{"gene":"SLC22A13","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1998,"finding":"ORCTL3 (SLC22A13) was molecularly cloned and mapped to a 52-kb genomic region at 3p22→p21.3, encoding a novel organic-cation transporter-family protein with highest similarity to rat OCT-1r, rat NLT, and mouse NKT; transcripts were expressed ubiquitously with some tissue-specific expression in kidney, testis, and skeletal muscle.","method":"Large-scale genomic DNA sequencing, molecular cloning, sequence homology analysis, tissue expression profiling","journal":"Cytogenetics and cell genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — molecular cloning and expression characterization in single study, no functional transport assay performed","pmids":["10072596"],"is_preprint":false},{"year":2009,"finding":"ORCTL3 (SLC22A13) induces apoptosis specifically in oncogene-transformed cells (H-ras- and v-src-transformed NRK cells and human tumor cell lines) but not in normal cells; this apoptotic activity is independent of its putative transporter function and is mediated via an endoplasmic reticulum stress pathway, evidenced by accumulation of the ER-stress marker ATF4 but not BiP.","method":"High-throughput cDNA screen, synthetic lethal assay in isogenic normal vs. transformed cells, ER stress marker analysis (ATF4, BiP), transporter activity assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (functional screen, isogenic cell comparison, ER stress markers) in single lab","pmids":["19282870"],"is_preprint":false},{"year":2014,"finding":"SLC22A13 (ORCTL3) is localized to the basolateral membrane of type A intercalated cells in rat kidney (co-localizing with anion exchanger 1), and mediates unidirectional efflux (not bidirectional transport) of aspartate, glutamate, taurine, and guanidinosuccinate; heterologous expression in HEK-293 cells stimulated efflux of these substrates while counteracting endogenous uptake of [3H]aspartate and [3H]glutamate.","method":"Immunohistochemistry, double-staining with AE1 marker, LC-MS difference shading, [3H]aspartate/[3H]glutamate uptake assays, LC-MS/MS velocity measurements in HEK-293 cells","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (immunohistochemistry for localization, LC-MS functional assay, radiolabeled substrate assays) in single study establishing both localization and transport directionality","pmids":["24147638"],"is_preprint":false},{"year":2014,"finding":"ORCTL3 (SLC22A13) induces tumor-specific apoptosis by targeting stearoyl-CoA desaturase-1 (SCD1) in fatty acid metabolism; transmembrane domains 3 and 4 are responsible for this activity; SCD1 is upregulated upon renal cell transformation and its inhibition via ORCTL3 causes cell death specifically in transformed cells; exogenous supplementation of the SCD1 product oleic acid or SCD1 co-transfection inhibits ORCTL3-induced apoptosis; an adenovirus expressing ORCTL3 inhibited renal tumor growth in vivo and destroyed patient kidney tumor cells ex vivo.","method":"Isogenic cell transformation assay, SCD1 co-transfection rescue experiments, oleic acid supplementation rescue, transmembrane domain deletion/mutagenesis, in vivo xenograft adenoviral injection, ex vivo patient tumor cell assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (genetic rescue, domain mutagenesis, in vivo and ex vivo models) establishing mechanistic target","pmids":["24769897"],"is_preprint":false},{"year":2022,"finding":"OAT10 (SLC22A13) functions as a renal urate re-absorber localized to the apical membrane of renal proximal tubular cells; carriers of the dysfunctional missense variant p.R377C exhibit significantly lower serum urate and higher fractional excretion of uric acid, indicating that OAT10 mediates urate reabsorption from urine; losartan and lesinurad inhibit OAT10 (losartan more potently than URAT1), implicating OAT10 inhibition in their uricosuric effect.","method":"Quantitative trait locus analyses (n=4,521), immunohistochemistry, functional transport assays (HEK293 cells), pharmacological inhibition assays","journal":"Frontiers in pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal human genetics plus functional assay plus immunohistochemical localization, replicated across multiple methods","pmids":["35462902"],"is_preprint":false},{"year":2022,"finding":"OAT10 (SLC22A13) physically interacts with monocarboxylate transporter MCT1 (SLC16A1); co-immunoprecipitation followed by LC-MS/MS identified MCT1 as a binding partner of OAT10. Knockdown of MCT1 in OAT10-expressing HEK293 cells increased uptake of β-hydroxybutyrate and nicotinate (shared substrates of OAT10 and MCT1) but not orotate (OAT10-only substrate), indicating MCT1 acts as an efflux escape route for substrates taken up by OAT10, thereby altering apparent substrate selectivity.","method":"Co-immunoprecipitation, LC-MS/MS interactome analysis, siRNA knockdown of MCT1, transport assays in Xenopus oocytes and HEK293 cells","journal":"Journal of pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown with specific substrate readouts in single lab","pmids":["35926947"],"is_preprint":false},{"year":2024,"finding":"The SLC22A13 (OAT10) variant p.R16H (rs72542450) significantly reduces urate transport activity in functional in vitro assays without markedly affecting protein levels or plasma membrane localization, establishing it as a loss-of-function transport variant.","method":"Site-directed mutagenesis, functional transport assay in HEK293A cells, immunoblotting, fluorescent microscopy","journal":"Disease markers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis plus functional assay plus localization in single study","pmids":["38222853"],"is_preprint":false}],"current_model":"SLC22A13 (OAT10/ORCTL3) is a multi-functional plasma membrane transporter expressed primarily in the kidney: at the apical membrane of renal proximal tubular cells it mediates urate reabsorption (and is inhibited by uricosuric drugs losartan and lesinurad), while at the basolateral membrane of type A intercalated cells it catalyzes unidirectional efflux of aspartate and glutamate; additionally, it physically couples with MCT1 which modulates its apparent substrate selectivity, and when overexpressed in transformed cells it triggers tumor-specific apoptosis by inhibiting stearoyl-CoA desaturase-1 (SCD1) via its transmembrane domains 3 and 4 through an ER stress pathway."},"narrative":{"mechanistic_narrative":"SLC22A13 (OAT10/ORCTL3) is a polytopic plasma-membrane organic-anion transporter of the organic-cation transporter family, expressed prominently in kidney where it serves dual transport roles defined by membrane polarity [PMID:10072596, PMID:24147638, PMID:35462902]. At the apical membrane of renal proximal tubular cells it reabsorbs urate from urine; carriers of the dysfunctional p.R377C variant show lower serum urate and elevated fractional uric-acid excretion, and the uricosuric drugs losartan and lesinurad inhibit OAT10, accounting for part of their urate-lowering action [PMID:35462902]. The independent loss-of-function variant p.R16H further confirms its role in urate transport by reducing activity without altering protein levels or membrane localization [PMID:38222853]. At the basolateral membrane of type A intercalated cells it co-localizes with anion exchanger 1 and catalyzes unidirectional efflux of aspartate, glutamate, taurine, and guanidinosuccinate [PMID:24147638]. OAT10 physically associates with the monocarboxylate transporter MCT1 (SLC16A1), which provides an efflux escape route for shared substrates and thereby shapes the transporter's apparent substrate selectivity [PMID:35926947]. Independent of transport function, ORCTL3 selectively triggers apoptosis in oncogene-transformed cells but not normal cells by inhibiting stearoyl-CoA desaturase-1 (SCD1) through its transmembrane domains 3 and 4, an effect engaging an ER-stress pathway and rescuable by the SCD1 product oleic acid; adenoviral ORCTL3 suppresses renal tumor growth in vivo and ex vivo [PMID:19282870, PMID:24769897].","teleology":[{"year":1998,"claim":"Established SLC22A13 as a distinct organic-cation-transporter-family gene with a defined chromosomal locus and expression pattern, providing the molecular entry point before any function was known.","evidence":"Genomic sequencing, molecular cloning, homology analysis and tissue expression profiling","pmids":["10072596"],"confidence":"Medium","gaps":["No transport substrate or activity demonstrated","Subcellular localization unresolved","Physiological role inferred only from family homology"]},{"year":2009,"claim":"Revealed an unexpected transport-independent role in selectively killing transformed cells via ER stress, distinguishing a tumor-specific pro-apoptotic function from any transporter activity.","evidence":"cDNA synthetic-lethal screen in isogenic normal vs transformed cells with ATF4/BiP ER-stress marker analysis","pmids":["19282870"],"confidence":"Medium","gaps":["Molecular target of apoptotic activity not identified","Mechanism linking ORCTL3 to ER stress undefined","Single-lab observation"]},{"year":2014,"claim":"Defined the first transport function and its membrane polarity, showing basolateral OAT10 in type A intercalated cells performs unidirectional efflux of acidic amino acids rather than bidirectional exchange.","evidence":"Immunohistochemistry with AE1 co-staining plus LC-MS and radiolabeled-substrate efflux/uptake assays in HEK-293 cells","pmids":["24147638"],"confidence":"High","gaps":["Driving force / coupling ion of efflux not established","Relationship between this efflux role and apical urate role unaddressed"]},{"year":2014,"claim":"Identified SCD1 in fatty-acid metabolism as the molecular target of ORCTL3's tumor-specific apoptosis and mapped the responsible transmembrane domains, converting the 2009 phenotype into a defined mechanism with therapeutic potential.","evidence":"SCD1 co-transfection and oleic-acid rescue, transmembrane-domain mutagenesis, in vivo xenograft and ex vivo patient tumor assays","pmids":["24769897"],"confidence":"High","gaps":["Physical interaction between ORCTL3 TM3/4 and SCD1 not structurally resolved","How SCD1 inhibition triggers ER stress not detailed"]},{"year":2022,"claim":"Established OAT10 as an apical renal urate reabsorber and a pharmacological target, linking a human dysfunctional variant to lower serum urate and explaining uricosuric drug action.","evidence":"QTL analysis (n=4,521), immunohistochemistry, functional transport and pharmacological inhibition assays in HEK293 cells","pmids":["35462902"],"confidence":"High","gaps":["Quantitative contribution of OAT10 to total renal urate handling vs URAT1 not resolved","Counter-ion/exchange substrate for urate uptake unspecified"]},{"year":2022,"claim":"Showed OAT10 physically partners with MCT1, with MCT1 serving as an efflux escape route that modulates OAT10's apparent substrate selectivity, adding a regulatory layer to its transport.","evidence":"Co-IP/LC-MS/MS interactome, MCT1 siRNA knockdown with substrate-specific transport readouts in oocytes and HEK293 cells","pmids":["35926947"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of OAT10-MCT1 interaction unknown","Physiological tissue context of the interaction not established","Single-lab finding"]},{"year":2024,"claim":"Characterized a second loss-of-function urate-transport variant (p.R16H), reinforcing OAT10's role in urate handling by separating transport defect from protein expression/localization defects.","evidence":"Site-directed mutagenesis, functional transport assay, immunoblotting and fluorescence microscopy in HEK293A cells","pmids":["38222853"],"confidence":"Medium","gaps":["Population-level clinical consequence of p.R16H not quantified","Mechanism by which R16H impairs transport not defined"]},{"year":null,"claim":"How OAT10's two membrane-polarized transport roles, its MCT1 partnership, and its transport-independent SCD1-targeting apoptotic activity are integrated within one protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of substrate binding or domain architecture","Coupling/energetics of urate and amino-acid transport unknown","Whether apoptotic and transport functions occur in the same cellular contexts unaddressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[1,3]}],"complexes":[],"partners":["SLC16A1","SCD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y226","full_name":"Solute carrier family 22 member 13","aliases":["Organic anion transporter 10","OAT10","Organic cation transporter-like 3","ORCTL-3","ORCTL3"],"length_aa":551,"mass_kda":60.9,"function":"Anion antiporter that mediates the transport of urate, orotate and nicotinate in exchange for organic or inorganic anions (PubMed:18411268, PubMed:31780526, PubMed:35144162, PubMed:35462902). Translocates urate and orotate across the apical membrane of proximal tubule epithelial cells and involved in urate renal reabsorption (PubMed:18411268, PubMed:31780526, PubMed:35144162). Possibly involved in orotate renal reabsorption and nicotinate intestinal reabsorption (PubMed:18411268, PubMed:35144162). Mediates urate uptake by an exchange with organic anions such as (S)-lactate, succinate, glutathione and nicotinate (PubMed:18411268). Urate and orotate transports are Cl(-)-dependent (PubMed:35144162, PubMed:35462902). Shows similar transport characteristics as the urate/orotate renal antiporter SLC22A12/URAT1 and may act as a compensator of SLC22A12/URAT1 in certain conditions (Probable)","subcellular_location":"Apical cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y226/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC22A13","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SLC22A13","total_profiled":1310},"omim":[{"mim_id":"604048","title":"SOLUTE CARRIER FAMILY 22, MEMBER 14; SLC22A14","url":"https://www.omim.org/entry/604048"},{"mim_id":"604047","title":"SOLUTE CARRIER FAMILY 22 (ORGANIC ANION/URATE TRANSPORTER), MEMBER 13; SLC22A13","url":"https://www.omim.org/entry/604047"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"kidney","ntpm":8.4}],"url":"https://www.proteinatlas.org/search/SLC22A13"},"hgnc":{"alias_symbol":["OCTL1","OCTL3","OAT10"],"prev_symbol":["ORCTL3"]},"alphafold":{"accession":"Q9Y226","domains":[{"cath_id":"1.20.1250.20","chopping":"26-47_124-289","consensus_level":"medium","plddt":90.9835,"start":26,"end":289},{"cath_id":"-","chopping":"50-119","consensus_level":"high","plddt":79.478,"start":50,"end":119},{"cath_id":"1.20.1250.20","chopping":"317-513","consensus_level":"medium","plddt":89.4722,"start":317,"end":513}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y226","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y226-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y226-F1-predicted_aligned_error_v6.png","plddt_mean":84.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC22A13","jax_strain_url":"https://www.jax.org/strain/search?query=SLC22A13"},"sequence":{"accession":"Q9Y226","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y226.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y226/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y226"}},"corpus_meta":[{"pmid":"16914559","id":"PMC_16914559","title":"Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are substrates for human organic cation transporters (SLC22A1-3 and multidrug and toxin extrusion family).","date":"2006","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/16914559","citation_count":269,"is_preprint":false},{"pmid":"10072596","id":"PMC_10072596","title":"Molecular cloning, mapping, and characterization of two novel human genes, ORCTL3 and ORCTL4, bearing homology to organic-cation transporters.","date":"1998","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10072596","citation_count":23,"is_preprint":false},{"pmid":"35462902","id":"PMC_35462902","title":"OAT10/SLC22A13 Acts as a Renal Urate Re-Absorber: Clinico-Genetic and Functional Analyses With Pharmacological Impacts.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35462902","citation_count":20,"is_preprint":false},{"pmid":"24147638","id":"PMC_24147638","title":"SLC22A13 catalyses unidirectional efflux of aspartate and glutamate at the basolateral membrane of type A intercalated cells in the renal collecting duct.","date":"2014","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/24147638","citation_count":16,"is_preprint":false},{"pmid":"19282870","id":"PMC_19282870","title":"Isolation of ORCTL3 in a novel genetic screen for tumor-specific apoptosis inducers.","date":"2009","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19282870","citation_count":12,"is_preprint":false},{"pmid":"24769897","id":"PMC_24769897","title":"The anticancer gene ORCTL3 targets stearoyl-CoA desaturase-1 for tumour-specific apoptosis.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24769897","citation_count":11,"is_preprint":false},{"pmid":"35926947","id":"PMC_35926947","title":"Functional coupling of organic anion transporter OAT10 (SLC22A13) and monocarboxylate transporter MCT1 (SLC16A1) influencing the transport function of OAT10.","date":"2022","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35926947","citation_count":7,"is_preprint":false},{"pmid":"38222853","id":"PMC_38222853","title":"Examining the Association of Rare Allelic Variants in Urate Transporters SLC22A11, SLC22A13, and SLC17A1 with Hyperuricemia and Gout.","date":"2024","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/38222853","citation_count":6,"is_preprint":false},{"pmid":"35163125","id":"PMC_35163125","title":"MPP+-Induced Changes in Cellular Impedance as a Measure for Organic Cation Transporter (SLC22A1-3) Activity and Inhibition.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35163125","citation_count":5,"is_preprint":false},{"pmid":"25001539","id":"PMC_25001539","title":"Isolation and characterization of the anticancer gene organic cation transporter like-3 (ORCTL3).","date":"2014","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/25001539","citation_count":4,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7222,"output_tokens":2133,"usd":0.026831,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9116,"output_tokens":2695,"usd":0.056477,"stage2_stop_reason":"end_turn"},"total_usd":0.083308,"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\": 1998,\n      \"finding\": \"ORCTL3 (SLC22A13) was molecularly cloned and mapped to a 52-kb genomic region at 3p22→p21.3, encoding a novel organic-cation transporter-family protein with highest similarity to rat OCT-1r, rat NLT, and mouse NKT; transcripts were expressed ubiquitously with some tissue-specific expression in kidney, testis, and skeletal muscle.\",\n      \"method\": \"Large-scale genomic DNA sequencing, molecular cloning, sequence homology analysis, tissue expression profiling\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — molecular cloning and expression characterization in single study, no functional transport assay performed\",\n      \"pmids\": [\"10072596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ORCTL3 (SLC22A13) induces apoptosis specifically in oncogene-transformed cells (H-ras- and v-src-transformed NRK cells and human tumor cell lines) but not in normal cells; this apoptotic activity is independent of its putative transporter function and is mediated via an endoplasmic reticulum stress pathway, evidenced by accumulation of the ER-stress marker ATF4 but not BiP.\",\n      \"method\": \"High-throughput cDNA screen, synthetic lethal assay in isogenic normal vs. transformed cells, ER stress marker analysis (ATF4, BiP), transporter activity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (functional screen, isogenic cell comparison, ER stress markers) in single lab\",\n      \"pmids\": [\"19282870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SLC22A13 (ORCTL3) is localized to the basolateral membrane of type A intercalated cells in rat kidney (co-localizing with anion exchanger 1), and mediates unidirectional efflux (not bidirectional transport) of aspartate, glutamate, taurine, and guanidinosuccinate; heterologous expression in HEK-293 cells stimulated efflux of these substrates while counteracting endogenous uptake of [3H]aspartate and [3H]glutamate.\",\n      \"method\": \"Immunohistochemistry, double-staining with AE1 marker, LC-MS difference shading, [3H]aspartate/[3H]glutamate uptake assays, LC-MS/MS velocity measurements in HEK-293 cells\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (immunohistochemistry for localization, LC-MS functional assay, radiolabeled substrate assays) in single study establishing both localization and transport directionality\",\n      \"pmids\": [\"24147638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ORCTL3 (SLC22A13) induces tumor-specific apoptosis by targeting stearoyl-CoA desaturase-1 (SCD1) in fatty acid metabolism; transmembrane domains 3 and 4 are responsible for this activity; SCD1 is upregulated upon renal cell transformation and its inhibition via ORCTL3 causes cell death specifically in transformed cells; exogenous supplementation of the SCD1 product oleic acid or SCD1 co-transfection inhibits ORCTL3-induced apoptosis; an adenovirus expressing ORCTL3 inhibited renal tumor growth in vivo and destroyed patient kidney tumor cells ex vivo.\",\n      \"method\": \"Isogenic cell transformation assay, SCD1 co-transfection rescue experiments, oleic acid supplementation rescue, transmembrane domain deletion/mutagenesis, in vivo xenograft adenoviral injection, ex vivo patient tumor cell assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (genetic rescue, domain mutagenesis, in vivo and ex vivo models) establishing mechanistic target\",\n      \"pmids\": [\"24769897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OAT10 (SLC22A13) functions as a renal urate re-absorber localized to the apical membrane of renal proximal tubular cells; carriers of the dysfunctional missense variant p.R377C exhibit significantly lower serum urate and higher fractional excretion of uric acid, indicating that OAT10 mediates urate reabsorption from urine; losartan and lesinurad inhibit OAT10 (losartan more potently than URAT1), implicating OAT10 inhibition in their uricosuric effect.\",\n      \"method\": \"Quantitative trait locus analyses (n=4,521), immunohistochemistry, functional transport assays (HEK293 cells), pharmacological inhibition assays\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal human genetics plus functional assay plus immunohistochemical localization, replicated across multiple methods\",\n      \"pmids\": [\"35462902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OAT10 (SLC22A13) physically interacts with monocarboxylate transporter MCT1 (SLC16A1); co-immunoprecipitation followed by LC-MS/MS identified MCT1 as a binding partner of OAT10. Knockdown of MCT1 in OAT10-expressing HEK293 cells increased uptake of β-hydroxybutyrate and nicotinate (shared substrates of OAT10 and MCT1) but not orotate (OAT10-only substrate), indicating MCT1 acts as an efflux escape route for substrates taken up by OAT10, thereby altering apparent substrate selectivity.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS interactome analysis, siRNA knockdown of MCT1, transport assays in Xenopus oocytes and HEK293 cells\",\n      \"journal\": \"Journal of pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional knockdown with specific substrate readouts in single lab\",\n      \"pmids\": [\"35926947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SLC22A13 (OAT10) variant p.R16H (rs72542450) significantly reduces urate transport activity in functional in vitro assays without markedly affecting protein levels or plasma membrane localization, establishing it as a loss-of-function transport variant.\",\n      \"method\": \"Site-directed mutagenesis, functional transport assay in HEK293A cells, immunoblotting, fluorescent microscopy\",\n      \"journal\": \"Disease markers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis plus functional assay plus localization in single study\",\n      \"pmids\": [\"38222853\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC22A13 (OAT10/ORCTL3) is a multi-functional plasma membrane transporter expressed primarily in the kidney: at the apical membrane of renal proximal tubular cells it mediates urate reabsorption (and is inhibited by uricosuric drugs losartan and lesinurad), while at the basolateral membrane of type A intercalated cells it catalyzes unidirectional efflux of aspartate and glutamate; additionally, it physically couples with MCT1 which modulates its apparent substrate selectivity, and when overexpressed in transformed cells it triggers tumor-specific apoptosis by inhibiting stearoyl-CoA desaturase-1 (SCD1) via its transmembrane domains 3 and 4 through an ER stress pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC22A13 (OAT10/ORCTL3) is a polytopic plasma-membrane organic-anion transporter of the organic-cation transporter family, expressed prominently in kidney where it serves dual transport roles defined by membrane polarity [#0, #2, #4]. At the apical membrane of renal proximal tubular cells it reabsorbs urate from urine; carriers of the dysfunctional p.R377C variant show lower serum urate and elevated fractional uric-acid excretion, and the uricosuric drugs losartan and lesinurad inhibit OAT10, accounting for part of their urate-lowering action [#4]. The independent loss-of-function variant p.R16H further confirms its role in urate transport by reducing activity without altering protein levels or membrane localization [#6]. At the basolateral membrane of type A intercalated cells it co-localizes with anion exchanger 1 and catalyzes unidirectional efflux of aspartate, glutamate, taurine, and guanidinosuccinate [#2]. OAT10 physically associates with the monocarboxylate transporter MCT1 (SLC16A1), which provides an efflux escape route for shared substrates and thereby shapes the transporter's apparent substrate selectivity [#5]. Independent of transport function, ORCTL3 selectively triggers apoptosis in oncogene-transformed cells but not normal cells by inhibiting stearoyl-CoA desaturase-1 (SCD1) through its transmembrane domains 3 and 4, an effect engaging an ER-stress pathway and rescuable by the SCD1 product oleic acid; adenoviral ORCTL3 suppresses renal tumor growth in vivo and ex vivo [#1, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established SLC22A13 as a distinct organic-cation-transporter-family gene with a defined chromosomal locus and expression pattern, providing the molecular entry point before any function was known.\",\n      \"evidence\": \"Genomic sequencing, molecular cloning, homology analysis and tissue expression profiling\",\n      \"pmids\": [\"10072596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transport substrate or activity demonstrated\", \"Subcellular localization unresolved\", \"Physiological role inferred only from family homology\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed an unexpected transport-independent role in selectively killing transformed cells via ER stress, distinguishing a tumor-specific pro-apoptotic function from any transporter activity.\",\n      \"evidence\": \"cDNA synthetic-lethal screen in isogenic normal vs transformed cells with ATF4/BiP ER-stress marker analysis\",\n      \"pmids\": [\"19282870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of apoptotic activity not identified\", \"Mechanism linking ORCTL3 to ER stress undefined\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the first transport function and its membrane polarity, showing basolateral OAT10 in type A intercalated cells performs unidirectional efflux of acidic amino acids rather than bidirectional exchange.\",\n      \"evidence\": \"Immunohistochemistry with AE1 co-staining plus LC-MS and radiolabeled-substrate efflux/uptake assays in HEK-293 cells\",\n      \"pmids\": [\"24147638\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Driving force / coupling ion of efflux not established\", \"Relationship between this efflux role and apical urate role unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified SCD1 in fatty-acid metabolism as the molecular target of ORCTL3's tumor-specific apoptosis and mapped the responsible transmembrane domains, converting the 2009 phenotype into a defined mechanism with therapeutic potential.\",\n      \"evidence\": \"SCD1 co-transfection and oleic-acid rescue, transmembrane-domain mutagenesis, in vivo xenograft and ex vivo patient tumor assays\",\n      \"pmids\": [\"24769897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical interaction between ORCTL3 TM3/4 and SCD1 not structurally resolved\", \"How SCD1 inhibition triggers ER stress not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established OAT10 as an apical renal urate reabsorber and a pharmacological target, linking a human dysfunctional variant to lower serum urate and explaining uricosuric drug action.\",\n      \"evidence\": \"QTL analysis (n=4,521), immunohistochemistry, functional transport and pharmacological inhibition assays in HEK293 cells\",\n      \"pmids\": [\"35462902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of OAT10 to total renal urate handling vs URAT1 not resolved\", \"Counter-ion/exchange substrate for urate uptake unspecified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed OAT10 physically partners with MCT1, with MCT1 serving as an efflux escape route that modulates OAT10's apparent substrate selectivity, adding a regulatory layer to its transport.\",\n      \"evidence\": \"Co-IP/LC-MS/MS interactome, MCT1 siRNA knockdown with substrate-specific transport readouts in oocytes and HEK293 cells\",\n      \"pmids\": [\"35926947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of OAT10-MCT1 interaction unknown\", \"Physiological tissue context of the interaction not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Characterized a second loss-of-function urate-transport variant (p.R16H), reinforcing OAT10's role in urate handling by separating transport defect from protein expression/localization defects.\",\n      \"evidence\": \"Site-directed mutagenesis, functional transport assay, immunoblotting and fluorescence microscopy in HEK293A cells\",\n      \"pmids\": [\"38222853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Population-level clinical consequence of p.R16H not quantified\", \"Mechanism by which R16H impairs transport not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OAT10's two membrane-polarized transport roles, its MCT1 partnership, and its transport-independent SCD1-targeting apoptotic activity are integrated within one protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of substrate binding or domain architecture\", \"Coupling/energetics of urate and amino-acid transport unknown\", \"Whether apoptotic and transport functions occur in the same cellular contexts unaddressed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SLC16A1\", \"SCD1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}