{"gene":"TTC21A","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2019,"finding":"Bi-allelic loss-of-function mutations in TTC21A (encoding an IFT-associated protein with tetratricopeptide repeat domains) cause asthenoteratospermia with defects of the sperm flagella and head-tail conjunction in humans; CRISPR-Cas9 Ttc21a knockout mice recapitulate the sperm structural defects of the flagella and connecting piece, establishing TTC21A as required for flagellar assembly and sperm head-tail junction integrity.","method":"Whole-exome sequencing of human MMAF cohorts; CRISPR-Cas9 knockout mouse model with sperm ultrastructure analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic evidence corroborated by mouse KO phenocopy with defined structural readout, replicated across two independent cohorts","pmids":["30929735"],"is_preprint":false},{"year":2020,"finding":"TTC21A (Thm2) and its paralog Thm1 (Ttc21b) have both unique and redundant roles in primary cilia function in mouse embryonic fibroblasts. Thm2-null MEF show normal ciliary dynamics and Hedgehog signaling individually, but combined loss of Thm1 and Thm2 enhances cilia disassembly and impairs INPP5E ciliary import. Double knockout causes mid-gestational lethality, indicating genetic interaction in embryogenesis.","method":"Mouse embryonic fibroblast (MEF) genetic epistasis analysis with single and double mutants; cilia assembly/disassembly assays; Smoothened trafficking assay; INPP5E ciliary entry assay; embryo survival counting","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple orthogonal cellular assays (cilia dynamics, IFT protein trafficking, Hedgehog signaling, membrane protein import) in a single rigorous study","pmids":["32167205"],"is_preprint":false},{"year":2021,"finding":"TTC21A (Thm2) localizes to primary cilia and sensitizes to Hedgehog signaling in postnatal skeletogenesis through a genetic interaction with paralog Thm1. Thm2-/-; Thm1aln/+ mice exhibit impaired chondrocyte differentiation with expanded proliferation zone and diminished hypertrophic zone, increased Hedgehog signaling in growth plate chondrocytes, and markedly impaired bone nodule formation in osteoblasts. Deletion of one Gli2 allele exacerbated the small stature phenotype, implicating a pathway involving Gli2.","method":"Mouse double-mutant genetic analysis; radiography and micro-CT of bone; growth plate histology; primary osteoblast bone nodule formation assay; Hedgehog pathway signaling assay; genetic epistasis with Gli2","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple orthogonal readouts (bone morphology, histology, signaling assays, in vitro osteoblast function) in a single lab","pmids":["33683377"],"is_preprint":false},{"year":2022,"finding":"TTC21A (Thm2) genetically interacts with Thm1 to regulate postnatal craniofacial bone formation. Thm2-/-; Thm1aln/+ triple allele mutant mice show micrognathia, midface hypoplasia, and impaired in vitro bone formation in calvarial-derived osteoblasts, which is rescued by Hedgehog agonist SAG, placing Thm2/Thm1 upstream of Hedgehog signaling in craniofacial osteoblast differentiation.","method":"Micro-computed tomography of craniofacial structures; in vitro bone formation assay with calvarial osteoblasts; pharmacological rescue with Hedgehog agonist SAG","journal":"Journal of developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with micro-CT and in vitro functional rescue, single lab","pmids":["35645293"],"is_preprint":false},{"year":2023,"finding":"TTC21A (IFT139A/Thm2) was identified as an interacting protein of CEP78 by co-immunoprecipitation. CEP78 regulates the interaction, stability, and centriolar localization of TTC21A; insufficient CEP78 or its interacting proteins causes abnormal centriole elongation and cilia shortening, placing TTC21A downstream of CEP78 in a centriole/cilia regulatory complex.","method":"Co-immunoprecipitation (interaction screen); centriole elongation and cilia length measurement in CEP78-deficient cells; stability and localization analysis of interacting proteins","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP identification of interaction with functional follow-up on localization and stability, single lab","pmids":["36756949"],"is_preprint":false}],"current_model":"TTC21A (also known as Thm2/IFT139A) encodes an IFT-A complex-associated protein with tetratricopeptide repeat domains that localizes to primary cilia and is required for sperm flagellar assembly and head-tail junction integrity, cilia disassembly regulation, ciliary import of membrane proteins (e.g., INPP5E), Hedgehog signaling transduction (acting redundantly with paralog Thm1), and postnatal skeletogenesis and craniofacial bone formation; it physically interacts with CEP78, whose loss destabilizes TTC21A and disrupts centriolar localization, causing centriole elongation and cilia shortening."},"narrative":{"mechanistic_narrative":"TTC21A (Thm2/IFT139A) is an intraflagellar transport-associated tetratricopeptide-repeat protein required for ciliary and flagellar assembly and for Hedgehog-dependent skeletogenesis [PMID:30929735, PMID:33683377]. Bi-allelic loss-of-function mutations cause asthenoteratospermia with defects of the sperm flagella and head-tail conjunction in humans, and Ttc21a-knockout mice phenocopy these flagellar and connecting-piece structural defects, establishing the protein as essential for flagellar assembly and head-tail junction integrity [PMID:30929735]. In primary cilia, TTC21A acts redundantly with its paralog Thm1 (Ttc21b): single loss is tolerated, but combined loss accelerates cilia disassembly and impairs ciliary import of INPP5E, with double-knockout embryos dying mid-gestation [PMID:32167205]. Through genetic interaction with Thm1, TTC21A sensitizes Hedgehog signaling during postnatal endochondral and craniofacial skeletogenesis, acting upstream of the pathway: compound mutants show dysregulated growth-plate chondrocyte differentiation and impaired osteoblast bone formation that is rescued by the Hedgehog agonist SAG and modified by Gli2 dosage [PMID:33683377, PMID:35645293]. At the centriole, TTC21A is a CEP78 interactor whose stability and centriolar localization depend on CEP78, situating it within a CEP78-controlled centriole/cilia regulatory module that governs centriole length and cilia length [PMID:36756949].","teleology":[{"year":2019,"claim":"Established TTC21A as a disease gene and defined its core requirement: whether this IFT-associated TPR protein had a non-redundant in vivo function was unknown until human mutations and a mouse knockout linked it to sperm flagellar and head-tail junction assembly.","evidence":"Whole-exome sequencing of human MMAF cohorts plus CRISPR-Cas9 knockout mouse with sperm ultrastructure analysis","pmids":["30929735"],"confidence":"High","gaps":["Molecular mechanism by which TTC21A supports head-tail junction integrity not defined","Does not address ciliary roles outside the male germ line","No biochemical demonstration of IFT cargo or transport activity"]},{"year":2020,"claim":"Resolved why TTC21A loss is tolerated in many tissues by showing it acts redundantly with paralog Thm1 in primary cilia, controlling cilia disassembly and INPP5E import.","evidence":"Single and double mutant MEF genetic epistasis with cilia dynamics, Smoothened trafficking, and INPP5E entry assays plus embryo survival counts","pmids":["32167205"],"confidence":"High","gaps":["Direct biochemical mechanism of INPP5E import not established","Whether TTC21A is a stable IFT-A subunit not shown structurally","Cause of mid-gestational lethality not pinpointed"]},{"year":2021,"claim":"Connected TTC21A to a developmental signaling output by demonstrating it sensitizes Hedgehog signaling in growth-plate chondrocytes and osteoblasts, controlling postnatal endochondral skeletogenesis via a Gli2-dependent pathway.","evidence":"Mouse double-mutant analysis with radiography/micro-CT, growth plate histology, osteoblast bone nodule assays, Hedgehog signaling readouts and Gli2 epistasis","pmids":["33683377"],"confidence":"High","gaps":["Whether ciliary defects directly cause the Hedgehog dysregulation not isolated","Mechanistic link between TTC21A and Gli2 regulation unresolved"]},{"year":2022,"claim":"Extended the skeletal role to craniofacial bone, placing Thm2/Thm1 upstream of Hedgehog signaling through pharmacological rescue of the osteoblast defect.","evidence":"Craniofacial micro-CT, calvarial osteoblast bone formation assays, and rescue with Hedgehog agonist SAG","pmids":["35645293"],"confidence":"Medium","gaps":["Single-lab study without independent replication","Direct ciliary mechanism in craniofacial osteoblasts not shown"]},{"year":2023,"claim":"Identified a physical regulator of TTC21A by showing CEP78 binds it and controls its stability and centriolar localization, embedding TTC21A in a centriole/cilia length-control module.","evidence":"Co-immunoprecipitation interaction screen with centriole elongation and cilia length measurements in CEP78-deficient cells","pmids":["36756949"],"confidence":"Medium","gaps":["Single Co-IP identification without reciprocal structural mapping of the interaction interface","Whether CEP78-TTC21A axis operates in sperm flagellar or skeletal contexts not tested","Direct molecular activity of TTC21A at the centriole undefined"]},{"year":null,"claim":"The biochemical activity of TTC21A within the IFT machinery — its specific cargo, transport directionality, and structural role in the IFT-A complex — remains uncharacterized.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of TTC21A within IFT-A","No defined transport substrate beyond correlative INPP5E import phenotype","Mechanism coupling ciliary IFT function to Hedgehog output not resolved"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,3]}],"complexes":["IFT-A"],"partners":["CEP78","TTC21B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NDW8","full_name":"Tetratricopeptide repeat protein 21A","aliases":["Stress-inducible protein 2"],"length_aa":1320,"mass_kda":150.9,"function":"Intraflagellar transport (IFT)-associated protein required for spermatogenesis (PubMed:30929735). Required for sperm flagellar formation and intraflagellar transport (PubMed:30929735)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8NDW8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TTC21A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TTC21A","total_profiled":1310},"omim":[{"mim_id":"618429","title":"SPERMATOGENIC FAILURE 37; SPGF37","url":"https://www.omim.org/entry/618429"},{"mim_id":"612014","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 21B; TTC21B","url":"https://www.omim.org/entry/612014"},{"mim_id":"611430","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 21A; TTC21A","url":"https://www.omim.org/entry/611430"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":43.1}],"url":"https://www.proteinatlas.org/search/TTC21A"},"hgnc":{"alias_symbol":["STI2","IFT139A","Thm2"],"prev_symbol":[]},"alphafold":{"accession":"Q8NDW8","domains":[{"cath_id":"1.25.40.10","chopping":"229-366","consensus_level":"medium","plddt":80.2813,"start":229,"end":366},{"cath_id":"1.25.40,1.25.40","chopping":"572-602_618-674","consensus_level":"medium","plddt":81.6506,"start":572,"end":674},{"cath_id":"1.25.40.10","chopping":"727-794","consensus_level":"medium","plddt":80.1432,"start":727,"end":794},{"cath_id":"1.25.40.10","chopping":"813-1041","consensus_level":"medium","plddt":82.0357,"start":813,"end":1041},{"cath_id":"1.25.40.10","chopping":"1233-1320","consensus_level":"medium","plddt":84.3515,"start":1233,"end":1320}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDW8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDW8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NDW8-F1-predicted_aligned_error_v6.png","plddt_mean":81.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TTC21A","jax_strain_url":"https://www.jax.org/strain/search?query=TTC21A"},"sequence":{"accession":"Q8NDW8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NDW8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NDW8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NDW8"}},"corpus_meta":[{"pmid":"30929735","id":"PMC_30929735","title":"Bi-allelic Mutations in TTC21A Induce Asthenoteratospermia in Humans and Mice.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30929735","citation_count":96,"is_preprint":false},{"pmid":"12543795","id":"PMC_12543795","title":"An integrated physical and gene map of the 3.5-Mb chromosome 3p21.3 (AP20) region implicated in major human epithelial malignancies.","date":"2003","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12543795","citation_count":38,"is_preprint":false},{"pmid":"24977159","id":"PMC_24977159","title":"Epigenetic alterations of chromosome 3 revealed by NotI-microarrays in clear cell renal cell carcinoma.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24977159","citation_count":34,"is_preprint":false},{"pmid":"32636717","id":"PMC_32636717","title":"The plasma peptides of sepsis.","date":"2020","source":"Clinical 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flagellar assembly and sperm head-tail junction integrity.\",\n      \"method\": \"Whole-exome sequencing of human MMAF cohorts; CRISPR-Cas9 knockout mouse model with sperm ultrastructure analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic evidence corroborated by mouse KO phenocopy with defined structural readout, replicated across two independent cohorts\",\n      \"pmids\": [\"30929735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TTC21A (Thm2) and its paralog Thm1 (Ttc21b) have both unique and redundant roles in primary cilia function in mouse embryonic fibroblasts. Thm2-null MEF show normal ciliary dynamics and Hedgehog signaling individually, but combined loss of Thm1 and Thm2 enhances cilia disassembly and impairs INPP5E ciliary import. Double knockout causes mid-gestational lethality, indicating genetic interaction in embryogenesis.\",\n      \"method\": \"Mouse embryonic fibroblast (MEF) genetic epistasis analysis with single and double mutants; cilia assembly/disassembly assays; Smoothened trafficking assay; INPP5E ciliary entry assay; embryo survival counting\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple orthogonal cellular assays (cilia dynamics, IFT protein trafficking, Hedgehog signaling, membrane protein import) in a single rigorous study\",\n      \"pmids\": [\"32167205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TTC21A (Thm2) localizes to primary cilia and sensitizes to Hedgehog signaling in postnatal skeletogenesis through a genetic interaction with paralog Thm1. Thm2-/-; Thm1aln/+ mice exhibit impaired chondrocyte differentiation with expanded proliferation zone and diminished hypertrophic zone, increased Hedgehog signaling in growth plate chondrocytes, and markedly impaired bone nodule formation in osteoblasts. Deletion of one Gli2 allele exacerbated the small stature phenotype, implicating a pathway involving Gli2.\",\n      \"method\": \"Mouse double-mutant genetic analysis; radiography and micro-CT of bone; growth plate histology; primary osteoblast bone nodule formation assay; Hedgehog pathway signaling assay; genetic epistasis with Gli2\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple orthogonal readouts (bone morphology, histology, signaling assays, in vitro osteoblast function) in a single lab\",\n      \"pmids\": [\"33683377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TTC21A (Thm2) genetically interacts with Thm1 to regulate postnatal craniofacial bone formation. Thm2-/-; Thm1aln/+ triple allele mutant mice show micrognathia, midface hypoplasia, and impaired in vitro bone formation in calvarial-derived osteoblasts, which is rescued by Hedgehog agonist SAG, placing Thm2/Thm1 upstream of Hedgehog signaling in craniofacial osteoblast differentiation.\",\n      \"method\": \"Micro-computed tomography of craniofacial structures; in vitro bone formation assay with calvarial osteoblasts; pharmacological rescue with Hedgehog agonist SAG\",\n      \"journal\": \"Journal of developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with micro-CT and in vitro functional rescue, single lab\",\n      \"pmids\": [\"35645293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TTC21A (IFT139A/Thm2) was identified as an interacting protein of CEP78 by co-immunoprecipitation. CEP78 regulates the interaction, stability, and centriolar localization of TTC21A; insufficient CEP78 or its interacting proteins causes abnormal centriole elongation and cilia shortening, placing TTC21A downstream of CEP78 in a centriole/cilia regulatory complex.\",\n      \"method\": \"Co-immunoprecipitation (interaction screen); centriole elongation and cilia length measurement in CEP78-deficient cells; stability and localization analysis of interacting proteins\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP identification of interaction with functional follow-up on localization and stability, single lab\",\n      \"pmids\": [\"36756949\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TTC21A (also known as Thm2/IFT139A) encodes an IFT-A complex-associated protein with tetratricopeptide repeat domains that localizes to primary cilia and is required for sperm flagellar assembly and head-tail junction integrity, cilia disassembly regulation, ciliary import of membrane proteins (e.g., INPP5E), Hedgehog signaling transduction (acting redundantly with paralog Thm1), and postnatal skeletogenesis and craniofacial bone formation; it physically interacts with CEP78, whose loss destabilizes TTC21A and disrupts centriolar localization, causing centriole elongation and cilia shortening.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TTC21A (Thm2/IFT139A) is an intraflagellar transport-associated tetratricopeptide-repeat protein required for ciliary and flagellar assembly and for Hedgehog-dependent skeletogenesis [#0, #2]. Bi-allelic loss-of-function mutations cause asthenoteratospermia with defects of the sperm flagella and head-tail conjunction in humans, and Ttc21a-knockout mice phenocopy these flagellar and connecting-piece structural defects, establishing the protein as essential for flagellar assembly and head-tail junction integrity [#0]. In primary cilia, TTC21A acts redundantly with its paralog Thm1 (Ttc21b): single loss is tolerated, but combined loss accelerates cilia disassembly and impairs ciliary import of INPP5E, with double-knockout embryos dying mid-gestation [#1]. Through genetic interaction with Thm1, TTC21A sensitizes Hedgehog signaling during postnatal endochondral and craniofacial skeletogenesis, acting upstream of the pathway: compound mutants show dysregulated growth-plate chondrocyte differentiation and impaired osteoblast bone formation that is rescued by the Hedgehog agonist SAG and modified by Gli2 dosage [#2, #3]. At the centriole, TTC21A is a CEP78 interactor whose stability and centriolar localization depend on CEP78, situating it within a CEP78-controlled centriole/cilia regulatory module that governs centriole length and cilia length [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established TTC21A as a disease gene and defined its core requirement: whether this IFT-associated TPR protein had a non-redundant in vivo function was unknown until human mutations and a mouse knockout linked it to sperm flagellar and head-tail junction assembly.\",\n      \"evidence\": \"Whole-exome sequencing of human MMAF cohorts plus CRISPR-Cas9 knockout mouse with sperm ultrastructure analysis\",\n      \"pmids\": [\"30929735\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which TTC21A supports head-tail junction integrity not defined\", \"Does not address ciliary roles outside the male germ line\", \"No biochemical demonstration of IFT cargo or transport activity\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved why TTC21A loss is tolerated in many tissues by showing it acts redundantly with paralog Thm1 in primary cilia, controlling cilia disassembly and INPP5E import.\",\n      \"evidence\": \"Single and double mutant MEF genetic epistasis with cilia dynamics, Smoothened trafficking, and INPP5E entry assays plus embryo survival counts\",\n      \"pmids\": [\"32167205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical mechanism of INPP5E import not established\", \"Whether TTC21A is a stable IFT-A subunit not shown structurally\", \"Cause of mid-gestational lethality not pinpointed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TTC21A to a developmental signaling output by demonstrating it sensitizes Hedgehog signaling in growth-plate chondrocytes and osteoblasts, controlling postnatal endochondral skeletogenesis via a Gli2-dependent pathway.\",\n      \"evidence\": \"Mouse double-mutant analysis with radiography/micro-CT, growth plate histology, osteoblast bone nodule assays, Hedgehog signaling readouts and Gli2 epistasis\",\n      \"pmids\": [\"33683377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ciliary defects directly cause the Hedgehog dysregulation not isolated\", \"Mechanistic link between TTC21A and Gli2 regulation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the skeletal role to craniofacial bone, placing Thm2/Thm1 upstream of Hedgehog signaling through pharmacological rescue of the osteoblast defect.\",\n      \"evidence\": \"Craniofacial micro-CT, calvarial osteoblast bone formation assays, and rescue with Hedgehog agonist SAG\",\n      \"pmids\": [\"35645293\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study without independent replication\", \"Direct ciliary mechanism in craniofacial osteoblasts not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a physical regulator of TTC21A by showing CEP78 binds it and controls its stability and centriolar localization, embedding TTC21A in a centriole/cilia length-control module.\",\n      \"evidence\": \"Co-immunoprecipitation interaction screen with centriole elongation and cilia length measurements in CEP78-deficient cells\",\n      \"pmids\": [\"36756949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP identification without reciprocal structural mapping of the interaction interface\", \"Whether CEP78-TTC21A axis operates in sperm flagellar or skeletal contexts not tested\", \"Direct molecular activity of TTC21A at the centriole undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical activity of TTC21A within the IFT machinery — its specific cargo, transport directionality, and structural role in the IFT-A complex — remains uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of TTC21A within IFT-A\", \"No defined transport substrate beyond correlative INPP5E import phenotype\", \"Mechanism coupling ciliary IFT function to Hedgehog output not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [\"IFT-A\"],\n    \"partners\": [\"CEP78\", \"TTC21B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}