{"gene":"TECR","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2011,"finding":"A missense mutation in TECR (p.Pro182Leu) causes autosomal recessive non-syndromic mental retardation, identifying TECR (trans-2,3-enoyl-CoA reductase) as a synaptic glycoprotein whose loss of function results in intellectual disability.","method":"Exome sequencing, linkage/homozygosity mapping, segregation analysis in affected sibship","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mapping plus exome sequencing with segregation in five affected and eight unaffected siblings; single family, no functional rescue experiment","pmids":["21212097"],"is_preprint":false},{"year":2022,"finding":"EC-specific knockout of Tecr in mice compromises angiogenesis (delayed vascular sprouting) and increases transcytosis across the blood-brain barrier without disrupting tight junctions; lipidomic analysis shows Tecr expression correlates with omega-3 fatty acid content, which directly suppresses caveolae vesicle formation, linking very-long-chain fatty acid synthesis to BBB integrity.","method":"Endothelial-cell-specific conditional knockout, lipidomic analysis, single-cell transcriptomics, vascular permeability assays","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean cell-type-specific KO with defined cellular phenotype and lipidomic mechanistic follow-up; single lab, multiple orthogonal methods","pmids":["35465346"],"is_preprint":false},{"year":2025,"finding":"TECR (trans-2,3-enoyl-CoA reductase) is required for a nonapoptotic cell death mechanism triggered by tegavivint and CIL56 in sarcoma and other cancer cells; this lethal mechanism is distinct from ferroptosis, necroptosis, and pyroptosis, and appears to operate via synthesis of the saturated long-chain fatty acid palmitate.","method":"TECR loss-of-function (genetic), cell death assays distinguishing apoptotic/non-apoptotic modalities, lipid metabolite profiling","journal":"Nature chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and pathway placement relative to known cell death modalities; single lab, multiple orthogonal assays reported","pmids":["40419770"],"is_preprint":false}],"current_model":"TECR (trans-2,3-enoyl-CoA reductase) is an ER-resident lipid metabolic enzyme that synthesizes very-long-chain fatty acids; loss-of-function causes intellectual disability in humans, EC-specific deletion impairs angiogenesis and increases BBB transcytosis by reducing omega-3 fatty acid content and suppressing caveolae formation, and pharmacological activation of TECR-dependent palmitate synthesis can drive a non-apoptotic, non-ferroptotic cell death program in cancer cells."},"narrative":{"mechanistic_narrative":"TECR (trans-2,3-enoyl-CoA reductase) is a lipid-metabolic enzyme that catalyzes the reduction step in very-long-chain fatty acid synthesis, and its activity governs cellular processes ranging from neuronal function to vascular barrier integrity and cell death [PMID:21212097, PMID:35465346, PMID:40419770]. A homozygous missense mutation (p.Pro182Leu) causes autosomal recessive non-syndromic intellectual disability, establishing TECR loss of function as a cause of Mendelian neurodevelopmental disease [PMID:21212097]. In endothelial cells, TECR-dependent very-long-chain fatty acid synthesis sustains the omega-3 fatty acid content that suppresses caveolae formation; endothelial-specific deletion delays vascular sprouting and increases transcytosis across the blood-brain barrier without disrupting tight junctions [PMID:35465346]. TECR also enables a nonapoptotic, non-ferroptotic cell death program triggered by tegavivint and CIL56 in sarcoma and other cancer cells, operating through synthesis of the saturated fatty acid palmitate [PMID:40419770].","teleology":[{"year":2011,"claim":"Establishing that TECR loss of function causes human disease moved it from a metabolic enzyme to a clinically relevant neurodevelopmental gene.","evidence":"Exome sequencing with linkage/homozygosity mapping and segregation analysis in an affected sibship","pmids":["21212097"],"confidence":"Medium","gaps":["Single family with no functional rescue experiment","Mechanism linking enzyme deficiency to synaptic/neuronal dysfunction not defined","Effect of the mutation on enzymatic activity not directly measured"]},{"year":2022,"claim":"Endothelial-specific deletion connected TECR's very-long-chain fatty acid synthesis to vascular barrier control, showing the enzyme regulates caveolae-mediated transcytosis via lipid composition rather than tight junctions.","evidence":"Endothelial-cell-specific conditional knockout in mice with lipidomics, single-cell transcriptomics, and vascular permeability assays","pmids":["35465346"],"confidence":"Medium","gaps":["Single lab; molecular link between omega-3 content and caveolae suppression not fully resolved","Whether the same lipid mechanism operates in non-endothelial tissues unknown"]},{"year":2025,"claim":"Loss-of-function studies placed TECR within a distinct cell death pathway, showing its palmitate-synthesis activity is required for a nonapoptotic, non-ferroptotic lethal program in cancer cells.","evidence":"Genetic TECR loss-of-function with cell death modality assays and lipid metabolite profiling in sarcoma and other cancer cells","pmids":["40419770"],"confidence":"Medium","gaps":["Single lab; downstream effectors of palmitate-driven death not identified","Direct enzymatic role of TECR in generating the lethal lipid species not biochemically reconstituted","Generality across tumor types beyond those tested unknown"]},{"year":null,"claim":"How a single very-long-chain fatty acid reductase coordinates such divergent outcomes — neuronal function, BBB integrity, and cell death — through distinct lipid products remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying biochemical model linking TECR enzyme activity to its different downstream lipid species across contexts","No structural characterization in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":[],"other_free_text":[]}},"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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single family, no functional rescue experiment\",\n      \"pmids\": [\"21212097\"],\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 across the blood-brain barrier without disrupting tight junctions; lipidomic analysis shows Tecr expression correlates with omega-3 fatty acid content, which directly suppresses caveolae vesicle formation, linking very-long-chain fatty acid synthesis to BBB integrity.\",\n      \"method\": \"Endothelial-cell-specific conditional knockout, lipidomic analysis, single-cell transcriptomics, vascular permeability assays\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean cell-type-specific KO with defined cellular phenotype and lipidomic mechanistic follow-up; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35465346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TECR (trans-2,3-enoyl-CoA reductase) is required for a nonapoptotic cell death mechanism triggered by tegavivint and CIL56 in sarcoma and other cancer cells; this lethal mechanism is distinct from ferroptosis, necroptosis, and pyroptosis, and appears to operate via synthesis of the saturated long-chain fatty acid palmitate.\",\n      \"method\": \"TECR loss-of-function (genetic), cell death assays distinguishing apoptotic/non-apoptotic modalities, lipid metabolite profiling\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype and pathway placement relative to known cell death modalities; single lab, multiple orthogonal assays reported\",\n      \"pmids\": [\"40419770\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TECR (trans-2,3-enoyl-CoA reductase) is an ER-resident lipid metabolic enzyme that synthesizes very-long-chain fatty acids; loss-of-function causes intellectual disability in humans, EC-specific deletion impairs angiogenesis and increases BBB transcytosis by reducing omega-3 fatty acid content and suppressing caveolae formation, and pharmacological activation of TECR-dependent palmitate synthesis can drive a non-apoptotic, non-ferroptotic cell death program in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TECR (trans-2,3-enoyl-CoA reductase) is a lipid-metabolic enzyme that catalyzes the reduction step in very-long-chain fatty acid synthesis, and its activity governs cellular processes ranging from neuronal function to vascular barrier integrity and cell death [#0, #1, #2]. A homozygous missense mutation (p.Pro182Leu) causes autosomal recessive non-syndromic intellectual disability, establishing TECR loss of function as a cause of Mendelian neurodevelopmental disease [#0]. In endothelial cells, TECR-dependent very-long-chain fatty acid synthesis sustains the omega-3 fatty acid content that suppresses caveolae formation; endothelial-specific deletion delays vascular sprouting and increases transcytosis across the blood-brain barrier without disrupting tight junctions [#1]. TECR also enables a nonapoptotic, non-ferroptotic cell death program triggered by tegavivint and CIL56 in sarcoma and other cancer cells, operating through synthesis of the saturated fatty acid palmitate [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that TECR loss of function causes human disease moved it from a metabolic enzyme to a clinically relevant neurodevelopmental gene.\",\n      \"evidence\": \"Exome sequencing with linkage/homozygosity mapping and segregation analysis in an affected sibship\",\n      \"pmids\": [\"21212097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single family with no functional rescue experiment\",\n        \"Mechanism linking enzyme deficiency to synaptic/neuronal dysfunction not defined\",\n        \"Effect of the mutation on enzymatic activity not directly measured\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Endothelial-specific deletion connected TECR's very-long-chain fatty acid synthesis to vascular barrier control, showing the enzyme regulates caveolae-mediated transcytosis via lipid composition rather than tight junctions.\",\n      \"evidence\": \"Endothelial-cell-specific conditional knockout in mice with lipidomics, single-cell transcriptomics, and vascular permeability assays\",\n      \"pmids\": [\"35465346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; molecular link between omega-3 content and caveolae suppression not fully resolved\",\n        \"Whether the same lipid mechanism operates in non-endothelial tissues unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Loss-of-function studies placed TECR within a distinct cell death pathway, showing its palmitate-synthesis activity is required for a nonapoptotic, non-ferroptotic lethal program in cancer cells.\",\n      \"evidence\": \"Genetic TECR loss-of-function with cell death modality assays and lipid metabolite profiling in sarcoma and other cancer cells\",\n      \"pmids\": [\"40419770\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab; downstream effectors of palmitate-driven death not identified\",\n        \"Direct enzymatic role of TECR in generating the lethal lipid species not biochemically reconstituted\",\n        \"Generality across tumor types beyond those tested unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single very-long-chain fatty acid reductase coordinates such divergent outcomes — neuronal function, BBB integrity, and cell death — through distinct lipid products remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying biochemical model linking TECR enzyme activity to its different downstream lipid species across contexts\",\n        \"No structural characterization in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}