{"gene":"TUBD1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2025,"finding":"TUBD1 (delta tubulin) stabilizes kinetochores during male mouse meiosis, enabling meiotic progression, and is required for appropriate spindle polarity and cytokinesis. In haploid cells, TUBD1 works in partnership with microtubule-severing enzymes KATNAL2 and KATNB1 to regulate manchette remodeling and sperm head shaping. Conditional knockout of TUBD1 in male germ cells causes sterility.","method":"Conditional knockout mouse model, in vivo spermatogenesis analysis, cell biology assays for kinetochore stability, spindle polarity, cytokinesis, and manchette remodeling","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with multiple defined cellular phenotypes (meiotic kinetochore stabilization, spindle polarity, cytokinesis, manchette remodeling) established by in vivo loss-of-function in a single rigorous study with multiple orthogonal readouts","pmids":["40586731"],"is_preprint":false},{"year":2020,"finding":"Impairment of TUBD1 (along with TUBE1 and POC1B) disturbs the integrity of centriole microtubules and prevents centriole-to-centrosome conversion, placing TUBD1 in a centriole biogenesis pathway (CEP295–CEP44–POC1B–TUBE1–TUBD1) that operates in the centriole lumen and on the cytoplasmic side.","method":"siRNA depletion of TUBD1 in human somatic cell lines, centriole structure and centrosome conversion assays, epistasis with CEP295/CEP44/POC1B/TUBE1","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockdown with defined structural phenotype (centriole-to-centrosome conversion failure), pathway placement by genetic epistasis, single lab with multiple pathway members tested orthogonally","pmids":["32060285"],"is_preprint":false},{"year":2017,"finding":"TUBD1 was identified as a positive regulator of Hedgehog (Hh) signaling involved in ciliary functions. Loss of Tubd1 reduced target cell sensitivity to Sonic Hedgehog, consistent with a role in primary cilia-dependent Hh signal transduction.","method":"Genome-wide CRISPR loss-of-function screens in two cell types, validated with multiple Hh signaling and neural differentiation assays","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen validated in multiple cell types and assays, but mechanistic detail on how TUBD1 acts in cilia is not resolved beyond ciliary function assignment","pmids":["29290584"],"is_preprint":false},{"year":2016,"finding":"A missense mutation in TUBD1 (p.H210R) causes high perinatal and juvenile mortality in Braunvieh and Fleckvieh cattle with autosomal recessive inheritance, and homozygous calves suffer from chronic airway disease with pathology consistent with defective respiratory cilia, demonstrating that functional TUBD1 is essential for cilia integrity in vivo.","method":"Whole-genome sequencing of cattle populations, haplotype analysis, clinical and pathological examination of homozygous calves","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — natural loss-of-function allele validated across two breeds with clinical phenotype (ciliary dysfunction), but mechanistic dissection at the molecular level not performed in this study","pmids":["27225349"],"is_preprint":false},{"year":2017,"finding":"ILDR1 (and ILDR2) bind splicing factors TRA2A, TRA2B, and SRSF1, and when endogenous ILDR1 and ILDR2 are knocked down, the alternative splicing of TUBD1 is altered, indicating that the ILDR1/2–splicing factor axis regulates TUBD1 pre-mRNA processing.","method":"Co-immunoprecipitation of ILDR1/2 with splicing factors, siRNA knockdown of ILDR1/2 in cultured cells with RT-PCR detection of TUBD1 alternative splicing","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA knockdown with splicing readout and Co-IP for binding partners, single lab, establishes upstream regulation of TUBD1 splicing but does not characterize TUBD1 protein function itself","pmids":["28785060"],"is_preprint":false}],"current_model":"TUBD1 (delta tubulin) is a noncanonical tubulin that is required for the structural integrity of centriole microtubules and centriole-to-centrosome conversion in somatic cells, acts as a positive regulator of primary cilia-dependent Hedgehog signaling, and in male germ cells stabilizes meiotic kinetochores, regulates spindle polarity and cytokinesis, and partners with KATNAL2/KATNB1 for manchette remodeling during spermatogenesis; loss of TUBD1 causes male sterility in mice and ciliopathy-like airway disease in cattle."},"narrative":{"mechanistic_narrative":"TUBD1 (delta tubulin) is a noncanonical tubulin required for the structural integrity of centriole microtubules and for cilium-dependent signaling in both somatic and germ cells [PMID:32060285, PMID:29290584]. In human somatic cells it operates within a centriole biogenesis pathway (CEP295–CEP44–POC1B–TUBE1–TUBD1), where its depletion disturbs centriole microtubule integrity and blocks centriole-to-centrosome conversion [PMID:32060285]. Consistent with a role in ciliary function, TUBD1 acts as a positive regulator of primary cilia-dependent Hedgehog signaling, and its loss reduces target-cell sensitivity to Sonic Hedgehog [PMID:29290584]. In male germ cells TUBD1 stabilizes meiotic kinetochores, governs spindle polarity and cytokinesis, and partners with the microtubule-severing enzymes KATNAL2 and KATNB1 to remodel the manchette during sperm head shaping [PMID:40586731]. Loss of TUBD1 causes male sterility in conditional-knockout mice [PMID:40586731], and a recessive missense allele (p.H210R) causes ciliopathy-like chronic airway disease and perinatal mortality in cattle, establishing TUBD1 as essential for cilia integrity in vivo [PMID:27225349]. TUBD1 pre-mRNA processing is itself subject to regulation, with the ILDR1/2–splicing-factor axis altering its alternative splicing [PMID:28785060].","teleology":[{"year":2016,"claim":"Established that functional TUBD1 is essential for cilia integrity in a whole organism, linking the gene to ciliary disease rather than leaving it as an uncharacterized tubulin.","evidence":"Whole-genome sequencing, haplotype analysis, and pathology of homozygous p.H210R calves in two cattle breeds","pmids":["27225349"],"confidence":"Medium","gaps":["No molecular mechanism for how the H210R substitution impairs ciliary function","Does not define the protein-level activity of TUBD1"]},{"year":2017,"claim":"Placed TUBD1 in a defined signaling context by showing it is a positive regulator of primary cilia-dependent Hedgehog signal transduction.","evidence":"Genome-wide CRISPR loss-of-function screens in two cell types with Hh signaling and neural differentiation validation assays","pmids":["29290584"],"confidence":"Medium","gaps":["Mechanism by which TUBD1 acts within cilia to promote Hh signaling unresolved","Does not distinguish a direct ciliary role from indirect effects on cilium formation"]},{"year":2017,"claim":"Identified an upstream regulatory layer on TUBD1 expression by showing ILDR1/2 and associated splicing factors control its alternative splicing.","evidence":"Co-immunoprecipitation of ILDR1/2 with TRA2A, TRA2B, SRSF1 and siRNA knockdown with RT-PCR readout of TUBD1 splicing","pmids":["28785060"],"confidence":"Medium","gaps":["Functional consequence of the altered TUBD1 splice forms not determined","Single lab; binding shown by Co-IP without reciprocal or direct interaction validation"]},{"year":2020,"claim":"Defined the molecular pathway context of TUBD1 in centriole biogenesis, showing it is required for centriole microtubule integrity and centriole-to-centrosome conversion.","evidence":"siRNA depletion in human somatic cell lines with centriole/centrosome conversion assays and epistasis against CEP295/CEP44/POC1B/TUBE1","pmids":["32060285"],"confidence":"High","gaps":["Biochemical activity of TUBD1 within the centriole lumen not resolved","Direct physical interactions among the pathway members not established"]},{"year":2025,"claim":"Revealed germ-cell-specific roles, showing TUBD1 stabilizes meiotic kinetochores, controls spindle polarity and cytokinesis, and partners with katanin enzymes for manchette remodeling.","evidence":"Conditional germ-cell knockout mouse with in vivo spermatogenesis and cell-biology readouts of kinetochore stability, spindle polarity, cytokinesis, and manchette remodeling","pmids":["40586731"],"confidence":"High","gaps":["Molecular basis of the TUBD1–KATNAL2/KATNB1 partnership not biochemically dissected","Whether kinetochore and manchette functions reflect a shared or distinct molecular activity is unresolved"]},{"year":null,"claim":"The intrinsic biochemical activity of delta-tubulin TUBD1 and how it physically integrates into centriole and germ-cell microtubule structures remain undefined.","evidence":"No reconstitution or structural study in the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model of TUBD1 in the centriole","No direct demonstration of TUBD1 incorporation into microtubule lattices","Mechanistic link between somatic centriole role and germ-cell phenotypes untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,0]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":["centriole"],"partners":["TUBE1","POC1B","CEP295","CEP44","KATNAL2","KATNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UJT1","full_name":"Tubulin delta chain","aliases":["Delta-tubulin"],"length_aa":453,"mass_kda":51.0,"function":"Acts as a positive regulator of hedgehog signaling and regulates ciliary function","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cell projection, cilium","url":"https://www.uniprot.org/uniprotkb/Q9UJT1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TUBD1","classification":"Not Classified","n_dependent_lines":511,"n_total_lines":1208,"dependency_fraction":0.4230132450331126},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CCT2","stoichiometry":0.2},{"gene":"CCT4","stoichiometry":0.2},{"gene":"CCT7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TUBD1","total_profiled":1310},"omim":[{"mim_id":"620217","title":"CENTROSOMAL PROTEIN, 44-KD; CEP44","url":"https://www.omim.org/entry/620217"},{"mim_id":"607344","title":"TUBULIN, DELTA-1; TUBD1","url":"https://www.omim.org/entry/607344"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TUBD1"},"hgnc":{"alias_symbol":["FLJ12709","TUBD"],"prev_symbol":[]},"alphafold":{"accession":"Q9UJT1","domains":[{"cath_id":"3.40.50.1440","chopping":"3-273","consensus_level":"medium","plddt":93.3488,"start":3,"end":273},{"cath_id":"3.30.1330.20","chopping":"278-402","consensus_level":"medium","plddt":82.1901,"start":278,"end":402},{"cath_id":"-","chopping":"405-453","consensus_level":"medium","plddt":95.6922,"start":405,"end":453}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJT1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJT1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UJT1-F1-predicted_aligned_error_v6.png","plddt_mean":90.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TUBD1","jax_strain_url":"https://www.jax.org/strain/search?query=TUBD1"},"sequence":{"accession":"Q9UJT1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UJT1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UJT1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UJT1"}},"corpus_meta":[{"pmid":"29290584","id":"PMC_29290584","title":"CRISPR 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conversion.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/32060285","citation_count":40,"is_preprint":false},{"pmid":"27225349","id":"PMC_27225349","title":"A missense mutation in TUBD1 is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle.","date":"2016","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/27225349","citation_count":39,"is_preprint":false},{"pmid":"19454617","id":"PMC_19454617","title":"Genetic variation in the chromosome 17q23 amplicon and breast cancer risk.","date":"2009","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19454617","citation_count":39,"is_preprint":false},{"pmid":"32097101","id":"PMC_32097101","title":"Circular RNA TUBD1 Acts as the miR-146a-5p Sponge to Affect the Viability and Pro-Inflammatory Cytokine Production of LX-2 Cells through the TLR4 Pathway.","date":"2020","source":"Radiation research","url":"https://pubmed.ncbi.nlm.nih.gov/32097101","citation_count":24,"is_preprint":false},{"pmid":"30153835","id":"PMC_30153835","title":"Discovery and characterization of the tubercidin biosynthetic pathway from Streptomyces tubercidicus NBRC 13090.","date":"2018","source":"Microbial cell factories","url":"https://pubmed.ncbi.nlm.nih.gov/30153835","citation_count":20,"is_preprint":false},{"pmid":"32143512","id":"PMC_32143512","title":"Phylogenetic Analysis and Development of Molecular Tool for Detection of Diaporthe citri Causing Melanose Disease of Citrus.","date":"2020","source":"Plants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32143512","citation_count":19,"is_preprint":false},{"pmid":"35806403","id":"PMC_35806403","title":"Per1/Per2 Disruption Reduces Testosterone Synthesis and Impairs Fertility in Elderly Male Mice.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35806403","citation_count":17,"is_preprint":false},{"pmid":"28785060","id":"PMC_28785060","title":"Angulin proteins ILDR1 and ILDR2 regulate alternative pre-mRNA splicing through binding to splicing factors TRA2A, TRA2B, or SRSF1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28785060","citation_count":17,"is_preprint":false},{"pmid":"32197842","id":"PMC_32197842","title":"Novel haplotypes responsible for prenatal death in Nordic Red and Danish Jersey cattle.","date":"2020","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/32197842","citation_count":15,"is_preprint":false},{"pmid":"38201907","id":"PMC_38201907","title":"A Genome-Wide Association Study of Metabolic Syndrome in the Taiwanese 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Toxicology & pharmacology : CBP","url":"https://pubmed.ncbi.nlm.nih.gov/39864717","citation_count":1,"is_preprint":false},{"pmid":"38967046","id":"PMC_38967046","title":"Functional analysis of a panel of molecular markers for diagnosis of systemic lupus erythematosus in rats.","date":"2024","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/38967046","citation_count":0,"is_preprint":false},{"pmid":"41117539","id":"PMC_41117539","title":"Plasmodium berghei IMC1j interacts with δ-tubulin to orchestrate subpellicular microtubule organization in ookinetes.","date":"2025","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/41117539","citation_count":0,"is_preprint":false},{"pmid":"41096794","id":"PMC_41096794","title":"Identification of Anticancer Targets in Ovarian Cancer Using Genomic Drug Sensitivity Data.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41096794","citation_count":0,"is_preprint":false},{"pmid":"27273999","id":"PMC_27273999","title":"A proof-of-concept study in engineering synthetic protein for selective recognition of substrate-free polyubiquitin.","date":"2016","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/27273999","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14643,"output_tokens":1490,"usd":0.03314,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8217,"output_tokens":2307,"usd":0.04938,"stage2_stop_reason":"end_turn"},"total_usd":0.08252,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"TUBD1 (delta tubulin) stabilizes kinetochores during male mouse meiosis, enabling meiotic progression, and is required for appropriate spindle polarity and cytokinesis. In haploid cells, TUBD1 works in partnership with microtubule-severing enzymes KATNAL2 and KATNB1 to regulate manchette remodeling and sperm head shaping. Conditional knockout of TUBD1 in male germ cells causes sterility.\",\n      \"method\": \"Conditional knockout mouse model, in vivo spermatogenesis analysis, cell biology assays for kinetochore stability, spindle polarity, cytokinesis, and manchette remodeling\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with multiple defined cellular phenotypes (meiotic kinetochore stabilization, spindle polarity, cytokinesis, manchette remodeling) established by in vivo loss-of-function in a single rigorous study with multiple orthogonal readouts\",\n      \"pmids\": [\"40586731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Impairment of TUBD1 (along with TUBE1 and POC1B) disturbs the integrity of centriole microtubules and prevents centriole-to-centrosome conversion, placing TUBD1 in a centriole biogenesis pathway (CEP295–CEP44–POC1B–TUBE1–TUBD1) that operates in the centriole lumen and on the cytoplasmic side.\",\n      \"method\": \"siRNA depletion of TUBD1 in human somatic cell lines, centriole structure and centrosome conversion assays, epistasis with CEP295/CEP44/POC1B/TUBE1\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with defined structural phenotype (centriole-to-centrosome conversion failure), pathway placement by genetic epistasis, single lab with multiple pathway members tested orthogonally\",\n      \"pmids\": [\"32060285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TUBD1 was identified as a positive regulator of Hedgehog (Hh) signaling involved in ciliary functions. Loss of Tubd1 reduced target cell sensitivity to Sonic Hedgehog, consistent with a role in primary cilia-dependent Hh signal transduction.\",\n      \"method\": \"Genome-wide CRISPR loss-of-function screens in two cell types, validated with multiple Hh signaling and neural differentiation assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen validated in multiple cell types and assays, but mechanistic detail on how TUBD1 acts in cilia is not resolved beyond ciliary function assignment\",\n      \"pmids\": [\"29290584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A missense mutation in TUBD1 (p.H210R) causes high perinatal and juvenile mortality in Braunvieh and Fleckvieh cattle with autosomal recessive inheritance, and homozygous calves suffer from chronic airway disease with pathology consistent with defective respiratory cilia, demonstrating that functional TUBD1 is essential for cilia integrity in vivo.\",\n      \"method\": \"Whole-genome sequencing of cattle populations, haplotype analysis, clinical and pathological examination of homozygous calves\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural loss-of-function allele validated across two breeds with clinical phenotype (ciliary dysfunction), but mechanistic dissection at the molecular level not performed in this study\",\n      \"pmids\": [\"27225349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ILDR1 (and ILDR2) bind splicing factors TRA2A, TRA2B, and SRSF1, and when endogenous ILDR1 and ILDR2 are knocked down, the alternative splicing of TUBD1 is altered, indicating that the ILDR1/2–splicing factor axis regulates TUBD1 pre-mRNA processing.\",\n      \"method\": \"Co-immunoprecipitation of ILDR1/2 with splicing factors, siRNA knockdown of ILDR1/2 in cultured cells with RT-PCR detection of TUBD1 alternative splicing\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA knockdown with splicing readout and Co-IP for binding partners, single lab, establishes upstream regulation of TUBD1 splicing but does not characterize TUBD1 protein function itself\",\n      \"pmids\": [\"28785060\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TUBD1 (delta tubulin) is a noncanonical tubulin that is required for the structural integrity of centriole microtubules and centriole-to-centrosome conversion in somatic cells, acts as a positive regulator of primary cilia-dependent Hedgehog signaling, and in male germ cells stabilizes meiotic kinetochores, regulates spindle polarity and cytokinesis, and partners with KATNAL2/KATNB1 for manchette remodeling during spermatogenesis; loss of TUBD1 causes male sterility in mice and ciliopathy-like airway disease in cattle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TUBD1 (delta tubulin) is a noncanonical tubulin required for the structural integrity of centriole microtubules and for cilium-dependent signaling in both somatic and germ cells [#1, #2]. In human somatic cells it operates within a centriole biogenesis pathway (CEP295\\u2013CEP44\\u2013POC1B\\u2013TUBE1\\u2013TUBD1), where its depletion disturbs centriole microtubule integrity and blocks centriole-to-centrosome conversion [#1]. Consistent with a role in ciliary function, TUBD1 acts as a positive regulator of primary cilia-dependent Hedgehog signaling, and its loss reduces target-cell sensitivity to Sonic Hedgehog [#2]. In male germ cells TUBD1 stabilizes meiotic kinetochores, governs spindle polarity and cytokinesis, and partners with the microtubule-severing enzymes KATNAL2 and KATNB1 to remodel the manchette during sperm head shaping [#0]. Loss of TUBD1 causes male sterility in conditional-knockout mice [#0], and a recessive missense allele (p.H210R) causes ciliopathy-like chronic airway disease and perinatal mortality in cattle, establishing TUBD1 as essential for cilia integrity in vivo [#3]. TUBD1 pre-mRNA processing is itself subject to regulation, with the ILDR1/2\\u2013splicing-factor axis altering its alternative splicing [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Established that functional TUBD1 is essential for cilia integrity in a whole organism, linking the gene to ciliary disease rather than leaving it as an uncharacterized tubulin.\",\n      \"evidence\": \"Whole-genome sequencing, haplotype analysis, and pathology of homozygous p.H210R calves in two cattle breeds\",\n      \"pmids\": [\"27225349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism for how the H210R substitution impairs ciliary function\", \"Does not define the protein-level activity of TUBD1\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed TUBD1 in a defined signaling context by showing it is a positive regulator of primary cilia-dependent Hedgehog signal transduction.\",\n      \"evidence\": \"Genome-wide CRISPR loss-of-function screens in two cell types with Hh signaling and neural differentiation validation assays\",\n      \"pmids\": [\"29290584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which TUBD1 acts within cilia to promote Hh signaling unresolved\", \"Does not distinguish a direct ciliary role from indirect effects on cilium formation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified an upstream regulatory layer on TUBD1 expression by showing ILDR1/2 and associated splicing factors control its alternative splicing.\",\n      \"evidence\": \"Co-immunoprecipitation of ILDR1/2 with TRA2A, TRA2B, SRSF1 and siRNA knockdown with RT-PCR readout of TUBD1 splicing\",\n      \"pmids\": [\"28785060\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the altered TUBD1 splice forms not determined\", \"Single lab; binding shown by Co-IP without reciprocal or direct interaction validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the molecular pathway context of TUBD1 in centriole biogenesis, showing it is required for centriole microtubule integrity and centriole-to-centrosome conversion.\",\n      \"evidence\": \"siRNA depletion in human somatic cell lines with centriole/centrosome conversion assays and epistasis against CEP295/CEP44/POC1B/TUBE1\",\n      \"pmids\": [\"32060285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical activity of TUBD1 within the centriole lumen not resolved\", \"Direct physical interactions among the pathway members not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed germ-cell-specific roles, showing TUBD1 stabilizes meiotic kinetochores, controls spindle polarity and cytokinesis, and partners with katanin enzymes for manchette remodeling.\",\n      \"evidence\": \"Conditional germ-cell knockout mouse with in vivo spermatogenesis and cell-biology readouts of kinetochore stability, spindle polarity, cytokinesis, and manchette remodeling\",\n      \"pmids\": [\"40586731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the TUBD1\\u2013KATNAL2/KATNB1 partnership not biochemically dissected\", \"Whether kinetochore and manchette functions reflect a shared or distinct molecular activity is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic biochemical activity of delta-tubulin TUBD1 and how it physically integrates into centriole and germ-cell microtubule structures remain undefined.\",\n      \"evidence\": \"No reconstitution or structural study in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of TUBD1 in the centriole\", \"No direct demonstration of TUBD1 incorporation into microtubule lattices\", \"Mechanistic link between somatic centriole role and germ-cell phenotypes untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"centriole\"],\n    \"partners\": [\"TUBE1\", \"POC1B\", \"CEP295\", \"CEP44\", \"KATNAL2\", \"KATNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}