{"gene":"TEDC1","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2025,"finding":"TEDC1 and TEDC2 form a subcomplex in the absence of delta-tubulin and epsilon-tubulin, and all four proteins (delta-tubulin, epsilon-tubulin, TEDC1, TEDC2) physically interact as a tetramer, consistent with an AlphaFold Multimer structural model.","method":"Co-immunoprecipitation, physical interaction assays, AlphaFold Multimer structural modeling","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction data with subcomplex validation and structural model support","pmids":["40067174"],"is_preprint":false},{"year":2025,"finding":"TEDC1 and TEDC2 localize to centrosomes and are mutually dependent on each other and on delta-tubulin and epsilon-tubulin for centrosomal localization; loss of TEDC1 or TEDC2 results in centrioles lacking triplet microtubules, failure to recruit central core scaffold proteins (e.g., POC5), expanded proximal regions, and a cycle of centriole elongation followed by fragmentation and disintegration during mitosis.","method":"CRISPR knockout cell lines, ultrastructure expansion microscopy, immunofluorescence localization, genetic epistasis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined ultrastructural phenotype and localization dependency mapped across four proteins","pmids":["40067174"],"is_preprint":false},{"year":2025,"finding":"A C-terminally truncated TEDC1 protein (from a frameshift variant in the last coding exon) impairs binding with TEDC2, demonstrating that the C-terminus of TEDC1 is required for its interaction with TEDC2.","method":"Patient-derived cells with frameshift variant; binding assay between truncated TEDC1 and TEDC2","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — direct interaction assay using disease-relevant truncation mutant, single lab","pmids":["39979680"],"is_preprint":false},{"year":2025,"finding":"Loss of TEDC1 causes cell cycle abnormalities in patient-derived cells and cilia defects through impaired acetylated tubulin levels; tedc1-/- zebrafish recapitulate growth impairment, cranial bone dysplasia, and sterility with absent gonads.","method":"Patient-derived cell cycle analysis, CRISPR/Cas9 tedc1-/- zebrafish model, immunostaining for acetylated tubulin","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo loss-of-function with specific cellular and organismal phenotypes, single lab","pmids":["39979680"],"is_preprint":false},{"year":2019,"finding":"TEDC1 was identified as a candidate gene involved in the centrosome-related pathway underlying primary microcephaly, based on causative variants found in patients and functional studies.","method":"Exome sequencing with functional studies in patient cohort","journal":"Genetics in medicine : official journal of the American College of Medical Genetics","confidence":"Low","confidence_rationale":"Tier 3 — candidate gene identification with limited mechanistic detail, single cohort study","pmids":["30842647"],"is_preprint":false}],"current_model":"TEDC1 forms a tetrameric complex with TEDC2, delta-tubulin, and epsilon-tubulin at centrosomes — where TEDC1 and TEDC2 interact directly via a subcomplex — and this complex is required for the assembly of triplet microtubules and robust centriole architecture; loss of TEDC1 leads to structurally abnormal centrioles lacking triplet microtubules, failure to recruit central core scaffold proteins, cell cycle defects, and cilia abnormalities."},"narrative":{"teleology":[{"year":2019,"claim":"Establishing that TEDC1 is disease-relevant: exome sequencing in microcephaly patients identified TEDC1 as a candidate centrosome-pathway gene, linking it for the first time to a human developmental disorder.","evidence":"Exome sequencing with functional studies in a primary microcephaly cohort","pmids":["30842647"],"confidence":"Low","gaps":["Mechanistic detail of how TEDC1 variants cause microcephaly was not provided","No binding partners or protein complex defined at this stage","Single cohort without independent replication"]},{"year":2025,"claim":"Defining the molecular complex: TEDC1 physically associates with TEDC2, delta-tubulin, and epsilon-tubulin as a tetramer, with TEDC1–TEDC2 forming an independent subcomplex, resolving the compositional basis of the delta/epsilon-tubulin pathway.","evidence":"Reciprocal co-immunoprecipitation, subcomplex reconstitution in absence of tubulins, AlphaFold Multimer structural modeling (eLife)","pmids":["40067174"],"confidence":"High","gaps":["No experimentally determined atomic-resolution structure of the tetramer","Stoichiometry and assembly order of the complex in vivo remain undefined","Direct contacts between TEDC1 and delta/epsilon-tubulin versus TEDC2-mediated bridging not fully resolved"]},{"year":2025,"claim":"Establishing the ultrastructural function: loss of TEDC1 or TEDC2 eliminates triplet microtubules from centrioles, prevents recruitment of the central core scaffold (POC5), and causes centriole disintegration during mitosis, demonstrating that the tetramer is required for centriole architectural integrity.","evidence":"CRISPR knockout cell lines analyzed by ultrastructure expansion microscopy and immunofluorescence (eLife)","pmids":["40067174"],"confidence":"High","gaps":["Whether TEDC1 directly stabilizes the C-tubule or acts indirectly through tubulin modification is unknown","Temporal sequence of triplet loss versus scaffold recruitment failure not resolved"]},{"year":2025,"claim":"Mapping a functional domain and organismal phenotype: a patient-derived C-terminal truncation of TEDC1 disrupts TEDC2 binding, and tedc1-knockout zebrafish recapitulate growth impairment, cranial bone dysplasia, cilia defects, and sterility, linking the molecular interaction to disease pathophysiology.","evidence":"Binding assay with frameshift-truncated TEDC1, patient cell cycle analysis, CRISPR tedc1−/− zebrafish (EJHG)","pmids":["39979680"],"confidence":"Medium","gaps":["Precise residues mediating the TEDC1–TEDC2 interface beyond the C-terminal region are not mapped","Whether cilia defects are a direct consequence of triplet loss or a secondary effect of centriole disintegration is unclear","Only a single truncation variant tested; contribution of other domains untested"]},{"year":null,"claim":"Key unresolved question: how the TEDC1-containing tetramer mechanistically promotes C-tubule assembly and whether it acts catalytically, as a structural template, or by recruiting additional factors remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemical reconstitution of triplet microtubule assembly with purified tetramer","No high-resolution experimental structure of the TEDC1–TEDC2–tubulin complex","Relationship between TEDC1 loss and the specific cell cycle arrest checkpoint is undefined"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,3]}],"complexes":["delta-tubulin/epsilon-tubulin/TEDC1/TEDC2 tetramer"],"partners":["TEDC2","TUBD1","TUBE1","POC5"],"other_free_text":[]},"mechanistic_narrative":"TEDC1 is a centrosomal protein that forms a tetrameric complex with TEDC2, delta-tubulin, and epsilon-tubulin, and is essential for the assembly of triplet microtubules and structural integrity of centrioles [PMID:40067174]. Within this complex, TEDC1 and TEDC2 constitute a subcomplex whose formation requires the TEDC1 C-terminus, and all four subunits are mutually dependent for centrosomal localization; loss of TEDC1 produces centrioles lacking triplet microtubules, failure to recruit central core scaffold proteins such as POC5, and a cycle of centriole elongation, fragmentation, and disintegration during mitosis [PMID:40067174, PMID:39979680]. TEDC1 deficiency also causes cell cycle abnormalities, reduced acetylated tubulin levels, and cilia defects, and biallelic loss-of-function variants cause a syndromic disorder featuring primary microcephaly, cranial bone dysplasia, and sterility, as demonstrated in patient cells and tedc1-knockout zebrafish [PMID:39979680, PMID:30842647]."},"prefetch_data":{"uniprot":{"accession":"Q86SX3","full_name":"Tubulin epsilon and delta complex protein 1","aliases":[],"length_aa":495,"mass_kda":54.2,"function":"Acts as a positive regulator of ciliary hedgehog signaling. Required for centriole stability (By similarity). May play a role in counteracting perturbation of actin filaments, such as after treatment with the actin depolymerizing microbial metabolite Chivosazole F (PubMed:28796488)","subcellular_location":"Cell projection, cilium; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q86SX3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TEDC1","classification":"Not Classified","n_dependent_lines":488,"n_total_lines":1208,"dependency_fraction":0.40397350993377484},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TEDC1","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Golgi apparatus","reliability":"Uncertain"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TEDC1"},"hgnc":{"alias_symbol":[],"prev_symbol":["C14orf80"]},"alphafold":{"accession":"Q86SX3","domains":[{"cath_id":"-","chopping":"11-135_309-333","consensus_level":"medium","plddt":76.0933,"start":11,"end":333}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SX3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SX3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86SX3-F1-predicted_aligned_error_v6.png","plddt_mean":62.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TEDC1","jax_strain_url":"https://www.jax.org/strain/search?query=TEDC1"},"sequence":{"accession":"Q86SX3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86SX3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86SX3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86SX3"}},"corpus_meta":[{"pmid":"30842647","id":"PMC_30842647","title":"Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.","date":"2019","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30842647","citation_count":63,"is_preprint":false},{"pmid":"28796488","id":"PMC_28796488","title":"Direct Interaction of Chivosazole F with Actin Elicits Cell Responses Similar to Latrunculin A but Distinct from Chondramide.","date":"2017","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/28796488","citation_count":7,"is_preprint":false},{"pmid":"40067174","id":"PMC_40067174","title":"A delta-tubulin/epsilon-tubulin/Ted protein complex is required for centriole architecture.","date":"2025","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/40067174","citation_count":6,"is_preprint":false},{"pmid":"39979680","id":"PMC_39979680","title":"Biallelic TEDC1 variants cause a new syndrome with severe growth impairment and endocrine complications.","date":"2025","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/39979680","citation_count":2,"is_preprint":false},{"pmid":"39864717","id":"PMC_39864717","title":"Effects of in vitro cytochalasin D and hypoxia on mitochondrial energetics and biogenesis, cell signal status and actin/tubulin/Hsp/MMP entity in air-breathing fish heart.","date":"2025","source":"Comparative biochemistry and physiology. Toxicology & pharmacology : CBP","url":"https://pubmed.ncbi.nlm.nih.gov/39864717","citation_count":1,"is_preprint":false},{"pmid":"38252227","id":"PMC_38252227","title":"Second report of TEDC1-related microcephaly caused by a novel biallelic mutation in an Iranian consanguineous family.","date":"2024","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/38252227","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4439,"output_tokens":1149,"usd":0.015276},"stage2":{"model":"claude-opus-4-6","input_tokens":4374,"output_tokens":1552,"usd":0.091005},"total_usd":0.106281,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"TEDC1 and TEDC2 form a subcomplex in the absence of delta-tubulin and epsilon-tubulin, and all four proteins (delta-tubulin, epsilon-tubulin, TEDC1, TEDC2) physically interact as a tetramer, consistent with an AlphaFold Multimer structural model.\",\n      \"method\": \"Co-immunoprecipitation, physical interaction assays, AlphaFold Multimer structural modeling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction data with subcomplex validation and structural model support\",\n      \"pmids\": [\"40067174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TEDC1 and TEDC2 localize to centrosomes and are mutually dependent on each other and on delta-tubulin and epsilon-tubulin for centrosomal localization; loss of TEDC1 or TEDC2 results in centrioles lacking triplet microtubules, failure to recruit central core scaffold proteins (e.g., POC5), expanded proximal regions, and a cycle of centriole elongation followed by fragmentation and disintegration during mitosis.\",\n      \"method\": \"CRISPR knockout cell lines, ultrastructure expansion microscopy, immunofluorescence localization, genetic epistasis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined ultrastructural phenotype and localization dependency mapped across four proteins\",\n      \"pmids\": [\"40067174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A C-terminally truncated TEDC1 protein (from a frameshift variant in the last coding exon) impairs binding with TEDC2, demonstrating that the C-terminus of TEDC1 is required for its interaction with TEDC2.\",\n      \"method\": \"Patient-derived cells with frameshift variant; binding assay between truncated TEDC1 and TEDC2\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction assay using disease-relevant truncation mutant, single lab\",\n      \"pmids\": [\"39979680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of TEDC1 causes cell cycle abnormalities in patient-derived cells and cilia defects through impaired acetylated tubulin levels; tedc1-/- zebrafish recapitulate growth impairment, cranial bone dysplasia, and sterility with absent gonads.\",\n      \"method\": \"Patient-derived cell cycle analysis, CRISPR/Cas9 tedc1-/- zebrafish model, immunostaining for acetylated tubulin\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo loss-of-function with specific cellular and organismal phenotypes, single lab\",\n      \"pmids\": [\"39979680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TEDC1 was identified as a candidate gene involved in the centrosome-related pathway underlying primary microcephaly, based on causative variants found in patients and functional studies.\",\n      \"method\": \"Exome sequencing with functional studies in patient cohort\",\n      \"journal\": \"Genetics in medicine : official journal of the American College of Medical Genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — candidate gene identification with limited mechanistic detail, single cohort study\",\n      \"pmids\": [\"30842647\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TEDC1 forms a tetrameric complex with TEDC2, delta-tubulin, and epsilon-tubulin at centrosomes — where TEDC1 and TEDC2 interact directly via a subcomplex — and this complex is required for the assembly of triplet microtubules and robust centriole architecture; loss of TEDC1 leads to structurally abnormal centrioles lacking triplet microtubules, failure to recruit central core scaffold proteins, cell cycle defects, and cilia abnormalities.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TEDC1 is a centrosomal protein that forms a tetrameric complex with TEDC2, delta-tubulin, and epsilon-tubulin, and is essential for the assembly of triplet microtubules and structural integrity of centrioles [PMID:40067174]. Within this complex, TEDC1 and TEDC2 constitute a subcomplex whose formation requires the TEDC1 C-terminus, and all four subunits are mutually dependent for centrosomal localization; loss of TEDC1 produces centrioles lacking triplet microtubules, failure to recruit central core scaffold proteins such as POC5, and a cycle of centriole elongation, fragmentation, and disintegration during mitosis [PMID:40067174, PMID:39979680]. TEDC1 deficiency also causes cell cycle abnormalities, reduced acetylated tubulin levels, and cilia defects, and biallelic loss-of-function variants cause a syndromic disorder featuring primary microcephaly, cranial bone dysplasia, and sterility, as demonstrated in patient cells and tedc1-knockout zebrafish [PMID:39979680, PMID:30842647].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that TEDC1 is disease-relevant: exome sequencing in microcephaly patients identified TEDC1 as a candidate centrosome-pathway gene, linking it for the first time to a human developmental disorder.\",\n      \"evidence\": \"Exome sequencing with functional studies in a primary microcephaly cohort\",\n      \"pmids\": [\"30842647\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanistic detail of how TEDC1 variants cause microcephaly was not provided\",\n        \"No binding partners or protein complex defined at this stage\",\n        \"Single cohort without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining the molecular complex: TEDC1 physically associates with TEDC2, delta-tubulin, and epsilon-tubulin as a tetramer, with TEDC1–TEDC2 forming an independent subcomplex, resolving the compositional basis of the delta/epsilon-tubulin pathway.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, subcomplex reconstitution in absence of tubulins, AlphaFold Multimer structural modeling (eLife)\",\n      \"pmids\": [\"40067174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No experimentally determined atomic-resolution structure of the tetramer\",\n        \"Stoichiometry and assembly order of the complex in vivo remain undefined\",\n        \"Direct contacts between TEDC1 and delta/epsilon-tubulin versus TEDC2-mediated bridging not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Establishing the ultrastructural function: loss of TEDC1 or TEDC2 eliminates triplet microtubules from centrioles, prevents recruitment of the central core scaffold (POC5), and causes centriole disintegration during mitosis, demonstrating that the tetramer is required for centriole architectural integrity.\",\n      \"evidence\": \"CRISPR knockout cell lines analyzed by ultrastructure expansion microscopy and immunofluorescence (eLife)\",\n      \"pmids\": [\"40067174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TEDC1 directly stabilizes the C-tubule or acts indirectly through tubulin modification is unknown\",\n        \"Temporal sequence of triplet loss versus scaffold recruitment failure not resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Mapping a functional domain and organismal phenotype: a patient-derived C-terminal truncation of TEDC1 disrupts TEDC2 binding, and tedc1-knockout zebrafish recapitulate growth impairment, cranial bone dysplasia, cilia defects, and sterility, linking the molecular interaction to disease pathophysiology.\",\n      \"evidence\": \"Binding assay with frameshift-truncated TEDC1, patient cell cycle analysis, CRISPR tedc1−/− zebrafish (EJHG)\",\n      \"pmids\": [\"39979680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Precise residues mediating the TEDC1–TEDC2 interface beyond the C-terminal region are not mapped\",\n        \"Whether cilia defects are a direct consequence of triplet loss or a secondary effect of centriole disintegration is unclear\",\n        \"Only a single truncation variant tested; contribution of other domains untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved question: how the TEDC1-containing tetramer mechanistically promotes C-tubule assembly and whether it acts catalytically, as a structural template, or by recruiting additional factors remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical reconstitution of triplet microtubule assembly with purified tetramer\",\n        \"No high-resolution experimental structure of the TEDC1–TEDC2–tubulin complex\",\n        \"Relationship between TEDC1 loss and the specific cell cycle arrest checkpoint is undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\n      \"delta-tubulin/epsilon-tubulin/TEDC1/TEDC2 tetramer\"\n    ],\n    \"partners\": [\n      \"TEDC2\",\n      \"TUBD1\",\n      \"TUBE1\",\n      \"POC5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}