outward open geometry of the transporter.\",\n      \"method\": \"Xenopus oocyte expression and urate transport assay, molecular dynamics simulation, whole-exome sequencing\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro oocyte transport assay with molecular dynamics modeling, single lab, single method for functional assay\",\n      \"pmids\": [\"34572357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An intronic SLC2A9 variant (c.1419+1G>A) causes exon 11 skipping, producing a functionally null frameshift variant (p.Gly431GlufsTer28), confirmed as causal for renal hypouricemia type 2 by in vitro functional assays and identification in a second unrelated family.\",\n      \"method\": \"Whole exome sequencing, in vitro functional assay, mini-gene splicing assay, family segregation analysis\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro splicing and functional assay, confirmed in two unrelated families\",\n      \"pmids\": [\"36733941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"GLUT9/SLC2A9 protein (immunoreactive) was detected in ependymal cells, neurons, and brain capillaries of mouse brain by immunostaining and in situ hybridization, suggesting urate transport by SLC2A9 occurs in the murine brain, potentially providing neuroprotection.\",\n      \"method\": \"Immunostaining, highly-sensitive in situ hybridization\",\n      \"journal\": \"Fluids and barriers of the CNS\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization only by immunostaining and ISH, no functional consequence demonstrated in this study\",\n      \"pmids\": [\"27955673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC2A9 rs16890979 (V282I missense) reduces uric acid absorption in kidney organoids derived from gene-edited human embryonic stem cells. SLC2A9 overexpression increased urate absorption and SLC2A9 knockdown decreased it in the same system. Additionally, urate treatment of organoids with SLC2A9 overexpression induced epithelial-mesenchymal transition (EMT), suggesting a mechanism for hyperuricosuria-related renal injury.\",\n      \"method\": \"Human ESC-derived kidney organoids with CRISPR gene editing, SLC2A9 overexpression and shRNA knockdown, urate absorption assay, histopathological analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human organoid model with gene editing and knockdown controls, multiple readouts, single lab\",\n      \"pmids\": [\"38269090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SLC2A9 (GLUT9) was identified as a novel member of the facilitative glucose transporter family encoding a predicted 540 amino acid protein with 12 transmembrane domains. Northern analysis revealed expression primarily in kidney and liver. The gene was localized to chromosome 4p15.3-p16.\",\n      \"method\": \"cDNA cloning, Northern blot analysis, hydropathic analysis, somatic cell hybrid mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — initial molecular cloning with expression analysis; no functional transport assay performed in this paper\",\n      \"pmids\": [\"10860667\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC2A9 (GLUT9/URATv1) is a voltage-driven, high-capacity facilitative urate transporter with two isoforms: SLC2A9-L localizes to the basolateral membrane of renal proximal tubules (mediating urate efflux back to plasma) and SLC2A9-S localizes to the apical membrane of collecting duct cells; together these mediate transcellular urate reabsorption in the kidney, with transport being Na+-independent, electrogenic, and inhibitable by uricosuric drugs such as benzbromarone and probenecid. Cryo-EM structures captured in the inward-open conformation reveal the urate binding pocket and disease-mutation locations, and indicate an alternating-access mechanism. SLC2A9 is also expressed in enterocytes (regulating intestinal urate clearance) and in the liver; its transcription is regulated by HNF4α and p53, and p53-induced SLC2A9 expression reduces intracellular ROS by facilitating urate import as an antioxidant. Loss-of-function mutations in SLC2A9 cause renal hypouricemia type 2 in humans and hyperuricosuria in dogs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC2A9 (GLUT9/URATv1) is a Na+-independent, voltage-driven, high-capacity facilitative urate transporter that mediates transcellular urate reabsorption in the kidney and regulates whole-body uric acid handling [#0, #1, #9]. Originally cloned as a facilitative glucose transporter family member with 12 predicted transmembrane domains and kidney/liver expression [#19], it was reclassified when reconstitution in Xenopus oocytes showed urate is transported 45- to 60-fold faster than glucose, with transport that is saturable, electrogenic, enhanced by extracellular potassium, and dose-dependently inhibited by the uricosuric drug benzbromarone [#0, #1, #2]. Two isoforms partition the transport task across renal epithelia: the long isoform (SLC2A9-L) sorts to the basolateral membrane of proximal tubule cells via its unique N-terminus, while the short isoform (SLC2A9-S) localizes to the apical membrane of collecting duct cells [#5]. In vivo, inducible kidney-specific deletion sharply increases urinary urate excretion, establishing SLC2A9 as the principal mediator of renal urate reabsorption, while intestinal/enterocyte SLC2A9 governs whole-body urate clearance, with its loss producing hyperuricemia, hypertension, and dyslipidemia that are reversed by xanthine oxidase inhibition [#9, #10]. Transcription is activated by the nuclear receptor HNF4\\u03b1 binding the isoform-1 promoter and is induced by p53 under oxidative stress, where urate import lowers intracellular ROS, linking SLC2A9 to antioxidant defense and chemoresistance [#6, #7]. Cryo-EM structures in apo and urate-bound inward-open states define the urate selectivity pocket and an alternating-access mechanism, and map the loss-of-function disease mutations onto the transport pathway [#13, #12]. Loss-of-function mutations in SLC2A9 cause renal hypouricemia type 2 in humans and analogous hyperuricosuria in dogs [#4, #16, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the molecular identity of SLC2A9 as a facilitative transporter family member set the structural and expression baseline before any transport function was known.\",\n      \"evidence\": \"cDNA cloning, Northern blot, hydropathy analysis, chromosomal mapping\",\n      \"pmids\": [\"10860667\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transport substrate identified in this study\", \"Annotated as a glucose transporter, which proved misleading\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The central question of what SLC2A9 transports was answered by reconstitution showing it is a high-capacity, Na+-independent, electrogenic urate transporter rather than a glucose transporter, redefining its physiological role.\",\n      \"evidence\": \"Xenopus oocyte expression, two-electrode voltage clamp, radiolabeled urate flux, siRNA knockdown, benzbromarone inhibition\",\n      \"pmids\": [\"18842065\", \"18701466\", \"18327257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific subcellular localization not resolved\", \"Directionality (efflux vs reabsorption) in intact epithelium not directly shown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linking SLC2A9 loss-of-function to human renal hypouricemia connected the transport activity to a defined disease, demonstrating its essential role in renal urate reabsorption.\",\n      \"evidence\": \"Patient sequencing plus mutant transporter functional assays in oocytes; positional cloning in Dalmatian dogs\",\n      \"pmids\": [\"19026395\", \"18989453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apical vs basolateral contribution to reabsorption not dissected\", \"Dog study lacked direct in vitro transport assay\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Homozygous null and missense mutations producing extreme fractional urate excretion confirmed GLUT9 as essential and non-redundant for renal urate reabsorption.\",\n      \"evidence\": \"Homozygosity mapping, sequencing, in vitro transport assay of L75R mutant\",\n      \"pmids\": [\"19926891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of compensatory transport in heterozygotes unaddressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo kidney overexpression and additional patient mutations refined the model that renal SLC2A9 activity scales urate reabsorption and that disease mutations map to the urate-conducting channel.\",\n      \"evidence\": \"Kidney-specific transgenic mouse; oocyte transport assay with molecular modeling of R171C/T125M\",\n      \"pmids\": [\"22132990\", \"21810765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Plasma urate unchanged in transgenic mice implies unquantified compensation\", \"Channel model based on homology modeling, not experimental structure\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolving the two isoforms' distinct polarized localizations explained how a single gene executes transcellular urate movement across different nephron segments.\",\n      \"evidence\": \"Isoform-specific antibody staining of human kidney, GFP-fusion in MDCK cells, N-terminal mutagenesis\",\n      \"pmids\": [\"24409316\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each isoform to net reabsorption not measured\", \"Trafficking machinery recognizing the N-terminal sorting signal not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying HNF4\\u03b1 and p53 as transcriptional regulators placed SLC2A9 within gene-regulatory networks controlling renal expression and oxidative-stress responses, the latter via urate's antioxidant import.\",\n      \"evidence\": \"Reporter assays, ChIP, HNF4\\u03b1 overexpression (renal promoter); siRNA, reporter assay, ROS measurement, probenecid (p53/oxidative stress)\",\n      \"pmids\": [\"25209865\", \"24858040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53 promoter occupancy by ChIP not demonstrated\", \"Crosstalk between HNF4\\u03b1 and p53 regulation unexplored\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extending function beyond the kidney, intestinal SLC2A9 was shown to govern whole-body urate clearance, linking transport loss to hyperuricemia-driven metabolic and cardiovascular phenotypes.\",\n      \"evidence\": \"Whole-body knockout mouse, enterocyte urate transport kinetics, allopurinol pharmacological rescue\",\n      \"pmids\": [\"25100214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative renal vs intestinal contribution to systemic urate not quantified\", \"Molecular link between urate and hypertension/dyslipidemia not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Inducible kidney-specific knockout established in vivo that renal SLC2A9 directly mediates urate reabsorption, while systematic variant analysis classified disease mutations into surface-expression versus intrinsic-activity defects and implicated specific residues in the binding pocket.\",\n      \"evidence\": \"Tetracycline-inducible kidney KO mouse with urate/creatinine and blood pressure readouts; oocyte 14C-urate uptake, TEVC, surface biotinylation across multiple variants\",\n      \"pmids\": [\"30105595\", \"29967582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No urate variant conferred glucose transport, leaving substrate-switch determinants undefined at the time\", \"Cause of blood-pressure phenotype in kiKO mice not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structures in apo and urate-bound inward-open states defined the urate selectivity pocket and an alternating-access mechanism, providing the structural framework onto which disease mutations are mapped.\",\n      \"evidence\": \"Cryo-EM (3.3 \\u00c5 apo, 4.1 \\u00c5 urate-bound), modeling of outward-facing conformation; corroborated by oocyte/organoid variant studies and molecular dynamics\",\n      \"pmids\": [\"39937868\", \"34572357\", \"38269090\", \"36733941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Outward-open state captured only by modeling, not experimentally\", \"Structural basis for voltage dependence and potassium enhancement not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SLC2A9 activity is dynamically regulated across tissues (brain, liver, intestine) and how its antioxidant urate-import role integrates with its bulk reabsorptive function in disease remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Functional role of brain SLC2A9 shown only by localization, not activity\", \"Post-translational and trafficking regulation in vivo undefined\", \"Mechanism linking urate transport to EMT/renal injury not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 9, 12]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 9, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HNF4A\", \"TP53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}