{"gene":"SLC5A6","run_date":"2026-06-10T07:46:34","timeline":{"discoveries":[{"year":2003,"finding":"SMVT (SLC5A6) is the major (if not the only) biotin uptake system operating at physiological (nanomolar) concentrations in human intestinal Caco-2 and liver HepG2 epithelial cells; siRNA knockdown of SMVT severely inhibited carrier-mediated [3H]biotin uptake, demonstrating that a recently described second high-affinity biotin uptake system is not functional in these cells.","method":"siRNA knockdown of SMVT in Caco-2 and HepG2 cells followed by [3H]biotin uptake assays; RT-PCR and Western blot confirmation of knockdown","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with direct transport assay, replicated across two cell lines with molecular confirmation","pmids":["12646417"],"is_preprint":false},{"year":2007,"finding":"Holocarboxylase synthetase (HCS) senses biotin levels, translocates to the nucleus in proportion to biotin concentration, and biotinylates histone H4 at lysine 12 (K12Bio H4) at SMVT promoter 1, causing gene silencing and reducing SMVT expression by up to 86%; HCS knockdown disrupts this chromatin remodeling and leads to abnormal SMVT overexpression.","method":"Chromatin immunoprecipitation (ChIP) for HCS and K12Bio H4 at SMVT promoters; HCS knockdown cells; Jurkat lymphoma cells cultured at varying biotin concentrations","journal":"The Journal of nutritional biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with two orthogonal approaches (HCS binding and histone mark), single lab","pmids":["17904341"],"is_preprint":false},{"year":2010,"finding":"SMVT mediates Na+-coupled iodide (I−) transport; hSMVT-mediated Na+/I− symport is inhibited by the other organic SMVT substrates (biotin, pantothenic acid, α-lipoic acid) but not by NIS substrates, and is insensitive to perchlorate, distinguishing it mechanistically from the Na+/I− symporter NIS.","method":"Functional transport assays in hSMVT-expressing cells; substrate competition experiments; comparison with NIS substrates and inhibitors","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transport assay with substrate competition, single lab, multiple substrates tested","pmids":["20980265"],"is_preprint":false},{"year":2010,"finding":"SMVT is expressed in rat retinal capillary endothelial cells (TR-iBRB2) and mediates Na+-dependent, concentration-dependent, saturable biotin transport (Km ~146 μM) at the inner blood-retinal barrier; transport is inhibited by SMVT substrates biotin, pantothenic acid, lipoic acid, and desthiobiotin.","method":"In vivo integration plot and retinal uptake index in rats; [3H]biotin uptake assays in TR-iBRB2 cells; RT-PCR for SMVT mRNA","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro transport assays with substrate competition, single lab","pmids":["20599968"],"is_preprint":false},{"year":2012,"finding":"Intestine-specific conditional knockout of Slc5a6 in mice completely abolishes carrier-mediated biotin uptake in the intestine, demonstrating that SMVT is solely responsible for intestinal biotin absorption in vivo; KO mice develop growth retardation, decreased bone density, histological abnormalities, chronic intestinal inflammation, and premature death.","method":"Cre/lox intestine-specific conditional SMVT knockout mouse model; in vivo and in vitro [3H]biotin transport studies; histology; bone density measurements","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with direct in vivo transport assay, multiple phenotypic readouts, definitive loss-of-function","pmids":["23104561"],"is_preprint":false},{"year":2012,"finding":"SMVT mediates biotin uptake in human breast cancer T47D cells via a Na+-dependent, saturable, carrier-mediated mechanism (Km 9.24 μM); transport is regulated by calcium-calmodulin pathway (inhibited by calmidazolium) but not by PKC or PKA pathways.","method":"[3H]biotin uptake assays with kinetic analysis; pharmacological inhibitors of signaling pathways; RT-PCR for SMVT mRNA; competitive inhibition with structural analogs","journal":"International journal of pharmaceutics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional transport assays with pharmacological dissection, single lab","pmids":["23142496"],"is_preprint":false},{"year":2012,"finding":"SMVT localizes to the Chlamydia inclusion vacuole membrane within host cells, providing a mechanism for transport of biotin (and likely pantothenic acid and lipoic acid) from the host cytoplasm into the inclusion where bacterial transporters can further internalize them.","method":"Immunofluorescence microscopy of SMVT localization relative to Chlamydia inclusion; [3H]biotin uptake assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunofluorescence localization with functional context, single lab","pmids":["23029384"],"is_preprint":false},{"year":2015,"finding":"SLC5A6/SMVT is preferentially localized at the luminal membrane of human brain capillary endothelium and accounts for 88.7% and 98.6% of total [3H]biotin and [3H]pantothenic acid uptake, respectively, by human cerebral microvascular endothelial cells (hCMEC/D3); transport is also inhibited by NSAIDs and prostaglandin E2.","method":"Quantitative targeted absolute proteomics (QTAP) for protein expression; antibody-free membrane localization method; SLC5A6 siRNA knockdown in hCMEC/D3 cells; [3H]biotin and [3H]pantothenic acid uptake assays; competitive inhibition with substrates and drugs","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown combined with quantitative proteomics and direct transport assays, multiple substrates and inhibitors tested","pmids":["25809983"],"is_preprint":false},{"year":2016,"finding":"Loss-of-function mutations R94X (premature stop) and R123L (missense) in exon 3 of SLC5A6 severely impair biotin uptake; R94X mutant protein is poorly tolerated and localizes to the cytoplasm, while R123L mutant is predominantly retained in the endoplasmic reticulum, demonstrating that proper trafficking is required for SMVT function.","method":"[3H]biotin uptake assay in HuTu-80 and U87 cells expressing mutants; live cell confocal imaging of mutant localization; whole genome scanning to identify mutations","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transport assay combined with live-cell imaging of localization defects, single lab","pmids":["27904971"],"is_preprint":false},{"year":2016,"finding":"Intestinal-specific SMVT knockout leads to increased gut permeability and altered tight junction (TJ) protein expression; dietary-induced biotin deficiency in wild-type mice produces similar cecal inflammation and permeability changes, establishing that SMVT maintains intestinal mucosal integrity primarily through its role in providing biotin.","method":"Conditional SMVT knockout mouse model; gut permeability assays; TJ protein expression analysis; dietary biotin deficiency induction in wild-type mice; cytokine expression measurement","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus dietary deficiency model with multiple functional readouts, single lab","pmids":["27492331"],"is_preprint":false},{"year":2018,"finding":"Oversupplementation with biotin and pantothenic acid in the drinking water prevents early death, normalizes growth rate, restores intestinal integrity, and reverses pathology and inflammation in intestinal-specific SMVT-cKO mice, demonstrating that SMVT maintains intestinal health specifically through its transport of biotin and/or pantothenic acid.","method":"Biotin/pantothenic acid supplementation of SMVT-cKO mice; survival analysis; growth measurements; histology; intestinal permeability assays; inflammatory marker measurements","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment in conditional KO mouse model with multiple outcome measures, single lab","pmids":["29669219"],"is_preprint":false},{"year":2019,"finding":"Adult-onset intestinal-specific SMVT deletion activates NF-κB pathway and NLRP3 inflammasome, inducing spontaneous gut inflammation; broad-spectrum antibiotics reduced lethality and normalized intestinal inflammation, demonstrating that gut microbiota drives the inflammatory response when SMVT is absent.","method":"Tamoxifen-inducible intestine-specific SMVT-icKO mice; NF-κB and NLRP3 pathway analysis; antibiotic treatment experiment; cytokine and permeability measurements","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible conditional KO with pathway analysis and antibiotic rescue experiment, single lab","pmids":["31369292"],"is_preprint":false},{"year":2023,"finding":"SLC5A6 mutations cause defective B cell differentiation and antibody deficiency through biotin deficiency; biotin replenishment improved plasma cell maturation and recovered antibody production in the patient and in a CRISPR-Cas9 mouse model bearing patient-specific SLC5A6 variants; defective cells show aberrant mitochondrial respiration and reliance on glycolysis.","method":"Exome sequencing; CRISPR-Cas9 mouse model; B cell differentiation assays; plasma cell maturation assays; metabolic profiling (mitochondrial respiration, glycolysis); biotin replenishment rescue experiments","journal":"Clinical immunology (Orlando, Fla.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO model combined with cellular functional assays and metabolic profiling, single lab","pmids":["38036278"],"is_preprint":false},{"year":2024,"finding":"Cardiac-specific deletion of Slc5a6 in mice causes progressive dilated cardiomyopathy with cardiomyocyte hypertrophy, fibrosis, impaired Coenzyme A synthesis, and metabolic imbalance leading to premature death at 26 weeks; early proteomic analysis reveals mitochondrial metabolic disruption preceding overt cardiac dysfunction; vitamin supplementation from preconception prevents the cardiac phenotype entirely.","method":"Cardiac-specific Slc5a6 knockout mouse model; cardiac MRI; ECG; histology; proteomics; CoA synthesis assays; biotin/pantothenic acid supplementation rescue","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — cardiac-specific KO with multiple orthogonal methods (imaging, histology, proteomics, biochemistry) plus complete rescue experiment","pmids":["42228401"],"is_preprint":false},{"year":2024,"finding":"SLC5A6 variant c.393+2T>C causes mis-splicing with nonsense-mediated decay reducing mRNA to ~50% of control; the missense variant p.Ser429Gly results in ~90% reduction in biotin uptake in patient fibroblasts, functionally validating pathogenicity.","method":"RT-PCR splice analysis on patient blood mRNA; [3H]biotin uptake assays in patient fibroblasts; genome sequencing","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct transport assay in patient fibroblasts combined with molecular splice analysis, single study","pmids":["38816490"],"is_preprint":false},{"year":2024,"finding":"Foxd3 is a transcription factor that regulates SLC5A6 expression; SLC5A6 knockout in LUAD cells impairs mitochondrial function and induces apoptosis; mechanistically, reduced SLC5A6 decreases biotin-dependent acetyl-CoA carboxylase (ACC) expression, which in turn downregulates FASN, disrupting lipid metabolism; FASN knockdown reverses the growth-promoting effect of SLC5A6 overexpression.","method":"SLC5A6 knockout and overexpression in LUAD cell lines; transcriptomic analysis; FASN knockdown rescue experiments; in vivo xenograft experiments; Foxd3 transcription factor analysis","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via rescue experiment (FASN KD reverses SLC5A6 OE phenotype), transcriptomic pathway analysis, single lab","pmids":["39426496"],"is_preprint":false},{"year":2025,"finding":"Biotin and its p-aminophenylalanine derivative Bio-1 require SLC5A6 for cellular entry, while biotin and biotin methyl ester (Bio-2) can enter cells independently of SLC5A6, indicating alternative transport pathways exist for certain biotin derivatives.","method":"HEK293 cells with SLC5A6 gene inactivation (test system with BirA* biotin ligase reporter); comparative uptake of biotin derivatives in SLC5A6-intact vs. SLC5A6-inactivated cell lines","journal":"Acta naturae","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic inactivation with functional transport assay, single lab, novel test system","pmids":["41122322"],"is_preprint":false},{"year":2025,"finding":"SLC5A6 promotes cervical cancer progression through a pathway where SLC5A6-mediated biotin transport maintains expression of biotin-dependent acetyl-CoA carboxylase (ACC), which sustains FASN expression; FASN knockdown reverses the tumor-promoting effects of SLC5A6 overexpression, placing SLC5A6 upstream of ACC-FASN in a lipid metabolism pathway.","method":"SLC5A6 knockdown and overexpression in HeLa and SiHa cells; transcriptomic analysis; FASN knockdown rescue; ACC protein expression analysis; in vivo xenograft tumor growth","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via rescue experiment (FASN KD reverses SLC5A6 OE phenotype), in vivo and in vitro confirmation, single lab","pmids":["41108787"],"is_preprint":false}],"current_model":"SLC5A6 encodes SMVT, a 12-transmembrane-domain Na+-coupled symporter that co-transports biotin, pantothenic acid, α-lipoic acid, and iodide into cells; it is localized to the luminal/apical plasma membrane in polarized epithelia and endothelium, is the sole carrier for intestinal biotin absorption in vivo, and its expression is feedback-regulated by HCS-dependent biotinylation of histone H4 at its promoter; loss of SMVT function disrupts mitochondrial CoA synthesis and energy metabolism, activates NF-κB/NLRP3 inflammasome signaling through gut microbiota, impairs B cell and plasma cell maturation, causes dilated cardiomyopathy, and in cancer cells controls lipid metabolism via a biotin→ACC→FASN axis."},"narrative":{"mechanistic_narrative":"SLC5A6 encodes SMVT, a Na+-coupled symporter that serves as the major physiological route for cellular uptake of biotin and pantothenic acid, and is the sole carrier for intestinal biotin absorption in vivo [PMID:12646417, PMID:23104561, PMID:25809983]. The same transporter also mediates Na+-coupled iodide influx through a mechanism distinct from NIS, being insensitive to perchlorate and instead inhibited competitively by its own organic substrates [PMID:20980265]. SMVT is preferentially positioned at the luminal/apical membrane of polarized epithelium and barrier endothelium, where it accounts for the overwhelming majority of biotin and pantothenate transport at the intestinal, retinal, and brain capillary barriers [PMID:20599968, PMID:25809983]; correct trafficking to this membrane is essential, as loss-of-function mutations cause cytoplasmic or ER retention with abolished transport [PMID:27904971]. Because its substrates are precursors for biotin- and CoA-dependent metabolism, loss of SMVT function disrupts mitochondrial CoA synthesis and energy metabolism, an effect that drives dilated cardiomyopathy upon cardiac-specific deletion and defective B cell/plasma cell maturation with antibody deficiency in patients, both reversible by biotin/pantothenate supplementation [PMID:42228401, PMID:38036278]. In the intestine, SMVT loss compromises tight-junction integrity and mucosal barrier function, triggering NF-κB and NLRP3 inflammasome activation driven by gut microbiota, with growth retardation and premature death rescued by biotin and pantothenic acid [PMID:23104561, PMID:27492331, PMID:29669219, PMID:31369292]. SMVT expression is feedback-regulated by holocarboxylase synthetase, which biotinylates histone H4 at lysine 12 at the SLC5A6 promoter to silence transcription in proportion to biotin availability [PMID:17904341]. In cancer, SMVT-mediated biotin import sustains a biotin→ACC→FASN lipid-metabolism axis that promotes tumor growth [PMID:39426496, PMID:41108787]. Pathogenic SLC5A6 variants—nonsense, missense, and splice-disrupting alleles—reduce transporter expression or activity and are functionally validated by impaired biotin uptake [PMID:27904971, PMID:38816490].","teleology":[{"year":2003,"claim":"Established that SMVT, not a postulated second high-affinity system, is the dominant physiological biotin uptake route in human intestinal and hepatic epithelia, defining its primary transport function.","evidence":"siRNA knockdown of SMVT with [3H]biotin uptake assays in Caco-2 and HepG2 cells","pmids":["12646417"],"confidence":"High","gaps":["Did not address pantothenate or lipoate uptake","In vitro cell lines only; in vivo contribution not yet tested"]},{"year":2007,"claim":"Revealed a feedback loop in which biotin status, sensed by HCS, controls SMVT transcription via histone H4K12 biotinylation at the promoter, explaining how the transporter is downregulated under biotin sufficiency.","evidence":"ChIP for HCS and K12Bio H4 at SMVT promoters in Jurkat cells across biotin concentrations, plus HCS knockdown","pmids":["17904341"],"confidence":"Medium","gaps":["Single lab and cell type","Mechanism of HCS recruitment to the promoter unresolved"]},{"year":2010,"claim":"Defined the substrate breadth of SMVT by showing it transports iodide via a Na+-coupled mechanism mechanistically separable from the NIS symporter, and confirmed concentration-dependent biotin transport at the blood-retinal barrier.","evidence":"Functional transport and substrate-competition assays in hSMVT-expressing cells; in vivo retinal uptake and TR-iBRB2 cell assays","pmids":["20980265","20599968"],"confidence":"Medium","gaps":["Physiological relevance of SMVT-mediated iodide transport unestablished","Stoichiometry of Na+ coupling not quantified"]},{"year":2012,"claim":"Genetic proof in vivo that SMVT is solely responsible for intestinal biotin absorption, linking its loss to growth failure, bone defects, intestinal inflammation, and death.","evidence":"Intestine-specific Cre/lox Slc5a6 conditional knockout mice with in vivo/in vitro transport, histology, and bone density","pmids":["23104561"],"confidence":"High","gaps":["Did not separate biotin vs pantothenate contributions to phenotype","Mechanism linking deficiency to inflammation not yet defined"]},{"year":2012,"claim":"Extended SMVT transport function to cancer cells and uncovered calcium-calmodulin regulation of its activity.","evidence":"Kinetic [3H]biotin uptake assays with pharmacological pathway inhibitors in T47D breast cancer cells; SMVT localization to the Chlamydia inclusion membrane by immunofluorescence","pmids":["23142496","23029384"],"confidence":"Medium","gaps":["Calmodulin regulatory mechanism not molecularly defined","Pathogen subversion of SMVT not tested for pantothenate/lipoate directly"]},{"year":2015,"claim":"Quantified SMVT's dominant contribution to barrier transport and pinned its luminal localization in human brain capillary endothelium.","evidence":"Quantitative targeted absolute proteomics, antibody-free membrane localization, siRNA knockdown, and uptake assays in hCMEC/D3 cells","pmids":["25809983"],"confidence":"High","gaps":["Mechanism of apical/luminal targeting not defined","NSAID/PGE2 inhibition mechanism unresolved"]},{"year":2016,"claim":"Demonstrated that human loss-of-function mutations disrupt SMVT trafficking, establishing that membrane delivery is required for transport activity and linking specific variants to impaired biotin uptake.","evidence":"[3H]biotin uptake and live-cell confocal imaging of R94X and R123L mutants in HuTu-80 and U87 cells","pmids":["27904971"],"confidence":"Medium","gaps":["Clinical phenotype of carriers not fully characterized","Trafficking machinery interacting with SMVT unidentified"]},{"year":2016,"claim":"Connected SMVT loss to breakdown of intestinal barrier integrity via altered tight-junction proteins, attributing the defect specifically to biotin insufficiency.","evidence":"Conditional SMVT-KO mice and dietary biotin-deficiency in wild-type mice with permeability and tight-junction protein assays","pmids":["27492331"],"confidence":"Medium","gaps":["Molecular link between biotin and tight-junction regulation unresolved","Single lab"]},{"year":2018,"claim":"Causally proved the intestinal phenotype is due to vitamin transport loss by rescuing survival, growth, and inflammation with biotin/pantothenate supplementation.","evidence":"Biotin/pantothenic acid drinking-water supplementation rescue in SMVT-cKO mice with survival, histology, and inflammation readouts","pmids":["29669219"],"confidence":"Medium","gaps":["Relative contributions of biotin vs pantothenate not separated","Downstream metabolic targets not identified here"]},{"year":2019,"claim":"Identified the gut microbiota as the driver of inflammation in SMVT loss, acting through NF-κB and NLRP3 inflammasome signaling.","evidence":"Tamoxifen-inducible intestine-specific SMVT-icKO mice with pathway analysis and broad-spectrum antibiotic rescue","pmids":["31369292"],"confidence":"Medium","gaps":["Specific microbial taxa or metabolites not identified","Link between vitamin deficiency and microbiota shift undefined"]},{"year":2023,"claim":"Established a role in adaptive immunity, showing SLC5A6 mutations impair B cell differentiation and antibody production via biotin-dependent mitochondrial metabolism, rescuable by biotin.","evidence":"Exome sequencing, CRISPR-Cas9 mouse with patient variants, B cell/plasma cell assays, metabolic profiling, and biotin replenishment","pmids":["38036278"],"confidence":"Medium","gaps":["Mechanism linking biotin to plasma cell metabolic switch incomplete","Single patient lineage"]},{"year":2024,"claim":"Defined a cardiac requirement for SMVT, with deletion causing dilated cardiomyopathy through impaired CoA synthesis and mitochondrial metabolic disruption, fully preventable by vitamin supplementation.","evidence":"Cardiac-specific Slc5a6 knockout mice with MRI, ECG, histology, proteomics, CoA assays, and supplementation rescue","pmids":["42228401"],"confidence":"High","gaps":["Cardiomyocyte-autonomous vs systemic contributions not fully separated","Pantothenate-specific role in CoA defect quantified but mechanism upstream not detailed"]},{"year":2024,"claim":"Functionally validated additional pathogenic SLC5A6 alleles, linking splice-disrupting and missense variants to reduced mRNA or transport activity.","evidence":"RT-PCR splice analysis and [3H]biotin uptake in patient fibroblasts plus genome sequencing","pmids":["38816490"],"confidence":"Medium","gaps":["Full disease spectrum across variants not delineated","Single study"]},{"year":2024,"claim":"Placed SLC5A6 upstream of a biotin→ACC→FASN lipid-metabolism axis in lung adenocarcinoma and identified Foxd3 as a transcriptional regulator, defining a pro-tumor function.","evidence":"SLC5A6 knockout/overexpression in LUAD cells, transcriptomics, FASN knockdown rescue, and xenografts; Foxd3 analysis","pmids":["39426496"],"confidence":"Medium","gaps":["Direct Foxd3 binding to SLC5A6 promoter not shown","Single lab"]},{"year":2025,"claim":"Generalized the SLC5A6-ACC-FASN lipid axis to cervical cancer and refined SMVT substrate selectivity, showing certain biotin derivatives bypass the transporter.","evidence":"SLC5A6 knockdown/overexpression in HeLa/SiHa with FASN rescue and xenografts; comparative uptake of biotin derivatives in SLC5A6-inactivated HEK293 cells","pmids":["41108787","41122322"],"confidence":"Medium","gaps":["Alternative biotin-derivative transporters not identified","Therapeutic exploitability of the ACC-FASN axis untested"]},{"year":null,"claim":"The structural basis of substrate recognition and Na+ coupling, the machinery directing apical/luminal trafficking, and the mechanistic link between SMVT vitamin transport and tissue-specific outcomes (tight junctions, plasma cell metabolism, microbiota) remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure or transport stoichiometry","Trafficking/sorting determinants unidentified","Mechanistic bridge from biotin/pantothenate supply to each downstream phenotype incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,2,3,4,7]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,2,4,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,15,17]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y289","full_name":"Sodium-dependent multivitamin transporter","aliases":["Solute carrier family 5 member 6"],"length_aa":635,"mass_kda":68.6,"function":"Sodium-dependent multivitamin transporter that mediates the electrogenic transport of pantothenate, biotin, lipoate and iodide (PubMed:10329687, PubMed:15561972, PubMed:19211916, PubMed:20980265, PubMed:21570947, PubMed:22015582, PubMed:25809983, PubMed:25971966, PubMed:27904971, PubMed:28052864, PubMed:31754459). Functions as a Na(+)-coupled substrate symporter where the stoichiometry of Na(+):substrate is 2:1, creating an electrochemical Na(+) gradient used as driving force for substrate uptake (PubMed:10329687, PubMed:20980265). Required for biotin and pantothenate uptake in the intestine across the brush border membrane (PubMed:19211916). Plays a role in the maintenance of intestinal mucosa integrity, by providing the gut mucosa with biotin (By similarity). Contributes to the luminal uptake of biotin and pantothenate into the brain across the blood-brain barrier (PubMed:25809983)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y289/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SLC5A6","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000138074","cell_line_id":"CID001370","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001370","total_profiled":1310},"omim":[{"mim_id":"619903","title":"PERIPHERAL MOTOR NEUROPATHY, CHILDHOOD-ONSET, BIOTIN-RESPONSIVE; COMNB","url":"https://www.omim.org/entry/619903"},{"mim_id":"618973","title":"SODIUM-DEPENDENT MULTIVITAMIN TRANSPORTER DEFICIENCY; SMVTD","url":"https://www.omim.org/entry/618973"},{"mim_id":"608044","title":"SOLUTE CARRIER FAMILY 5 (IODIDE TRANSPORTER), MEMBER 8; SLC5A8","url":"https://www.omim.org/entry/608044"},{"mim_id":"604024","title":"SOLUTE CARRIER FAMILY 5 (SODIUM-DEPENDENT VITAMIN TRANSPORTER), MEMBER 6; SLC5A6","url":"https://www.omim.org/entry/604024"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":96.2}],"url":"https://www.proteinatlas.org/search/SLC5A6"},"hgnc":{"alias_symbol":["SMVT"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y289","domains":[{"cath_id":"1.20.1730.10","chopping":"33-417","consensus_level":"high","plddt":90.6846,"start":33,"end":417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y289","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y289-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y289-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SLC5A6","jax_strain_url":"https://www.jax.org/strain/search?query=SLC5A6"},"sequence":{"accession":"Q9Y289","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y289.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y289/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y289"}},"corpus_meta":[{"pmid":"25809983","id":"PMC_25809983","title":"Major involvement of Na(+) -dependent multivitamin transporter (SLC5A6/SMVT) in uptake of biotin and pantothenic acid by human brain capillary endothelial cells.","date":"2015","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25809983","citation_count":88,"is_preprint":false},{"pmid":"22420308","id":"PMC_22420308","title":"Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery.","date":"2012","source":"Current drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/22420308","citation_count":82,"is_preprint":false},{"pmid":"12646417","id":"PMC_12646417","title":"Biotin uptake by human intestinal and liver epithelial cells: role of the SMVT system.","date":"2003","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12646417","citation_count":80,"is_preprint":false},{"pmid":"21498711","id":"PMC_21498711","title":"Biotinylated PAMAM dendrimers for intracellular delivery of cisplatin to ovarian cancer: role of SMVT.","date":"2011","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21498711","citation_count":60,"is_preprint":false},{"pmid":"23104561","id":"PMC_23104561","title":"Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption.","date":"2012","source":"American journal of physiology. 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Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27492331","citation_count":24,"is_preprint":false},{"pmid":"31369292","id":"PMC_31369292","title":"Tamoxifen-induced, intestinal-specific deletion of Slc5a6 in adult mice leads to spontaneous inflammation: involvement of NF-κB, NLRP3, and gut microbiota.","date":"2019","source":"American journal of physiology. 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A case report and review of the literature.","date":"2000","source":"Chirurgia italiana","url":"https://pubmed.ncbi.nlm.nih.gov/10832545","citation_count":3,"is_preprint":false},{"pmid":"40004058","id":"PMC_40004058","title":"Human Embryonic Kidney HEK293 Cells as a Model to Study SMVT-Independent Transport of Biotin and Biotin-Furnished Nanoparticles in Targeted Therapy.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40004058","citation_count":2,"is_preprint":false},{"pmid":"41122322","id":"PMC_41122322","title":"Test System for Studying Biotin Transport upon SLC5A6 Gene Inactivation.","date":"2025","source":"Acta naturae","url":"https://pubmed.ncbi.nlm.nih.gov/41122322","citation_count":0,"is_preprint":false},{"pmid":"41108787","id":"PMC_41108787","title":"SLC5A6 Regulates Lipid Metabolism and Lymph Node Metastasis in Cervical Cancer via FASN.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/41108787","citation_count":0,"is_preprint":false},{"pmid":"40396389","id":"PMC_40396389","title":"SLC5A6 Mutations in Axonal Sensorimotor Polyneuropathy Patients Concurrent With Sodium Dependent Multivitamin Transporter Deficiency and Improved Effects by Multivitamin Therapy.","date":"2025","source":"Journal of the peripheral nervous system : JPNS","url":"https://pubmed.ncbi.nlm.nih.gov/40396389","citation_count":0,"is_preprint":false},{"pmid":"42228401","id":"PMC_42228401","title":"A Slc5a6-Deficient Mouse Model Reveals Metabolically Driven Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention.","date":"2026","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/42228401","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.06.658273","title":"A  <i>Slc5a6</i>  Deficient Mouse Model Reveals a Metabolically Driven Dilated Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention","date":"2025-06-09","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.06.658273","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19222,"output_tokens":4626,"usd":0.063528,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12849,"output_tokens":4669,"usd":0.090485,"stage2_stop_reason":"end_turn"},"total_usd":0.154013,"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\": 2003,\n      \"finding\": \"SMVT (SLC5A6) is the major (if not the only) biotin uptake system operating at physiological (nanomolar) concentrations in human intestinal Caco-2 and liver HepG2 epithelial cells; siRNA knockdown of SMVT severely inhibited carrier-mediated [3H]biotin uptake, demonstrating that a recently described second high-affinity biotin uptake system is not functional in these cells.\",\n      \"method\": \"siRNA knockdown of SMVT in Caco-2 and HepG2 cells followed by [3H]biotin uptake assays; RT-PCR and Western blot confirmation of knockdown\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with direct transport assay, replicated across two cell lines with molecular confirmation\",\n      \"pmids\": [\"12646417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Holocarboxylase synthetase (HCS) senses biotin levels, translocates to the nucleus in proportion to biotin concentration, and biotinylates histone H4 at lysine 12 (K12Bio H4) at SMVT promoter 1, causing gene silencing and reducing SMVT expression by up to 86%; HCS knockdown disrupts this chromatin remodeling and leads to abnormal SMVT overexpression.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) for HCS and K12Bio H4 at SMVT promoters; HCS knockdown cells; Jurkat lymphoma cells cultured at varying biotin concentrations\",\n      \"journal\": \"The Journal of nutritional biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with two orthogonal approaches (HCS binding and histone mark), single lab\",\n      \"pmids\": [\"17904341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SMVT mediates Na+-coupled iodide (I−) transport; hSMVT-mediated Na+/I− symport is inhibited by the other organic SMVT substrates (biotin, pantothenic acid, α-lipoic acid) but not by NIS substrates, and is insensitive to perchlorate, distinguishing it mechanistically from the Na+/I− symporter NIS.\",\n      \"method\": \"Functional transport assays in hSMVT-expressing cells; substrate competition experiments; comparison with NIS substrates and inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transport assay with substrate competition, single lab, multiple substrates tested\",\n      \"pmids\": [\"20980265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SMVT is expressed in rat retinal capillary endothelial cells (TR-iBRB2) and mediates Na+-dependent, concentration-dependent, saturable biotin transport (Km ~146 μM) at the inner blood-retinal barrier; transport is inhibited by SMVT substrates biotin, pantothenic acid, lipoic acid, and desthiobiotin.\",\n      \"method\": \"In vivo integration plot and retinal uptake index in rats; [3H]biotin uptake assays in TR-iBRB2 cells; RT-PCR for SMVT mRNA\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro transport assays with substrate competition, single lab\",\n      \"pmids\": [\"20599968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Intestine-specific conditional knockout of Slc5a6 in mice completely abolishes carrier-mediated biotin uptake in the intestine, demonstrating that SMVT is solely responsible for intestinal biotin absorption in vivo; KO mice develop growth retardation, decreased bone density, histological abnormalities, chronic intestinal inflammation, and premature death.\",\n      \"method\": \"Cre/lox intestine-specific conditional SMVT knockout mouse model; in vivo and in vitro [3H]biotin transport studies; histology; bone density measurements\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with direct in vivo transport assay, multiple phenotypic readouts, definitive loss-of-function\",\n      \"pmids\": [\"23104561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SMVT mediates biotin uptake in human breast cancer T47D cells via a Na+-dependent, saturable, carrier-mediated mechanism (Km 9.24 μM); transport is regulated by calcium-calmodulin pathway (inhibited by calmidazolium) but not by PKC or PKA pathways.\",\n      \"method\": \"[3H]biotin uptake assays with kinetic analysis; pharmacological inhibitors of signaling pathways; RT-PCR for SMVT mRNA; competitive inhibition with structural analogs\",\n      \"journal\": \"International journal of pharmaceutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional transport assays with pharmacological dissection, single lab\",\n      \"pmids\": [\"23142496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SMVT localizes to the Chlamydia inclusion vacuole membrane within host cells, providing a mechanism for transport of biotin (and likely pantothenic acid and lipoic acid) from the host cytoplasm into the inclusion where bacterial transporters can further internalize them.\",\n      \"method\": \"Immunofluorescence microscopy of SMVT localization relative to Chlamydia inclusion; [3H]biotin uptake assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunofluorescence localization with functional context, single lab\",\n      \"pmids\": [\"23029384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SLC5A6/SMVT is preferentially localized at the luminal membrane of human brain capillary endothelium and accounts for 88.7% and 98.6% of total [3H]biotin and [3H]pantothenic acid uptake, respectively, by human cerebral microvascular endothelial cells (hCMEC/D3); transport is also inhibited by NSAIDs and prostaglandin E2.\",\n      \"method\": \"Quantitative targeted absolute proteomics (QTAP) for protein expression; antibody-free membrane localization method; SLC5A6 siRNA knockdown in hCMEC/D3 cells; [3H]biotin and [3H]pantothenic acid uptake assays; competitive inhibition with substrates and drugs\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown combined with quantitative proteomics and direct transport assays, multiple substrates and inhibitors tested\",\n      \"pmids\": [\"25809983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss-of-function mutations R94X (premature stop) and R123L (missense) in exon 3 of SLC5A6 severely impair biotin uptake; R94X mutant protein is poorly tolerated and localizes to the cytoplasm, while R123L mutant is predominantly retained in the endoplasmic reticulum, demonstrating that proper trafficking is required for SMVT function.\",\n      \"method\": \"[3H]biotin uptake assay in HuTu-80 and U87 cells expressing mutants; live cell confocal imaging of mutant localization; whole genome scanning to identify mutations\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transport assay combined with live-cell imaging of localization defects, single lab\",\n      \"pmids\": [\"27904971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intestinal-specific SMVT knockout leads to increased gut permeability and altered tight junction (TJ) protein expression; dietary-induced biotin deficiency in wild-type mice produces similar cecal inflammation and permeability changes, establishing that SMVT maintains intestinal mucosal integrity primarily through its role in providing biotin.\",\n      \"method\": \"Conditional SMVT knockout mouse model; gut permeability assays; TJ protein expression analysis; dietary biotin deficiency induction in wild-type mice; cytokine expression measurement\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus dietary deficiency model with multiple functional readouts, single lab\",\n      \"pmids\": [\"27492331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Oversupplementation with biotin and pantothenic acid in the drinking water prevents early death, normalizes growth rate, restores intestinal integrity, and reverses pathology and inflammation in intestinal-specific SMVT-cKO mice, demonstrating that SMVT maintains intestinal health specifically through its transport of biotin and/or pantothenic acid.\",\n      \"method\": \"Biotin/pantothenic acid supplementation of SMVT-cKO mice; survival analysis; growth measurements; histology; intestinal permeability assays; inflammatory marker measurements\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment in conditional KO mouse model with multiple outcome measures, single lab\",\n      \"pmids\": [\"29669219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Adult-onset intestinal-specific SMVT deletion activates NF-κB pathway and NLRP3 inflammasome, inducing spontaneous gut inflammation; broad-spectrum antibiotics reduced lethality and normalized intestinal inflammation, demonstrating that gut microbiota drives the inflammatory response when SMVT is absent.\",\n      \"method\": \"Tamoxifen-inducible intestine-specific SMVT-icKO mice; NF-κB and NLRP3 pathway analysis; antibiotic treatment experiment; cytokine and permeability measurements\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible conditional KO with pathway analysis and antibiotic rescue experiment, single lab\",\n      \"pmids\": [\"31369292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SLC5A6 mutations cause defective B cell differentiation and antibody deficiency through biotin deficiency; biotin replenishment improved plasma cell maturation and recovered antibody production in the patient and in a CRISPR-Cas9 mouse model bearing patient-specific SLC5A6 variants; defective cells show aberrant mitochondrial respiration and reliance on glycolysis.\",\n      \"method\": \"Exome sequencing; CRISPR-Cas9 mouse model; B cell differentiation assays; plasma cell maturation assays; metabolic profiling (mitochondrial respiration, glycolysis); biotin replenishment rescue experiments\",\n      \"journal\": \"Clinical immunology (Orlando, Fla.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO model combined with cellular functional assays and metabolic profiling, single lab\",\n      \"pmids\": [\"38036278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cardiac-specific deletion of Slc5a6 in mice causes progressive dilated cardiomyopathy with cardiomyocyte hypertrophy, fibrosis, impaired Coenzyme A synthesis, and metabolic imbalance leading to premature death at 26 weeks; early proteomic analysis reveals mitochondrial metabolic disruption preceding overt cardiac dysfunction; vitamin supplementation from preconception prevents the cardiac phenotype entirely.\",\n      \"method\": \"Cardiac-specific Slc5a6 knockout mouse model; cardiac MRI; ECG; histology; proteomics; CoA synthesis assays; biotin/pantothenic acid supplementation rescue\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — cardiac-specific KO with multiple orthogonal methods (imaging, histology, proteomics, biochemistry) plus complete rescue experiment\",\n      \"pmids\": [\"42228401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SLC5A6 variant c.393+2T>C causes mis-splicing with nonsense-mediated decay reducing mRNA to ~50% of control; the missense variant p.Ser429Gly results in ~90% reduction in biotin uptake in patient fibroblasts, functionally validating pathogenicity.\",\n      \"method\": \"RT-PCR splice analysis on patient blood mRNA; [3H]biotin uptake assays in patient fibroblasts; genome sequencing\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct transport assay in patient fibroblasts combined with molecular splice analysis, single study\",\n      \"pmids\": [\"38816490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Foxd3 is a transcription factor that regulates SLC5A6 expression; SLC5A6 knockout in LUAD cells impairs mitochondrial function and induces apoptosis; mechanistically, reduced SLC5A6 decreases biotin-dependent acetyl-CoA carboxylase (ACC) expression, which in turn downregulates FASN, disrupting lipid metabolism; FASN knockdown reverses the growth-promoting effect of SLC5A6 overexpression.\",\n      \"method\": \"SLC5A6 knockout and overexpression in LUAD cell lines; transcriptomic analysis; FASN knockdown rescue experiments; in vivo xenograft experiments; Foxd3 transcription factor analysis\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via rescue experiment (FASN KD reverses SLC5A6 OE phenotype), transcriptomic pathway analysis, single lab\",\n      \"pmids\": [\"39426496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biotin and its p-aminophenylalanine derivative Bio-1 require SLC5A6 for cellular entry, while biotin and biotin methyl ester (Bio-2) can enter cells independently of SLC5A6, indicating alternative transport pathways exist for certain biotin derivatives.\",\n      \"method\": \"HEK293 cells with SLC5A6 gene inactivation (test system with BirA* biotin ligase reporter); comparative uptake of biotin derivatives in SLC5A6-intact vs. SLC5A6-inactivated cell lines\",\n      \"journal\": \"Acta naturae\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic inactivation with functional transport assay, single lab, novel test system\",\n      \"pmids\": [\"41122322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SLC5A6 promotes cervical cancer progression through a pathway where SLC5A6-mediated biotin transport maintains expression of biotin-dependent acetyl-CoA carboxylase (ACC), which sustains FASN expression; FASN knockdown reverses the tumor-promoting effects of SLC5A6 overexpression, placing SLC5A6 upstream of ACC-FASN in a lipid metabolism pathway.\",\n      \"method\": \"SLC5A6 knockdown and overexpression in HeLa and SiHa cells; transcriptomic analysis; FASN knockdown rescue; ACC protein expression analysis; in vivo xenograft tumor growth\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via rescue experiment (FASN KD reverses SLC5A6 OE phenotype), in vivo and in vitro confirmation, single lab\",\n      \"pmids\": [\"41108787\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SLC5A6 encodes SMVT, a 12-transmembrane-domain Na+-coupled symporter that co-transports biotin, pantothenic acid, α-lipoic acid, and iodide into cells; it is localized to the luminal/apical plasma membrane in polarized epithelia and endothelium, is the sole carrier for intestinal biotin absorption in vivo, and its expression is feedback-regulated by HCS-dependent biotinylation of histone H4 at its promoter; loss of SMVT function disrupts mitochondrial CoA synthesis and energy metabolism, activates NF-κB/NLRP3 inflammasome signaling through gut microbiota, impairs B cell and plasma cell maturation, causes dilated cardiomyopathy, and in cancer cells controls lipid metabolism via a biotin→ACC→FASN axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SLC5A6 encodes SMVT, a Na+-coupled symporter that serves as the major physiological route for cellular uptake of biotin and pantothenic acid, and is the sole carrier for intestinal biotin absorption in vivo [#0, #4, #7]. The same transporter also mediates Na+-coupled iodide influx through a mechanism distinct from NIS, being insensitive to perchlorate and instead inhibited competitively by its own organic substrates [#2]. SMVT is preferentially positioned at the luminal/apical membrane of polarized epithelium and barrier endothelium, where it accounts for the overwhelming majority of biotin and pantothenate transport at the intestinal, retinal, and brain capillary barriers [#3, #7]; correct trafficking to this membrane is essential, as loss-of-function mutations cause cytoplasmic or ER retention with abolished transport [#8]. Because its substrates are precursors for biotin- and CoA-dependent metabolism, loss of SMVT function disrupts mitochondrial CoA synthesis and energy metabolism, an effect that drives dilated cardiomyopathy upon cardiac-specific deletion and defective B cell/plasma cell maturation with antibody deficiency in patients, both reversible by biotin/pantothenate supplementation [#13, #12]. In the intestine, SMVT loss compromises tight-junction integrity and mucosal barrier function, triggering NF-κB and NLRP3 inflammasome activation driven by gut microbiota, with growth retardation and premature death rescued by biotin and pantothenic acid [#4, #9, #10, #11]. SMVT expression is feedback-regulated by holocarboxylase synthetase, which biotinylates histone H4 at lysine 12 at the SLC5A6 promoter to silence transcription in proportion to biotin availability [#1]. In cancer, SMVT-mediated biotin import sustains a biotin→ACC→FASN lipid-metabolism axis that promotes tumor growth [#15, #17]. Pathogenic SLC5A6 variants—nonsense, missense, and splice-disrupting alleles—reduce transporter expression or activity and are functionally validated by impaired biotin uptake [#8, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that SMVT, not a postulated second high-affinity system, is the dominant physiological biotin uptake route in human intestinal and hepatic epithelia, defining its primary transport function.\",\n      \"evidence\": \"siRNA knockdown of SMVT with [3H]biotin uptake assays in Caco-2 and HepG2 cells\",\n      \"pmids\": [\"12646417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address pantothenate or lipoate uptake\", \"In vitro cell lines only; in vivo contribution not yet tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a feedback loop in which biotin status, sensed by HCS, controls SMVT transcription via histone H4K12 biotinylation at the promoter, explaining how the transporter is downregulated under biotin sufficiency.\",\n      \"evidence\": \"ChIP for HCS and K12Bio H4 at SMVT promoters in Jurkat cells across biotin concentrations, plus HCS knockdown\",\n      \"pmids\": [\"17904341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and cell type\", \"Mechanism of HCS recruitment to the promoter unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the substrate breadth of SMVT by showing it transports iodide via a Na+-coupled mechanism mechanistically separable from the NIS symporter, and confirmed concentration-dependent biotin transport at the blood-retinal barrier.\",\n      \"evidence\": \"Functional transport and substrate-competition assays in hSMVT-expressing cells; in vivo retinal uptake and TR-iBRB2 cell assays\",\n      \"pmids\": [\"20980265\", \"20599968\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of SMVT-mediated iodide transport unestablished\", \"Stoichiometry of Na+ coupling not quantified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Genetic proof in vivo that SMVT is solely responsible for intestinal biotin absorption, linking its loss to growth failure, bone defects, intestinal inflammation, and death.\",\n      \"evidence\": \"Intestine-specific Cre/lox Slc5a6 conditional knockout mice with in vivo/in vitro transport, histology, and bone density\",\n      \"pmids\": [\"23104561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate biotin vs pantothenate contributions to phenotype\", \"Mechanism linking deficiency to inflammation not yet defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended SMVT transport function to cancer cells and uncovered calcium-calmodulin regulation of its activity.\",\n      \"evidence\": \"Kinetic [3H]biotin uptake assays with pharmacological pathway inhibitors in T47D breast cancer cells; SMVT localization to the Chlamydia inclusion membrane by immunofluorescence\",\n      \"pmids\": [\"23142496\", \"23029384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Calmodulin regulatory mechanism not molecularly defined\", \"Pathogen subversion of SMVT not tested for pantothenate/lipoate directly\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Quantified SMVT's dominant contribution to barrier transport and pinned its luminal localization in human brain capillary endothelium.\",\n      \"evidence\": \"Quantitative targeted absolute proteomics, antibody-free membrane localization, siRNA knockdown, and uptake assays in hCMEC/D3 cells\",\n      \"pmids\": [\"25809983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of apical/luminal targeting not defined\", \"NSAID/PGE2 inhibition mechanism unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that human loss-of-function mutations disrupt SMVT trafficking, establishing that membrane delivery is required for transport activity and linking specific variants to impaired biotin uptake.\",\n      \"evidence\": \"[3H]biotin uptake and live-cell confocal imaging of R94X and R123L mutants in HuTu-80 and U87 cells\",\n      \"pmids\": [\"27904971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical phenotype of carriers not fully characterized\", \"Trafficking machinery interacting with SMVT unidentified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected SMVT loss to breakdown of intestinal barrier integrity via altered tight-junction proteins, attributing the defect specifically to biotin insufficiency.\",\n      \"evidence\": \"Conditional SMVT-KO mice and dietary biotin-deficiency in wild-type mice with permeability and tight-junction protein assays\",\n      \"pmids\": [\"27492331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between biotin and tight-junction regulation unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Causally proved the intestinal phenotype is due to vitamin transport loss by rescuing survival, growth, and inflammation with biotin/pantothenate supplementation.\",\n      \"evidence\": \"Biotin/pantothenic acid drinking-water supplementation rescue in SMVT-cKO mice with survival, histology, and inflammation readouts\",\n      \"pmids\": [\"29669219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contributions of biotin vs pantothenate not separated\", \"Downstream metabolic targets not identified here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the gut microbiota as the driver of inflammation in SMVT loss, acting through NF-κB and NLRP3 inflammasome signaling.\",\n      \"evidence\": \"Tamoxifen-inducible intestine-specific SMVT-icKO mice with pathway analysis and broad-spectrum antibiotic rescue\",\n      \"pmids\": [\"31369292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific microbial taxa or metabolites not identified\", \"Link between vitamin deficiency and microbiota shift undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established a role in adaptive immunity, showing SLC5A6 mutations impair B cell differentiation and antibody production via biotin-dependent mitochondrial metabolism, rescuable by biotin.\",\n      \"evidence\": \"Exome sequencing, CRISPR-Cas9 mouse with patient variants, B cell/plasma cell assays, metabolic profiling, and biotin replenishment\",\n      \"pmids\": [\"38036278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking biotin to plasma cell metabolic switch incomplete\", \"Single patient lineage\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a cardiac requirement for SMVT, with deletion causing dilated cardiomyopathy through impaired CoA synthesis and mitochondrial metabolic disruption, fully preventable by vitamin supplementation.\",\n      \"evidence\": \"Cardiac-specific Slc5a6 knockout mice with MRI, ECG, histology, proteomics, CoA assays, and supplementation rescue\",\n      \"pmids\": [\"42228401\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cardiomyocyte-autonomous vs systemic contributions not fully separated\", \"Pantothenate-specific role in CoA defect quantified but mechanism upstream not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Functionally validated additional pathogenic SLC5A6 alleles, linking splice-disrupting and missense variants to reduced mRNA or transport activity.\",\n      \"evidence\": \"RT-PCR splice analysis and [3H]biotin uptake in patient fibroblasts plus genome sequencing\",\n      \"pmids\": [\"38816490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Full disease spectrum across variants not delineated\", \"Single study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed SLC5A6 upstream of a biotin→ACC→FASN lipid-metabolism axis in lung adenocarcinoma and identified Foxd3 as a transcriptional regulator, defining a pro-tumor function.\",\n      \"evidence\": \"SLC5A6 knockout/overexpression in LUAD cells, transcriptomics, FASN knockdown rescue, and xenografts; Foxd3 analysis\",\n      \"pmids\": [\"39426496\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Foxd3 binding to SLC5A6 promoter not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Generalized the SLC5A6-ACC-FASN lipid axis to cervical cancer and refined SMVT substrate selectivity, showing certain biotin derivatives bypass the transporter.\",\n      \"evidence\": \"SLC5A6 knockdown/overexpression in HeLa/SiHa with FASN rescue and xenografts; comparative uptake of biotin derivatives in SLC5A6-inactivated HEK293 cells\",\n      \"pmids\": [\"41108787\", \"41122322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Alternative biotin-derivative transporters not identified\", \"Therapeutic exploitability of the ACC-FASN axis untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of substrate recognition and Na+ coupling, the machinery directing apical/luminal trafficking, and the mechanistic link between SMVT vitamin transport and tissue-specific outcomes (tight junctions, plasma cell metabolism, microbiota) remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure or transport stoichiometry\", \"Trafficking/sorting determinants unidentified\", \"Mechanistic bridge from biotin/pantothenate supply to each downstream phenotype incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 2, 3, 4, 7]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 2, 4, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 15, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}