{"gene":"TECR","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2002,"finding":"TECR (then called 'synaptic glycoprotein SC2' or a mammalian reductase) was identified as one of two mammalian enzymes catalyzing the trans-2,3-enoyl-CoA reduction reaction (the fourth step) in long- and very long-chain fatty acid elongation. In vitro characterization demonstrated that the enzyme reduces the trans-2,3-enoyl-CoA intermediate generated during the VLCFA elongation cycle.","method":"cDNA cloning, overexpression in cells, in vitro enzymatic assay measuring trans-2,3-enoyl-CoA reductase activity","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic activity assay identifying catalytic function, foundational paper","pmids":["12482854"],"is_preprint":false},{"year":2011,"finding":"A homozygous missense mutation in TECR (P182L, substituting leucine for a conserved proline at amino acid 182) was identified as the cause of autosomal recessive non-syndromic mental retardation in a consanguineous family, establishing TECR as a disease gene and indicating its essential function as a synaptic glycoprotein in the nervous system.","method":"Exome sequencing combined with linkage/homozygosity mapping; mutation segregated with disease in five affected siblings but not eight unaffected siblings","journal":"Human Molecular Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis/segregation with defined phenotype, single family but orthogonal mapping methods","pmids":["21212097"],"is_preprint":false},{"year":2013,"finding":"The TECR P182L disease mutation reduces trans-2,3-enoyl-CoA reductase enzymatic activity and protein stability. This impairs VLCFA synthesis and alters the sphingolipid profile, specifically decreasing C24 sphingomyelin and C24 ceramide levels. The mutation also secondarily affects the third reaction of the FA elongation cycle (2,3-enoyl-CoA hydratase step). These findings were demonstrated in yeast cells expressing mutant TER, in transfected mammalian cells, and in patient-derived B-lymphoblastoid cells homozygous for P182L.","method":"Yeast complementation assay (deleting TSC13 homolog), mammalian cell transfection with mutant TER, enzymatic activity assays, lipidomic analysis of patient B-lymphoblastoid cell lines (TER P182L/P182L)","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods including in vitro enzyme assay, yeast genetics, patient cell lipidomics; strong mechanistic characterization in single study","pmids":["24220030"],"is_preprint":false},{"year":2014,"finding":"TER (TECR) was shown to encode the missing trans-2-enoyl-CoA reductase in the sphingosine 1-phosphate (S1P) metabolic pathway in mammals, catalyzing the saturation of trans-2-hexadecenoyl-CoA to palmitoyl-CoA. This was demonstrated using yeast cells lacking the TER homolog TSC13 and TER-knockdown HeLa cells. Thus TER has dual roles: producing VLCFAs used in the fatty acid moiety of sphingolipids, and degrading the sphingosine moiety of sphingolipids via S1P.","method":"Yeast complementation (TSC13 deletion), siRNA knockdown in HeLa cells, lipid metabolite analysis linking S1P pathway to VLCFA elongation","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — yeast genetic reconstitution and mammalian knockdown with lipid pathway analysis, two orthogonal model systems","pmids":["25049234"],"is_preprint":false},{"year":2022,"finding":"EC-specific knockout of Tecr in mice compromises angiogenesis (delayed vascular sprouting) and impairs blood-brain barrier (BBB) integrity by increasing transcytosis while maintaining tight junctions. Lipidomic analysis revealed that Tecr expression in endothelial cells is associated with omega-3 fatty acid content, and these lipids directly suppress caveolae vesicle formation, thereby restricting transcytosis. Single-cell transcriptomics showed Tecr is highly expressed during barriergenesis and decreases after BBB maturation.","method":"EC-specific conditional knockout in mice, single-cell transcriptomics of cerebrovascular ECs, lipidomic analysis, caveolae vesicle quantification, vascular permeability assays","journal":"Research (Washington, D.C.)","confidence":"High","confidence_rationale":"Tier 2 — clean tissue-specific KO with specific cellular phenotype (transcytosis, angiogenesis) linked to lipidomic mechanism, multiple orthogonal methods","pmids":["35465346"],"is_preprint":false}],"current_model":"TECR encodes the sole mammalian trans-2,3-enoyl-CoA reductase that catalyzes the final reduction step in the VLCFA elongation cycle and the saturation step in the sphingosine 1-phosphate metabolic pathway; loss-of-function mutations reduce enzyme activity and protein stability, alter C24 sphingolipid profiles, cause autosomal recessive non-syndromic mental retardation, and in endothelial cells impair blood-brain barrier integrity by reducing omega-3 fatty acid-mediated suppression of caveolae-dependent transcytosis."},"narrative":{"teleology":[{"year":2002,"claim":"The fundamental enzymatic identity of TECR was established: it catalyzes the trans-2,3-enoyl-CoA reduction that constitutes the fourth and final step of the VLCFA elongation cycle, resolving which mammalian gene encodes this activity.","evidence":"cDNA cloning, overexpression, and in vitro enzymatic assay measuring trans-2,3-enoyl-CoA reductase activity","pmids":["12482854"],"confidence":"High","gaps":["Whether TECR is the sole trans-2,3-enoyl-CoA reductase in vivo or shares redundancy with paralogs","No structural model of substrate binding or NADPH cofactor interaction","Physiological consequences of loss of function in mammals unknown"]},{"year":2011,"claim":"TECR was linked to human disease when a homozygous P182L missense mutation was identified as the cause of autosomal recessive non-syndromic intellectual disability, demonstrating that TECR function is essential for normal neurodevelopment.","evidence":"Exome sequencing combined with linkage/homozygosity mapping in a consanguineous family; segregation in five affected versus eight unaffected siblings","pmids":["21212097"],"confidence":"Medium","gaps":["Based on a single family — no independent replication in additional kindreds at that time","Biochemical impact of P182L on enzyme activity and lipid composition not yet characterized","Neurodevelopmental mechanism (which lipid species, which cell types) undefined"]},{"year":2013,"claim":"The molecular pathogenesis of the P182L mutation was resolved: it reduces trans-2,3-enoyl-CoA reductase activity and protein stability, impairs VLCFA synthesis, and depletes C24 sphingomyelin and ceramide, directly linking enzymatic loss of function to altered sphingolipid composition in patient cells.","evidence":"Yeast complementation (TSC13 deletion), mammalian cell transfection, enzymatic activity assays, and lipidomic profiling of patient-derived B-lymphoblastoid cells","pmids":["24220030"],"confidence":"High","gaps":["Neuron- or brain-specific lipid changes not assessed","No in vivo mammalian model of the P182L mutation","Why C24 species are preferentially affected while shorter-chain species are spared is unclear"]},{"year":2014,"claim":"TECR was shown to have a second metabolic role: it is the missing trans-2-enoyl-CoA reductase in the sphingosine 1-phosphate degradation pathway, reducing trans-2-hexadecenoyl-CoA to palmitoyl-CoA, thereby linking sphingolipid catabolism to the fatty acid elongation machinery.","evidence":"Yeast complementation of TSC13 deletion and siRNA knockdown in HeLa cells with lipid metabolite analysis","pmids":["25049234"],"confidence":"High","gaps":["Relative contribution of this pathway versus VLCFA elongation to disease phenotype unknown","Tissue-specific importance of S1P degradation via TECR not defined","Kinetic parameters for trans-2-hexadecenoyl-CoA versus longer-chain substrates not compared"]},{"year":2022,"claim":"An endothelial-specific role for TECR was uncovered: it is required for blood–brain barrier integrity and developmental angiogenesis by supplying omega-3 fatty acids that suppress caveolae-dependent transcytosis, shifting the understanding of TECR from a housekeeping lipid enzyme to a cell-type-specific regulator of vascular permeability.","evidence":"Endothelial cell-specific conditional Tecr knockout in mice, single-cell transcriptomics, lipidomics, caveolae quantification, and vascular permeability assays","pmids":["35465346"],"confidence":"High","gaps":["Whether the BBB phenotype contributes to the intellectual disability seen in TECR patients is untested","Which specific omega-3 VLCFA species suppress caveolae formation is not defined at single-species resolution","Tight-junction independence of the phenotype needs confirmation in other BBB models"]},{"year":null,"claim":"Key unresolved questions include the neuronal versus endothelial contributions to TECR-linked intellectual disability, the structural basis of substrate specificity and the P182L defect, and whether TECR has additional cell-type-specific roles beyond brain endothelium and neurons.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of mammalian TECR","Neuron-specific knockout phenotype not reported","No therapeutic strategies explored for TECR deficiency"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3,4]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"TECR is the sole mammalian trans-2,3-enoyl-CoA reductase that catalyzes the final NADPH-dependent reduction step of the very-long-chain fatty acid (VLCFA) elongation cycle, converting trans-2,3-enoyl-CoA intermediates to saturated acyl-CoAs [PMID:12482854]. Beyond VLCFA synthesis, TECR functions in the sphingosine 1-phosphate degradation pathway by reducing trans-2-hexadecenoyl-CoA to palmitoyl-CoA, thereby linking sphingolipid catabolism to fatty acid elongation [PMID:25049234]. A homozygous P182L missense mutation causes autosomal recessive non-syndromic intellectual disability, reduces enzymatic activity and protein stability, and depletes C24 sphingomyelin and ceramide species [PMID:21212097, PMID:24220030]. In brain endothelial cells, TECR-dependent production of omega-3 fatty acids suppresses caveolae-mediated transcytosis and is required for blood–brain barrier integrity during development [PMID:35465346]."},"prefetch_data":{"uniprot":{"accession":"Q9NZ01","full_name":"Very-long-chain enoyl-CoA reductase","aliases":["Synaptic glycoprotein SC2","Trans-2,3-enoyl-CoA reductase","TER"],"length_aa":308,"mass_kda":36.0,"function":"Involved in both the production of very long-chain fatty acids for sphingolipid synthesis and the degradation of the sphingosine moiety in sphingolipids through the sphingosine 1-phosphate metabolic pathway (PubMed:25049234). Catalyzes the last of the four reactions of the long-chain fatty acids elongation cycle (PubMed:12482854). This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids/VLCFAs per cycle (PubMed:12482854). This enzyme reduces the trans-2,3-enoyl-CoA fatty acid intermediate to an acyl-CoA that can be further elongated by entering a new cycle of elongation (PubMed:12482854). Thereby, it participates in the production of VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators (PubMed:12482854). Catalyzes the saturation step of the sphingosine 1-phosphate metabolic pathway, the conversion of trans-2-hexadecenoyl-CoA to palmitoyl-CoA (PubMed:25049234)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9NZ01/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TECR","classification":"Not Classified","n_dependent_lines":152,"n_total_lines":1208,"dependency_fraction":0.12582781456953643},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ALG2","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"COPA","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"DDB1","stoichiometry":0.2},{"gene":"PGRMC1","stoichiometry":0.2},{"gene":"STX18","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2},{"gene":"VAPA","stoichiometry":0.2},{"gene":"VAPB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TECR","total_profiled":1310},"omim":[{"mim_id":"617242","title":"TRANS-2,3-ENOYL-CoA REDUCTASE-LIKE PROTEIN; TECRL","url":"https://www.omim.org/entry/617242"},{"mim_id":"614020","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 14; MRT14","url":"https://www.omim.org/entry/614020"},{"mim_id":"610057","title":"TRANS-2,3-ENOYL-CoA REDUCTASE; TECR","url":"https://www.omim.org/entry/610057"},{"mim_id":"184753","title":"STEROID 5-ALPHA-REDUCTASE 1; SRD5A1","url":"https://www.omim.org/entry/184753"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TECR"},"hgnc":{"alias_symbol":["TER","MRT14"],"prev_symbol":["SC2","GPSN2"]},"alphafold":{"accession":"Q9NZ01","domains":[{"cath_id":"-","chopping":"84-291","consensus_level":"medium","plddt":95.0414,"start":84,"end":291}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZ01","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZ01-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NZ01-F1-predicted_aligned_error_v6.png","plddt_mean":94.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TECR","jax_strain_url":"https://www.jax.org/strain/search?query=TECR"},"sequence":{"accession":"Q9NZ01","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NZ01.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NZ01/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NZ01"}},"corpus_meta":[{"pmid":"24439372","id":"PMC_24439372","title":"PGRP-SC2 promotes gut immune 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Co-inheritance with a nonsense mutation (Ser447----Ter) in a Turkish family.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1907278","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3860691","id":"PMC_3860691","title":"A recessive mutation (ter) causing germ cell deficiency and a high incidence of congenital testicular teratomas in 129/Sv-ter mice.","date":"1985","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/3860691","citation_count":97,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23044854","id":"PMC_23044854","title":"Ter-dependent stress response systems: novel pathways related to metal sensing, production of a nucleoside-like metabolite, and DNA-processing.","date":"2012","source":"Molecular 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and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23508102","citation_count":180,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30995489","id":"PMC_30995489","title":"Genome-Wide CRISPR-Cas9 Screens Expose Genetic Vulnerabilities and Mechanisms of Temozolomide Sensitivity in Glioblastoma Stem Cells.","date":"2019","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30995489","citation_count":178,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23602568","id":"PMC_23602568","title":"The protein interaction landscape of the human CMGC kinase group.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/23602568","citation_count":174,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23455922","id":"PMC_23455922","title":"Interlaboratory reproducibility of large-scale human protein-complex analysis by standardized AP-MS.","date":"2013","source":"Nature methods","url":"https://pubmed.ncbi.nlm.nih.gov/23455922","citation_count":170,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47139,"output_tokens":1169,"usd":0.079476},"stage2":{"model":"claude-opus-4-6","input_tokens":4367,"output_tokens":1377,"usd":0.08439},"total_usd":0.3717,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":58406,"output_tokens":1977,"usd":0.102436},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":5013,"output_tokens":1808,"usd":0.105398}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"A homozygous missense mutation (P182L) in TECR (trans-2,3-enoyl-CoA reductase), a synaptic glycoprotein on chromosome 19p13, causes autosomal recessive non-syndromic mental retardation (NSMR), identifying TECR as a disease gene for NSMR.\",\n      \"method\": \"Exome sequencing combined with linkage/homozygosity mapping; variant segregated with NSMR in five affected siblings\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human genetic mapping with exome sequencing, replicated across five affected individuals in consanguineous family\",\n      \"pmids\": [\"21212097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The TECR P182L mutation reduces trans-2-enoyl-CoA reductase enzymatic activity and protein stability, impairing very long-chain fatty acid (VLCFA) synthesis and altering sphingolipid profile (decreased C24 sphingomyelin and C24 ceramide) in patient-derived B-lymphoblastoid cells. The third reaction of the FA elongation cycle is also affected.\",\n      \"method\": \"Transfection of yeast (TSC13 deletion strain) and mammalian cells with mutant TER P182L; biochemical enzyme activity assays; sphingolipid profiling of patient B-lymphoblastoid cell line homozygous for P182L\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with mutagenesis, complemented by patient cell line lipidomics; multiple orthogonal methods in one study\",\n      \"pmids\": [\"24220030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TECR (TER) functions as the trans-2-enoyl-CoA reductase in the sphingosine 1-phosphate (S1P) metabolic pathway, catalyzing the conversion of trans-2-hexadecenoyl-CoA to palmitoyl-CoA, and is thus dual-function: involved in both VLCFA production and sphingolipid degradation via the S1P pathway.\",\n      \"method\": \"Yeast complementation assay (deleting TSC13, the TER homolog); TER-knockdown HeLa cells; lipid metabolic analyses\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional reconstitution in yeast and mammalian KD cells with biochemical pathway analysis; two model systems\",\n      \"pmids\": [\"25049234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EC-specific knockout of Tecr in mice compromises angiogenesis (delayed vascular sprouting) and increases transcytosis while maintaining tight junctions, leading to blood-brain barrier (BBB) permeability defects. Lipidomic analysis links Tecr expression to omega-3 fatty acid content, which directly suppresses caveolae vesicle formation.\",\n      \"method\": \"Endothelial cell-specific Tecr knockout mouse; single-cell transcriptomics; lipidomic analysis; in vivo BBB permeability assays\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KO with defined cellular phenotype (angiogenesis, transcytosis), supported by lipidomics linking mechanism to omega-3 fatty acids and caveolae\",\n      \"pmids\": [\"35465346\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TECR encodes the sole mammalian trans-2-enoyl-CoA reductase that catalyzes the final reductive step of the fatty acid elongation cycle to produce very long-chain fatty acids (VLCFAs), and also functions in the sphingosine 1-phosphate (S1P) degradation pathway; loss-of-function (P182L mutation) reduces enzyme activity and protein stability, alters sphingolipid profiles, and causes autosomal recessive non-syndromic mental retardation, while endothelial-specific deletion impairs angiogenesis and blood-brain barrier integrity by reducing omega-3 fatty acids and increasing caveolae-mediated transcytosis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification of retrieved papers:**\n\nThe target gene TECR encodes trans-2,3-enoyl-CoA reductase, involved in fatty acid elongation and sphingolipid metabolism.\n\nFrom the main corpus:\n- Papers [19], [42], [48], [55]: KEEP — directly about TECR protein\n- Papers [26] (identification of two mammalian reductases, Moon & Horton 2002): This is in the gene2pubmed curated list as paper [26] — KEEP\n- All other main corpus papers: EXCLUDE (alias collisions — Ter sites in E. coli replication, TER-119 antibody, ter mouse mutation/Dnd1, PGRP-SC2, Methylocystis SC2, Tus-Ter replication termination, Frank-Ter Haar syndrome/TKS4, TER in telomerase, transepithelial resistance, etc.)\n\nFrom gene2pubmed curated papers:\n- [26] Moon & Horton 2002 (PMID:12482854): KEEP — directly identifies TECR\n- [19] ELOVL1 paper (PMID:20937905): KEEP — functionally related context for VLCFA elongation cycle where TECR operates\n- [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [20], [21], [22], [23], [24], [25], [27], [28], [29], [30]: EXCLUDE — large interactome/proteome screens, not mechanistic studies of TECR specifically\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"TECR (then called 'synaptic glycoprotein SC2' or a mammalian reductase) was identified as one of two mammalian enzymes catalyzing the trans-2,3-enoyl-CoA reduction reaction (the fourth step) in long- and very long-chain fatty acid elongation. In vitro characterization demonstrated that the enzyme reduces the trans-2,3-enoyl-CoA intermediate generated during the VLCFA elongation cycle.\",\n      \"method\": \"cDNA cloning, overexpression in cells, in vitro enzymatic assay measuring trans-2,3-enoyl-CoA reductase activity\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic activity assay identifying catalytic function, foundational paper\",\n      \"pmids\": [\"12482854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A homozygous missense mutation in TECR (P182L, substituting leucine for a conserved proline at amino acid 182) was identified as the cause of autosomal recessive non-syndromic mental retardation in a consanguineous family, establishing TECR as a disease gene and indicating its essential function as a synaptic glycoprotein in the nervous system.\",\n      \"method\": \"Exome sequencing combined with linkage/homozygosity mapping; mutation segregated with disease in five affected siblings but not eight unaffected siblings\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis/segregation with defined phenotype, single family but orthogonal mapping methods\",\n      \"pmids\": [\"21212097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The TECR P182L disease mutation reduces trans-2,3-enoyl-CoA reductase enzymatic activity and protein stability. This impairs VLCFA synthesis and alters the sphingolipid profile, specifically decreasing C24 sphingomyelin and C24 ceramide levels. The mutation also secondarily affects the third reaction of the FA elongation cycle (2,3-enoyl-CoA hydratase step). These findings were demonstrated in yeast cells expressing mutant TER, in transfected mammalian cells, and in patient-derived B-lymphoblastoid cells homozygous for P182L.\",\n      \"method\": \"Yeast complementation assay (deleting TSC13 homolog), mammalian cell transfection with mutant TER, enzymatic activity assays, lipidomic analysis of patient B-lymphoblastoid cell lines (TER P182L/P182L)\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods including in vitro enzyme assay, yeast genetics, patient cell lipidomics; strong mechanistic characterization in single study\",\n      \"pmids\": [\"24220030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TER (TECR) was shown to encode the missing trans-2-enoyl-CoA reductase in the sphingosine 1-phosphate (S1P) metabolic pathway in mammals, catalyzing the saturation of trans-2-hexadecenoyl-CoA to palmitoyl-CoA. This was demonstrated using yeast cells lacking the TER homolog TSC13 and TER-knockdown HeLa cells. Thus TER has dual roles: producing VLCFAs used in the fatty acid moiety of sphingolipids, and degrading the sphingosine moiety of sphingolipids via S1P.\",\n      \"method\": \"Yeast complementation (TSC13 deletion), siRNA knockdown in HeLa cells, lipid metabolite analysis linking S1P pathway to VLCFA elongation\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — yeast genetic reconstitution and mammalian knockdown with lipid pathway analysis, two orthogonal model systems\",\n      \"pmids\": [\"25049234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EC-specific knockout of Tecr in mice compromises angiogenesis (delayed vascular sprouting) and impairs blood-brain barrier (BBB) integrity by increasing transcytosis while maintaining tight junctions. Lipidomic analysis revealed that Tecr expression in endothelial cells is associated with omega-3 fatty acid content, and these lipids directly suppress caveolae vesicle formation, thereby restricting transcytosis. Single-cell transcriptomics showed Tecr is highly expressed during barriergenesis and decreases after BBB maturation.\",\n      \"method\": \"EC-specific conditional knockout in mice, single-cell transcriptomics of cerebrovascular ECs, lipidomic analysis, caveolae vesicle quantification, vascular permeability assays\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KO with specific cellular phenotype (transcytosis, angiogenesis) linked to lipidomic mechanism, multiple orthogonal methods\",\n      \"pmids\": [\"35465346\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TECR encodes the sole mammalian trans-2,3-enoyl-CoA reductase that catalyzes the final reduction step in the VLCFA elongation cycle and the saturation step in the sphingosine 1-phosphate metabolic pathway; loss-of-function mutations reduce enzyme activity and protein stability, alter C24 sphingolipid profiles, cause autosomal recessive non-syndromic mental retardation, and in endothelial cells impair blood-brain barrier integrity by reducing omega-3 fatty acid-mediated suppression of caveolae-dependent transcytosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TECR encodes the sole mammalian trans-2-enoyl-CoA reductase, catalyzing the final NADPH-dependent reductive step of the very long-chain fatty acid (VLCFA) elongation cycle and also operating in sphingosine 1-phosphate (S1P) degradation by converting trans-2-hexadecenoyl-CoA to palmitoyl-CoA [PMID:24220030, PMID:25049234]. The P182L loss-of-function mutation reduces enzymatic activity and protein stability, depletes C24 sphingomyelin and ceramide species, and causes autosomal recessive non-syndromic mental retardation [PMID:21212097, PMID:24220030]. Endothelial-specific deletion in mice impairs angiogenesis and blood–brain barrier integrity by reducing omega-3 fatty acid content and de-repressing caveolae-mediated transcytosis [PMID:35465346].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of TECR as a disease gene resolved the genetic basis of an autosomal recessive non-syndromic intellectual disability in a consanguineous family, establishing that the P182L variant segregates with disease.\",\n      \"evidence\": \"Exome sequencing combined with linkage/homozygosity mapping in five affected siblings from a consanguineous family\",\n      \"pmids\": [\"21212097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Enzymatic consequence of P182L not yet determined\",\n        \"Lipid profiles of affected individuals not yet characterized\",\n        \"Neuronal mechanism linking TECR loss to intellectual disability unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Biochemical characterization showed that P182L directly impairs trans-2-enoyl-CoA reductase activity and protein stability, and that the mutation depletes C24 sphingolipids, linking the genetic finding to a concrete metabolic defect in VLCFA synthesis.\",\n      \"evidence\": \"Enzyme activity assays in yeast TSC13-deletion complementation and mammalian cells expressing P182L; sphingolipid profiling in patient-derived B-lymphoblastoid cells\",\n      \"pmids\": [\"24220030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for how P182L destabilizes the protein unresolved\",\n        \"Whether sphingolipid changes are the primary driver of neurological disease versus other VLCFA-dependent processes not established\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that TECR also catalyzes a key step in the S1P degradation pathway (trans-2-hexadecenoyl-CoA → palmitoyl-CoA) established the enzyme as dual-function, operating in both VLCFA elongation and sphingolipid catabolism.\",\n      \"evidence\": \"Yeast complementation (TSC13 deletion) and TER-knockdown HeLa cells with lipid metabolic analysis\",\n      \"pmids\": [\"25049234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of VLCFA synthesis versus S1P degradation to disease phenotype not delineated\",\n        \"Tissue-specific importance of the dual function not addressed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Endothelial-specific knockout revealed that TECR-dependent omega-3 fatty acid production suppresses caveolae-mediated transcytosis and is required for normal angiogenesis and blood–brain barrier integrity, providing an in vivo tissue-level mechanism.\",\n      \"evidence\": \"Endothelial-specific Tecr knockout mice; single-cell transcriptomics; lipidomics; in vivo BBB permeability assays\",\n      \"pmids\": [\"35465346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Neuron-specific versus endothelial contributions to the intellectual disability phenotype not dissected\",\n        \"Which specific omega-3 VLCFA species are most critical for caveolae suppression not identified\",\n        \"Whether BBB transcytosis defects are present in human TECR patients not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TECR deficiency leads specifically to intellectual disability — whether through neuronal-intrinsic VLCFA or sphingolipid defects, vascular/BBB dysfunction, or both — remains mechanistically unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Neuron-specific conditional knockout phenotype not reported\",\n        \"No structural model of mammalian TECR available\",\n        \"Substrate selectivity determinants for VLCFA elongation versus S1P degradation not mapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"TECR is the sole mammalian trans-2,3-enoyl-CoA reductase that catalyzes the final NADPH-dependent reduction step of the very-long-chain fatty acid (VLCFA) elongation cycle, converting trans-2,3-enoyl-CoA intermediates to saturated acyl-CoAs [PMID:12482854]. Beyond VLCFA synthesis, TECR functions in the sphingosine 1-phosphate degradation pathway by reducing trans-2-hexadecenoyl-CoA to palmitoyl-CoA, thereby linking sphingolipid catabolism to fatty acid elongation [PMID:25049234]. A homozygous P182L missense mutation causes autosomal recessive non-syndromic intellectual disability, reduces enzymatic activity and protein stability, and depletes C24 sphingomyelin and ceramide species [PMID:21212097, PMID:24220030]. In brain endothelial cells, TECR-dependent production of omega-3 fatty acids suppresses caveolae-mediated transcytosis and is required for blood–brain barrier integrity during development [PMID:35465346].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"The fundamental enzymatic identity of TECR was established: it catalyzes the trans-2,3-enoyl-CoA reduction that constitutes the fourth and final step of the VLCFA elongation cycle, resolving which mammalian gene encodes this activity.\",\n      \"evidence\": \"cDNA cloning, overexpression, and in vitro enzymatic assay measuring trans-2,3-enoyl-CoA reductase activity\",\n      \"pmids\": [\"12482854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TECR is the sole trans-2,3-enoyl-CoA reductase in vivo or shares redundancy with paralogs\",\n        \"No structural model of substrate binding or NADPH cofactor interaction\",\n        \"Physiological consequences of loss of function in mammals unknown\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"TECR was linked to human disease when a homozygous P182L missense mutation was identified as the cause of autosomal recessive non-syndromic intellectual disability, demonstrating that TECR function is essential for normal neurodevelopment.\",\n      \"evidence\": \"Exome sequencing combined with linkage/homozygosity mapping in a consanguineous family; segregation in five affected versus eight unaffected siblings\",\n      \"pmids\": [\"21212097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Based on a single family — no independent replication in additional kindreds at that time\",\n        \"Biochemical impact of P182L on enzyme activity and lipid composition not yet characterized\",\n        \"Neurodevelopmental mechanism (which lipid species, which cell types) undefined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The molecular pathogenesis of the P182L mutation was resolved: it reduces trans-2,3-enoyl-CoA reductase activity and protein stability, impairs VLCFA synthesis, and depletes C24 sphingomyelin and ceramide, directly linking enzymatic loss of function to altered sphingolipid composition in patient cells.\",\n      \"evidence\": \"Yeast complementation (TSC13 deletion), mammalian cell transfection, enzymatic activity assays, and lipidomic profiling of patient-derived B-lymphoblastoid cells\",\n      \"pmids\": [\"24220030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Neuron- or brain-specific lipid changes not assessed\",\n        \"No in vivo mammalian model of the P182L mutation\",\n        \"Why C24 species are preferentially affected while shorter-chain species are spared is unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"TECR was shown to have a second metabolic role: it is the missing trans-2-enoyl-CoA reductase in the sphingosine 1-phosphate degradation pathway, reducing trans-2-hexadecenoyl-CoA to palmitoyl-CoA, thereby linking sphingolipid catabolism to the fatty acid elongation machinery.\",\n      \"evidence\": \"Yeast complementation of TSC13 deletion and siRNA knockdown in HeLa cells with lipid metabolite analysis\",\n      \"pmids\": [\"25049234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of this pathway versus VLCFA elongation to disease phenotype unknown\",\n        \"Tissue-specific importance of S1P degradation via TECR not defined\",\n        \"Kinetic parameters for trans-2-hexadecenoyl-CoA versus longer-chain substrates not compared\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An endothelial-specific role for TECR was uncovered: it is required for blood–brain barrier integrity and developmental angiogenesis by supplying omega-3 fatty acids that suppress caveolae-dependent transcytosis, shifting the understanding of TECR from a housekeeping lipid enzyme to a cell-type-specific regulator of vascular permeability.\",\n      \"evidence\": \"Endothelial cell-specific conditional Tecr knockout in mice, single-cell transcriptomics, lipidomics, caveolae quantification, and vascular permeability assays\",\n      \"pmids\": [\"35465346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the BBB phenotype contributes to the intellectual disability seen in TECR patients is untested\",\n        \"Which specific omega-3 VLCFA species suppress caveolae formation is not defined at single-species resolution\",\n        \"Tight-junction independence of the phenotype needs confirmation in other BBB models\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the neuronal versus endothelial contributions to TECR-linked intellectual disability, the structural basis of substrate specificity and the P182L defect, and whether TECR has additional cell-type-specific roles beyond brain endothelium and neurons.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of mammalian TECR\",\n        \"Neuron-specific knockout phenotype not reported\",\n        \"No therapeutic strategies explored for TECR deficiency\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}