{"gene":"ODAD4","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2011,"finding":"TTC25 (ODAD4) is required for ciliogenesis, Hedgehog signaling, and left-right patterning in Xenopus, and its expression is controlled by the RFX2 transcription factor.","method":"Morpholino knockdown in Xenopus embryos with phenotypic analysis of cilia, HH signaling, and left-right patterning; RFX2 knockdown with analysis of TTC25 expression","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function morpholino with defined cellular phenotypes in a vertebrate model, two orthogonal readouts (ciliogenesis and LR patterning), single lab","pmids":["22227339"],"is_preprint":false},{"year":2015,"finding":"TTC25 (ODAD4) associates by immunoprecipitation with components or entire complexes of IFT-A, IFT-B, or BBSome, suggesting participation in intraflagellar transport or IFT-related activities; zebrafish ttc25 morphants display ciliopathy phenotypes including curved body, abnormal otolith, hydrocephalus, defective left-right patterning, and pronephric cyst formation.","method":"Immunoprecipitation of TTC25 with IFT complex components; morpholino knockdown in zebrafish with phenotypic analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with IFT complex components and loss-of-function zebrafish model with multiple phenotypic readouts, single lab","pmids":["25860617"],"is_preprint":false},{"year":2020,"finding":"CFAP53 interacts with TTC25, a dynein docking complex component, and facilitates axonemal transport of TTC25 and outer dynein arms (ODAs) into node cilia; in Cfap53-/- mice, TTC25 and ODAs are lost from node (9+0) cilia but largely maintained in tracheal (9+2) cilia, establishing TTC25 as part of the ODA-docking complex and dependent on CFAP53 for its ciliary localization in node cilia.","method":"Co-immunoprecipitation of CFAP53 with TTC25; immunofluorescence in Cfap53-/- mouse cilia; genetic loss-of-function with phenotypic analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction by Co-IP, immunofluorescence localization in knockout mouse, and epistasis between CFAP53 and TTC25/ODA, replicated across two cilia types","pmids":["33347437"],"is_preprint":false},{"year":2023,"finding":"ODAD4 (TTC25) is part of the outer dynein arm (ODA)-docking complex in ciliary axonemes; CLXN (ODAD5) is absent from ciliary axonemes of individuals with defects in ODA-docking machinery components ODAD1, ODAD2, ODAD3, and ODAD4, placing ODAD4 as required for assembly of the ODA-docking complex.","method":"Immunofluorescence microscopy in human ciliary cells from individuals with ODAD1–ODAD4 defects; transmission electron microscopy","journal":"Genetics in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunofluorescence in human patient cells establishing ODA-docking complex membership, single study","pmids":["36727596"],"is_preprint":false},{"year":2025,"finding":"The ODAD4 frameshift variant c.245delA causes abnormal splicing with in-frame skipping of exon 2, producing a mildly shortened mRNA; however, Western blot shows complete absence of ODAD4 protein, electron microscopy reveals outer dynein arm defects, and functional analysis demonstrates overall static cilia and absence of in vivo mucociliary clearance, confirming ODAD4 is required for ODA assembly and ciliary motility.","method":"RT-PCR splicing analysis; Western blot for ODAD4 protein; electron microscopy; in vivo mucociliary clearance assay; nasal nitric oxide measurement","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (RT-PCR, Western blot, EM, functional motility assay) in a single rigorous study establishing mechanism of variant effect and ODA requirement","pmids":["41002425"],"is_preprint":false}],"current_model":"ODAD4 (TTC25) is a tetratricopeptide repeat-containing component of the outer dynein arm (ODA)-docking complex in motile cilia; it is required for ODA assembly and ciliary motility, interacts with IFT complexes (IFT-A, IFT-B, BBSome) and is transported to the axoneme in a CFAP53-dependent manner in node cilia, with loss of ODAD4 causing primary ciliary dyskinesia characterized by ODA defects, static cilia, and laterality abnormalities."},"narrative":{"mechanistic_narrative":"ODAD4 (TTC25) is a tetratricopeptide repeat-containing component of the outer dynein arm (ODA)-docking complex required for ODA assembly and motile ciliary function [PMID:36727596, PMID:41002425]. Loss of ODAD4 abolishes ciliary outer dynein arms, renders cilia static, and eliminates mucociliary clearance, while its absence also prevents incorporation of the docking-complex partner CLXN/ODAD5 into the axoneme, establishing ODAD4 as essential for assembly of the docking machinery [PMID:36727596, PMID:41002425]. ODAD4 is delivered to the axoneme in coordination with intraflagellar transport, co-precipitating with IFT-A, IFT-B, and BBSome components, and its transport into node cilia together with the ODAs depends on CFAP53 [PMID:25860617, PMID:33347437]. Consistent with these roles, ODAD4 is required for ciliogenesis and left-right body patterning across vertebrate models, where its developmental expression is controlled by the RFX2 transcription factor [PMID:22227339, PMID:25860617]. Pathogenic ODAD4 variants that ablate the protein cause primary ciliary dyskinesia with ODA defects and laterality abnormalities [PMID:41002425].","teleology":[{"year":2011,"claim":"Established that ODAD4/TTC25 is a ciliary gene functionally required for ciliogenesis and left-right patterning, and embedded it within a transcriptional program by identifying RFX2 as a regulator of its expression.","evidence":"Morpholino knockdown in Xenopus embryos with phenotypic analysis of cilia, Hedgehog signaling, and left-right patterning; RFX2 knockdown","pmids":["22227339"],"confidence":"Medium","gaps":["Did not define the molecular role of TTC25 within cilia","Morpholino phenotypes lack genetic rescue confirmation","No protein-level mechanism or interaction partners identified"]},{"year":2015,"claim":"Linked TTC25 physically to intraflagellar transport machinery and broadened its loss-of-function phenotype across vertebrate ciliopathy readouts, suggesting an IFT-related transport role.","evidence":"Immunoprecipitation of TTC25 with IFT-A, IFT-B, and BBSome components; morpholino knockdown in zebrafish","pmids":["25860617"],"confidence":"Medium","gaps":["Co-IP associations do not establish direct binary interactions or stoichiometry","Functional consequence of IFT association for TTC25 cargo behavior unresolved","Did not yet place TTC25 in the ODA-docking complex"]},{"year":2020,"claim":"Defined TTC25 as an ODA-docking complex component whose ciliary localization is selectively dependent on CFAP53 in node (9+0) cilia, distinguishing transport requirements between cilia subtypes.","evidence":"Co-immunoprecipitation of CFAP53 with TTC25 and immunofluorescence in Cfap53-/- mouse node and tracheal cilia","pmids":["33347437"],"confidence":"High","gaps":["Mechanism of differential dependence between 9+0 and 9+2 cilia not resolved","Direct binding interface between CFAP53 and TTC25 not mapped","How TTC25 couples ODAs to the axoneme structurally unknown"]},{"year":2023,"claim":"Confirmed ODAD4 membership in the human ODA-docking complex and showed it is required for assembly of the complex, since its defect prevents axonemal incorporation of CLXN/ODAD5.","evidence":"Immunofluorescence and transmission electron microscopy in ciliary cells from individuals with ODAD1–ODAD4 defects","pmids":["36727596"],"confidence":"Medium","gaps":["Hierarchy and assembly order among ODAD1–ODAD5 not fully defined","No structural model of the docking complex","Does not establish which docking subunits ODAD4 contacts directly"]},{"year":2025,"claim":"Established the molecular pathogenic mechanism of an ODAD4 variant and directly tied protein loss to ODA assembly failure, static cilia, and abolished mucociliary clearance in primary ciliary dyskinesia.","evidence":"RT-PCR splicing analysis, Western blot, electron microscopy, in vivo mucociliary clearance assay, and nasal nitric oxide measurement","pmids":["41002425"],"confidence":"High","gaps":["Single variant characterized; full mutational spectrum not surveyed","Quantitative contribution of ODAD4 to docking-complex stoichiometry unknown","Structural basis of ODA recruitment by ODAD4 not determined"]},{"year":null,"claim":"How ODAD4 structurally bridges the ODA to the axonemal microtubule doublet and the assembly order of the ODA-docking complex remain undefined.","evidence":"No direct structural or reconstitution evidence in the available corpus","pmids":[],"confidence":"Medium","gaps":["No structural model of ODAD4 within the docking complex","Direct binding partners and contact interfaces unmapped","Assembly hierarchy among ODAD1–ODAD5 not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,3,4]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,4]}],"complexes":["outer dynein arm (ODA)-docking complex"],"partners":["CFAP53","CLXN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96NG3","full_name":"Outer dynein arm-docking complex subunit 4","aliases":["Tetratricopeptide repeat protein 25","TPR repeat protein 25"],"length_aa":672,"mass_kda":76.7,"function":"Component of the outer dynein arm-docking complex (ODA-DC) that mediates outer dynein arms (ODA) binding onto the doublet microtubule. Plays an essential role for the assembly of ODA-DC and for the docking of ODA in ciliary axoneme","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme","url":"https://www.uniprot.org/uniprotkb/Q96NG3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ODAD4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":74,"dependency_fraction":0.02702702702702703},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ODAD4","total_profiled":1310},"omim":[{"mim_id":"617095","title":"OUTER DYNEIN ARM DOCKING COMPLEX SUBUNIT 4; ODAD4","url":"https://www.omim.org/entry/617095"},{"mim_id":"617092","title":"CILIARY DYSKINESIA, PRIMARY, 35; CILD35","url":"https://www.omim.org/entry/617092"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Centrosome","reliability":"Uncertain"},{"location":"Basal body","reliability":"Uncertain"},{"location":"Acrosome","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":11.5},{"tissue":"fallopian tube","ntpm":16.0},{"tissue":"testis","ntpm":22.5}],"url":"https://www.proteinatlas.org/search/ODAD4"},"hgnc":{"alias_symbol":["DKFZP434H0115"],"prev_symbol":["TTC25"]},"alphafold":{"accession":"Q96NG3","domains":[{"cath_id":"1.25.40.10","chopping":"14-133","consensus_level":"high","plddt":92.34,"start":14,"end":133},{"cath_id":"1.25.40.10","chopping":"271-381","consensus_level":"medium","plddt":93.766,"start":271,"end":381},{"cath_id":"1.25.40.10","chopping":"391-520","consensus_level":"medium","plddt":89.2702,"start":391,"end":520},{"cath_id":"1.10.287","chopping":"193-245","consensus_level":"medium","plddt":81.007,"start":193,"end":245}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NG3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NG3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96NG3-F1-predicted_aligned_error_v6.png","plddt_mean":71.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ODAD4","jax_strain_url":"https://www.jax.org/strain/search?query=ODAD4"},"sequence":{"accession":"Q96NG3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96NG3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96NG3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96NG3"}},"corpus_meta":[{"pmid":"22227339","id":"PMC_22227339","title":"RFX2 is broadly required for ciliogenesis during vertebrate development.","date":"2011","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/22227339","citation_count":90,"is_preprint":false},{"pmid":"25860617","id":"PMC_25860617","title":"Characterization of tetratricopeptide repeat-containing proteins critical for cilia formation and function.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25860617","citation_count":48,"is_preprint":false},{"pmid":"34215651","id":"PMC_34215651","title":"Whole-exome sequencing reveals a monogenic cause in 56% of individuals with laterality disorders and associated congenital heart defects.","date":"2021","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34215651","citation_count":25,"is_preprint":false},{"pmid":"33347437","id":"PMC_33347437","title":"CFAP53 regulates mammalian cilia-type motility patterns through differential localization and recruitment of axonemal dynein components.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33347437","citation_count":21,"is_preprint":false},{"pmid":"33732283","id":"PMC_33732283","title":"The Novel Key Genes of Non-obstructive Azoospermia Affect Spermatogenesis: Transcriptomic Analysis Based on RNA-Seq and scRNA-Seq Data.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33732283","citation_count":18,"is_preprint":false},{"pmid":"28056766","id":"PMC_28056766","title":"LPS-induced modules of co-expressed genes in equine peripheral blood mononuclear cells.","date":"2017","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/28056766","citation_count":12,"is_preprint":false},{"pmid":"36727596","id":"PMC_36727596","title":"Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia.","date":"2023","source":"Genetics in medicine : official journal of the American College of Medical Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36727596","citation_count":10,"is_preprint":false},{"pmid":"33853517","id":"PMC_33853517","title":"Rapid genetic adaptation to recently colonized environments is driven by genes underlying life history traits.","date":"2021","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/33853517","citation_count":9,"is_preprint":false},{"pmid":"33746037","id":"PMC_33746037","title":"A splice site and copy number variant responsible for TTC25-related primary ciliary dyskinesia.","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33746037","citation_count":7,"is_preprint":false},{"pmid":"40945691","id":"PMC_40945691","title":"Single-nucleus mRNA-sequencing reveals dynamics of lipogenic and thermogenic adipocyte populations in murine brown adipose tissue in response to cold exposure.","date":"2025","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40945691","citation_count":7,"is_preprint":false},{"pmid":"28513607","id":"PMC_28513607","title":"Variants in TTC25 affect autistic trait in patients with autism spectrum disorder and general population.","date":"2017","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/28513607","citation_count":6,"is_preprint":false},{"pmid":"39180133","id":"PMC_39180133","title":"Characterization of pathogenic genetic variants in Russian patients with primary ciliary dyskinesia using gene panel sequencing and transcript analysis.","date":"2024","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/39180133","citation_count":5,"is_preprint":false},{"pmid":"36159986","id":"PMC_36159986","title":"Subtyping children with asthma by clustering analysis of mRNA expression data.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36159986","citation_count":1,"is_preprint":false},{"pmid":"39969775","id":"PMC_39969775","title":"Identification of novel biallelic mutations in CFAP53 associated with fetal situs inversus totalis and literature review.","date":"2025","source":"Journal of applied genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39969775","citation_count":1,"is_preprint":false},{"pmid":"41002425","id":"PMC_41002425","title":"ODAD4-Related Primary Ciliary Dyskinesia: Report of Five Cases and a Founder Variant in Quebec.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41002425","citation_count":0,"is_preprint":false},{"pmid":"42131108","id":"PMC_42131108","title":"Identification of common genes associated with diabetic nephropathy and diabetic retinopathy.","date":"2026","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/42131108","citation_count":0,"is_preprint":false},{"pmid":"41267578","id":"PMC_41267578","title":"Prevalence and Nationality Distribution of Known and Novel Genetic Variants in Children With Primary Ciliary Dyskinesia in the State of Qatar.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41267578","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11001,"output_tokens":1459,"usd":0.027444,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8119,"output_tokens":2247,"usd":0.048385,"stage2_stop_reason":"end_turn"},"total_usd":0.075829,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"TTC25 (ODAD4) is required for ciliogenesis, Hedgehog signaling, and left-right patterning in Xenopus, and its expression is controlled by the RFX2 transcription factor.\",\n      \"method\": \"Morpholino knockdown in Xenopus embryos with phenotypic analysis of cilia, HH signaling, and left-right patterning; RFX2 knockdown with analysis of TTC25 expression\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function morpholino with defined cellular phenotypes in a vertebrate model, two orthogonal readouts (ciliogenesis and LR patterning), single lab\",\n      \"pmids\": [\"22227339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TTC25 (ODAD4) associates by immunoprecipitation with components or entire complexes of IFT-A, IFT-B, or BBSome, suggesting participation in intraflagellar transport or IFT-related activities; zebrafish ttc25 morphants display ciliopathy phenotypes including curved body, abnormal otolith, hydrocephalus, defective left-right patterning, and pronephric cyst formation.\",\n      \"method\": \"Immunoprecipitation of TTC25 with IFT complex components; morpholino knockdown in zebrafish with phenotypic analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with IFT complex components and loss-of-function zebrafish model with multiple phenotypic readouts, single lab\",\n      \"pmids\": [\"25860617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CFAP53 interacts with TTC25, a dynein docking complex component, and facilitates axonemal transport of TTC25 and outer dynein arms (ODAs) into node cilia; in Cfap53-/- mice, TTC25 and ODAs are lost from node (9+0) cilia but largely maintained in tracheal (9+2) cilia, establishing TTC25 as part of the ODA-docking complex and dependent on CFAP53 for its ciliary localization in node cilia.\",\n      \"method\": \"Co-immunoprecipitation of CFAP53 with TTC25; immunofluorescence in Cfap53-/- mouse cilia; genetic loss-of-function with phenotypic analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction by Co-IP, immunofluorescence localization in knockout mouse, and epistasis between CFAP53 and TTC25/ODA, replicated across two cilia types\",\n      \"pmids\": [\"33347437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ODAD4 (TTC25) is part of the outer dynein arm (ODA)-docking complex in ciliary axonemes; CLXN (ODAD5) is absent from ciliary axonemes of individuals with defects in ODA-docking machinery components ODAD1, ODAD2, ODAD3, and ODAD4, placing ODAD4 as required for assembly of the ODA-docking complex.\",\n      \"method\": \"Immunofluorescence microscopy in human ciliary cells from individuals with ODAD1–ODAD4 defects; transmission electron microscopy\",\n      \"journal\": \"Genetics in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunofluorescence in human patient cells establishing ODA-docking complex membership, single study\",\n      \"pmids\": [\"36727596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The ODAD4 frameshift variant c.245delA causes abnormal splicing with in-frame skipping of exon 2, producing a mildly shortened mRNA; however, Western blot shows complete absence of ODAD4 protein, electron microscopy reveals outer dynein arm defects, and functional analysis demonstrates overall static cilia and absence of in vivo mucociliary clearance, confirming ODAD4 is required for ODA assembly and ciliary motility.\",\n      \"method\": \"RT-PCR splicing analysis; Western blot for ODAD4 protein; electron microscopy; in vivo mucociliary clearance assay; nasal nitric oxide measurement\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (RT-PCR, Western blot, EM, functional motility assay) in a single rigorous study establishing mechanism of variant effect and ODA requirement\",\n      \"pmids\": [\"41002425\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ODAD4 (TTC25) is a tetratricopeptide repeat-containing component of the outer dynein arm (ODA)-docking complex in motile cilia; it is required for ODA assembly and ciliary motility, interacts with IFT complexes (IFT-A, IFT-B, BBSome) and is transported to the axoneme in a CFAP53-dependent manner in node cilia, with loss of ODAD4 causing primary ciliary dyskinesia characterized by ODA defects, static cilia, and laterality abnormalities.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ODAD4 (TTC25) is a tetratricopeptide repeat-containing component of the outer dynein arm (ODA)-docking complex required for ODA assembly and motile ciliary function [#3, #4]. Loss of ODAD4 abolishes ciliary outer dynein arms, renders cilia static, and eliminates mucociliary clearance, while its absence also prevents incorporation of the docking-complex partner CLXN/ODAD5 into the axoneme, establishing ODAD4 as essential for assembly of the docking machinery [#3, #4]. ODAD4 is delivered to the axoneme in coordination with intraflagellar transport, co-precipitating with IFT-A, IFT-B, and BBSome components, and its transport into node cilia together with the ODAs depends on CFAP53 [#1, #2]. Consistent with these roles, ODAD4 is required for ciliogenesis and left-right body patterning across vertebrate models, where its developmental expression is controlled by the RFX2 transcription factor [#0, #1]. Pathogenic ODAD4 variants that ablate the protein cause primary ciliary dyskinesia with ODA defects and laterality abnormalities [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that ODAD4/TTC25 is a ciliary gene functionally required for ciliogenesis and left-right patterning, and embedded it within a transcriptional program by identifying RFX2 as a regulator of its expression.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus embryos with phenotypic analysis of cilia, Hedgehog signaling, and left-right patterning; RFX2 knockdown\",\n      \"pmids\": [\"22227339\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular role of TTC25 within cilia\", \"Morpholino phenotypes lack genetic rescue confirmation\", \"No protein-level mechanism or interaction partners identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked TTC25 physically to intraflagellar transport machinery and broadened its loss-of-function phenotype across vertebrate ciliopathy readouts, suggesting an IFT-related transport role.\",\n      \"evidence\": \"Immunoprecipitation of TTC25 with IFT-A, IFT-B, and BBSome components; morpholino knockdown in zebrafish\",\n      \"pmids\": [\"25860617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP associations do not establish direct binary interactions or stoichiometry\", \"Functional consequence of IFT association for TTC25 cargo behavior unresolved\", \"Did not yet place TTC25 in the ODA-docking complex\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined TTC25 as an ODA-docking complex component whose ciliary localization is selectively dependent on CFAP53 in node (9+0) cilia, distinguishing transport requirements between cilia subtypes.\",\n      \"evidence\": \"Co-immunoprecipitation of CFAP53 with TTC25 and immunofluorescence in Cfap53-/- mouse node and tracheal cilia\",\n      \"pmids\": [\"33347437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of differential dependence between 9+0 and 9+2 cilia not resolved\", \"Direct binding interface between CFAP53 and TTC25 not mapped\", \"How TTC25 couples ODAs to the axoneme structurally unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed ODAD4 membership in the human ODA-docking complex and showed it is required for assembly of the complex, since its defect prevents axonemal incorporation of CLXN/ODAD5.\",\n      \"evidence\": \"Immunofluorescence and transmission electron microscopy in ciliary cells from individuals with ODAD1–ODAD4 defects\",\n      \"pmids\": [\"36727596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy and assembly order among ODAD1–ODAD5 not fully defined\", \"No structural model of the docking complex\", \"Does not establish which docking subunits ODAD4 contacts directly\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the molecular pathogenic mechanism of an ODAD4 variant and directly tied protein loss to ODA assembly failure, static cilia, and abolished mucociliary clearance in primary ciliary dyskinesia.\",\n      \"evidence\": \"RT-PCR splicing analysis, Western blot, electron microscopy, in vivo mucociliary clearance assay, and nasal nitric oxide measurement\",\n      \"pmids\": [\"41002425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single variant characterized; full mutational spectrum not surveyed\", \"Quantitative contribution of ODAD4 to docking-complex stoichiometry unknown\", \"Structural basis of ODA recruitment by ODAD4 not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ODAD4 structurally bridges the ODA to the axonemal microtubule doublet and the assembly order of the ODA-docking complex remain undefined.\",\n      \"evidence\": \"No direct structural or reconstitution evidence in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ODAD4 within the docking complex\", \"Direct binding partners and contact interfaces unmapped\", \"Assembly hierarchy among ODAD1–ODAD5 not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"outer dynein arm (ODA)-docking complex\"],\n    \"partners\": [\"CFAP53\", \"CLXN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":5,"faith_pct":60.0}}