{"gene":"CEP83","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2013,"finding":"CCDC41 (CEP83) localizes specifically to the distal end of the mother centriole and interacts with CEP164, a distal appendage component. A pool of CCDC41 colocalizes with IFT20 at the Golgi complex. Knockdown of CCDC41 inhibits recruitment of IFT20 to the centrosome and blocks ciliogenesis at the ciliary vesicle docking step.","method":"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, electron microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with defined cellular phenotype, multiple orthogonal methods, replicated in subsequent studies","pmids":["23530209"],"is_preprint":false},{"year":2014,"finding":"Biallelic mutations in CEP83 cause altered distal appendage (DAP) composition and ciliary defects in patient fibroblasts and tubular renal cells, establishing CEP83 as a key component of distal appendages required for ciliogenesis.","method":"Patient fibroblast and renal cell analysis, immunofluorescence of distal appendage markers, targeted exon sequencing","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in patient cells with defined ciliary phenotype, single study with two orthogonal cellular readouts","pmids":["24882706"],"is_preprint":false},{"year":2015,"finding":"CEP83, as a distal appendage protein, is required for the mother centriole to contact the plasma membrane at the immunological synapse in cytotoxic T lymphocytes (CTLs). siRNA knockdown of CEP83 impairs CTL secretion, demonstrating a role in centrosome docking without full ciliogenesis.","method":"siRNA knockdown, high-resolution TEM tomography, functional secretion assay","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined functional phenotype (impaired secretion) and structural imaging, single lab","pmids":["26670998"],"is_preprint":false},{"year":2018,"finding":"CEP83 and SCLT1 are core distal appendage proteins that recruit LRRC45 to the mother centriole, placing CEP83 upstream of LRRC45 in the distal appendage assembly hierarchy.","method":"siRNA knockdown, immunofluorescence, epistasis analysis of protein recruitment","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by knockdown showing recruitment dependency, single lab with clear pathway placement","pmids":["30131441"],"is_preprint":false},{"year":2019,"finding":"TTBK2 phosphorylates CEP83 at four specific phosphorylation sites. CEP164-dependent TTBK2 recruitment to distal appendages is required for CEP83 phosphorylation. TTBK2-dependent CEP83 phosphorylation is important for ciliary vesicle docking and CP110 removal during early ciliogenesis.","method":"Biochemical phosphorylation assays, mass spectrometry, superresolution microscopy, site-directed mutagenesis of phosphorylation sites, knockdown/rescue","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis of specific sites, functional ciliogenesis readouts, superresolution microscopy, replicated by independent study (PMID:32129703)","pmids":["31455668"],"is_preprint":false},{"year":2019,"finding":"RABL2 recruitment to the mother centriole is dependent on the distal appendage proteins CEP164 and CEP83, placing CEP83 upstream of RABL2 in the pathway controlling ciliary GPCR trafficking.","method":"Immunofluorescence, siRNA knockdown, epistasis analysis of protein recruitment","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown epistasis showing CEP83-dependent RABL2 recruitment, single lab","pmids":["30578315"],"is_preprint":false},{"year":2019,"finding":"CEP83 (FBF1) and distal appendage proteins are required for GFP-Rabin8 centrosomal accumulation, supporting a role for CEP83 in tethering preciliary vesicles to the mother centriole via the TRAPPII complex pathway.","method":"siRNA knockdown, live-cell fluorescence imaging of GFP-Rabin8, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined molecular phenotype (loss of Rabin8 centrosomal recruitment), single lab","pmids":["31467083"],"is_preprint":false},{"year":2020,"finding":"CEP83 is a substrate of TTBK2 kinase in vitro and in vivo, with specific phosphosites characterized. TTBK2-induced phosphorylations of CEP83 are part of a broader substrate set including CEP89, CCDC92, Rabin8, and DVL3 that regulate ciliogenesis.","method":"In vitro kinase assay, mass spectrometry phosphosite mapping, cell-based phosphorylation assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus in vivo phosphosite characterization, independently confirms PMID:31455668","pmids":["32129703"],"is_preprint":false},{"year":2020,"finding":"Selective removal of CEP83 in mouse radial glial progenitors (RGPs) eliminates distal appendages and disrupts centrosome anchorage to the apical membrane, resulting in microtubule disorganization, apical membrane stiffening, YAP activation, excessive RGP proliferation, overproduction of intermediate progenitor cells, and cortical enlargement with abnormal folding. Simultaneous elimination of YAP suppresses these cortical phenotypes.","method":"Conditional knockout mouse, genetic epistasis (CEP83 KO + YAP KO), electron microscopy, live imaging, mechanical measurements, immunofluorescence","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined cellular and tissue phenotype, genetic epistasis with YAP, multiple orthogonal methods including structural EM and mechanical measurements","pmids":["32238932"],"is_preprint":false},{"year":2022,"finding":"CEP90, FOPNL, and OFD1, recruited by MNR (Moonraker), are required upstream of CEP83, CEP89, and CEP164 for distal appendage assembly. CEP83 localization to the distal centriole depends on this upstream module.","method":"CRISPR-Cas9 knockouts, ultrastructure expansion microscopy, epistasis analysis of protein recruitment in mammalian cells and Paramecium","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO epistasis demonstrating CEP83 recruitment dependency, replicated across two model systems (mammalian and Paramecium)","pmids":["36070319"],"is_preprint":false},{"year":2022,"finding":"CEP83 inactivation in human iPSCs causes absent or elongated primary cilia in induced mesodermal cells and perturbs differentiation toward intermediate mesoderm (IM) progenitors, with decreased expression of IM genes (PAX8, EYA1, HOXB7) and aberrant induction of lateral plate mesoderm markers, leading to failure to generate kidney cell types in organoid culture.","method":"CRISPR-Cas9 inactivating deletions in hiPSCs, single-cell and bulk transcriptomics, organoid culture, immunofluorescence of cilia","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined differentiation phenotype and transcriptomic characterization, single lab","pmids":["36222666"],"is_preprint":false},{"year":2023,"finding":"CEP83 and SCLT1 form a critical module for structural assembly of distal appendages. Deletion of CEP83-SCLT1-CEP164-TTBK2 severely compromises all four steps of cilium formation: preciliary vesicle recruitment, IFT recruitment, IFT initiation, and CP110 removal. CEP83 knockout disrupts recruitment of downstream distal appendage proteins in a hierarchical manner.","method":"CRISPR-Cas9 knockouts, superresolution microscopy, functional ciliogenesis assays (preprint version of PMID:39882846)","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple functional readouts; preprint later published as peer-reviewed paper","pmids":["36711481"],"is_preprint":true},{"year":2024,"finding":"CEP83 belongs to a functional subgroup of distal appendage proteins (with SCLT1 and CEP164) primarily essential for ciliary assembly and centriole docking, distinct from CEP89/FBF1 which regulate ciliary disassembly. siRNA-mediated depletion of CEP83 impairs ciliogenesis but does not affect Aurora A kinase-mediated ciliary disassembly.","method":"siRNA knockdown, immunofluorescence, kinetics of ciliation/deciliation assays, Aurora A kinase localization analysis","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined functional categorization across assembly and disassembly, single lab","pmids":["39696441"],"is_preprint":false},{"year":2025,"finding":"Comprehensive CRISPR-Cas9 analysis confirms CEP83-SCLT1 as one of two critical modules for distal appendage structural assembly. CEP83 deletion severely compromises all four steps of cilium formation (RAB34+ vesicle recruitment, IFT recruitment, IFT initiation, CP110 removal) and disrupts recruitment of multiple downstream distal appendage proteins.","method":"CRISPR-Cas9 knockouts, superresolution microscopy, functional ciliogenesis assays for four distinct steps, epistasis analysis of 12+ proteins","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — comprehensive CRISPR KO panel with multiple orthogonal functional assays across 12+ proteins, peer-reviewed publication confirming preprint findings","pmids":["39882846"],"is_preprint":false},{"year":2025,"finding":"In zebrafish RGPs, Pcm1 is asymmetrically associated with Cep83 as a mother centrosome marker. CEP83 is used as a marker distinguishing mother from daughter centrioles, with conserved PARD3-PCM1-CEP83-RAB11 associations detected in human cortical brain organoids.","method":"In vivo time-lapse imaging, nanoscale expansion microscopy, co-localization analysis in zebrafish and human brain organoids","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CEP83 used as a marker rather than subject of mechanistic investigation; association with PCM1 reported by co-localization without biochemical validation of direct interaction","pmids":["41315244"],"is_preprint":false},{"year":2025,"finding":"Complete biallelic loss-of-function of CEP83 (abrogating CEP83 mRNA and protein expression) results in aberrantly long (elongated) primary cilia in patient fibroblasts, in contrast to the shorter/absent cilia phenotype seen with partial loss-of-function mutations, suggesting a dosage-dependent mechanism in cilia length regulation.","method":"Patient fibroblast analysis, whole genome sequencing, RT-PCR, Western blot, immunofluorescence of cilia","journal":"NPJ genomic medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct measurement of cilia phenotype in patient cells with confirmed absent protein expression, single study","pmids":["41073425"],"is_preprint":false}],"current_model":"CEP83 is a core structural component of the distal appendages (DAPs) of the mother centriole that acts as an early and essential organizer of ciliogenesis: it interacts with CEP164 and forms a CEP83-SCLT1 module critical for DAP structural assembly, recruits downstream proteins (LRRC45, RABL2, IFT20) to the centrosome, and is phosphorylated by TTBK2 (recruited by CEP164) at four sites to drive ciliary vesicle docking and CP110 removal; in neural progenitors, CEP83-mediated centrosome anchoring to the apical membrane controls mechanical properties of the cell and suppresses YAP-driven proliferation, and in iPSC differentiation CEP83 is required for proper intermediate mesoderm specification via primary cilia."},"narrative":{"mechanistic_narrative":"CEP83 is a core structural component of the distal appendages (DAPs) of the mother centriole and functions as an early, essential organizer of ciliogenesis and centriole docking to the plasma membrane [PMID:23530209, PMID:39882846]. It localizes to the distal end of the mother centriole, where its own positioning depends on an upstream CEP90/FOPNL/OFD1 module, and together with SCLT1 it constitutes one of the two critical modules for DAP structural assembly, hierarchically recruiting downstream appendage proteins including LRRC45 and RABL2 [PMID:30131441, PMID:30578315, PMID:36070319, PMID:39882846]. Through these appendages CEP83 tethers preciliary/ciliary vesicles to the mother centriole and coordinates IFT recruitment — interacting with and recruiting IFT20 and supporting Rabin8/TRAPPII-dependent vesicle accumulation — and its loss compromises all four steps of cilium formation: vesicle recruitment, IFT recruitment, IFT initiation, and CP110 removal [PMID:23530209, PMID:31467083, PMID:39882846]. CEP83 is a direct substrate of TTBK2, which is recruited to appendages in a CEP164-dependent manner and phosphorylates CEP83 at four sites to drive ciliary vesicle docking and CP110 removal [PMID:31455668, PMID:32129703]. Functionally, CEP83 distinguishes a ciliary-assembly subgroup of DAP proteins distinct from disassembly regulators, mediates mother-centriole contact with the plasma membrane in non-ciliary contexts such as the immunological synapse in cytotoxic T lymphocytes, and in radial glial progenitors anchors the centrosome to the apical membrane to set cell mechanical properties and suppress YAP-driven proliferation [PMID:26670998, PMID:32238932, PMID:39696441]. Biallelic CEP83 mutations cause altered distal appendage composition and ciliary defects in patients, and CEP83 is required for primary cilia-dependent intermediate mesoderm specification during iPSC differentiation [PMID:24882706, PMID:36222666, PMID:41073425].","teleology":[{"year":2013,"claim":"Established CEP83 as a distal-appendage protein physically linked to the ciliogenesis machinery, answering where it acts and what step it controls.","evidence":"Immunofluorescence, reciprocal co-IP with CEP164, siRNA knockdown and EM in human cells","pmids":["23530209"],"confidence":"High","gaps":["Direct binding interface with CEP164 not mapped","Mechanism of IFT20 recruitment not resolved"]},{"year":2014,"claim":"Linked CEP83 loss-of-function to human disease, establishing that altered DAP composition underlies patient ciliary defects.","evidence":"Patient fibroblast/renal cell analysis with DAP marker immunofluorescence and targeted sequencing","pmids":["24882706"],"confidence":"Medium","gaps":["Genotype-phenotype relationship of specific alleles not dissected","Tissue specificity of phenotype unexplained"]},{"year":2015,"claim":"Showed CEP83 mediates centrosome docking to the plasma membrane beyond ciliogenesis, generalizing its appendage-tethering function.","evidence":"siRNA knockdown, TEM tomography and secretion assays at the immunological synapse in CTLs","pmids":["26670998"],"confidence":"Medium","gaps":["Molecular partners for plasma-membrane docking in CTLs not identified","Single lab"]},{"year":2018,"claim":"Placed CEP83 upstream in the DAP assembly hierarchy by defining LRRC45 recruitment dependency.","evidence":"siRNA knockdown and epistasis of protein recruitment by immunofluorescence","pmids":["30131441"],"confidence":"Medium","gaps":["Direct vs indirect recruitment of LRRC45 unresolved","Single lab"]},{"year":2019,"claim":"Identified CEP83 as a TTBK2 substrate phosphorylated at four sites and extended its role to RABL2/Rabin8-dependent vesicle tethering, connecting kinase regulation to vesicle docking and CP110 removal.","evidence":"In vitro kinase assays, mass spectrometry phosphosite mapping, site-directed mutagenesis, knockdown/rescue, and live imaging of Rabin8/RABL2","pmids":["31455668","30578315","31467083"],"confidence":"High","gaps":["Functional contribution of each individual phosphosite not separated","Direct CEP83-RABL2/Rabin8 binding not established"]},{"year":2020,"claim":"Independently confirmed CEP83 as a TTBK2 substrate within a broader phosphorylation network and defined the centrosome-anchoring/YAP mechanotransduction role in neural progenitors.","evidence":"In vitro/in vivo kinase and phosphosite assays; conditional knockout mouse with CEP83/YAP epistasis, EM, and mechanical measurements","pmids":["32129703","32238932"],"confidence":"High","gaps":["How appendage loss leads to apical membrane stiffening mechanically not fully resolved","Link between phosphorylation and the in vivo progenitor phenotype not connected"]},{"year":2022,"claim":"Defined the module upstream of CEP83 (CEP90/FOPNL/OFD1) and showed CEP83 is required for cilia-dependent intermediate mesoderm specification, extending its role to lineage differentiation.","evidence":"CRISPR knockouts with expansion microscopy epistasis; hiPSC inactivation with single-cell/bulk transcriptomics and kidney organoids","pmids":["36070319","36222666"],"confidence":"Medium","gaps":["Cilia-dependent signaling pathway driving IM gene expression not identified","Direct interactions within the upstream module not mapped"]},{"year":2025,"claim":"Comprehensive CRISPR analysis established CEP83-SCLT1 as a critical DAP assembly module controlling all four ciliogenesis steps, and functionally separated it from disassembly regulators.","evidence":"CRISPR-Cas9 knockout panels, superresolution microscopy, four-step ciliogenesis assays and epistasis across 12+ proteins; ciliation/deciliation kinetics with Aurora A analysis","pmids":["39882846","39696441"],"confidence":"High","gaps":["Structural basis of the CEP83-SCLT1 module not solved","Mechanism distinguishing assembly from disassembly roles not defined"]},{"year":2025,"claim":"Revealed dosage-dependent control of cilia length, with complete loss producing elongated cilia versus shorter/absent cilia from partial loss.","evidence":"Patient fibroblast analysis with whole genome sequencing, RT-PCR, Western blot and cilia immunofluorescence","pmids":["41073425"],"confidence":"Medium","gaps":["Molecular basis of dosage-dependent length regulation unknown","Single study"]},{"year":null,"claim":"How CEP83 mechanically integrates appendage assembly, vesicle docking, TTBK2 phosphorylation, and downstream cilia-dependent signaling into tissue-level outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of CEP83 or the CEP83-SCLT1 module","Direct physical partners largely inferred from recruitment epistasis rather than biochemistry","Causal chain from phosphosites to in vivo phenotypes incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,5,13]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3,9,13]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,10,13]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,4,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[8,10]}],"complexes":["distal appendage","CEP83-SCLT1 module"],"partners":["CEP164","SCLT1","IFT20","LRRC45","RABL2","TTBK2","PCM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y592","full_name":"Centrosomal protein of 83 kDa","aliases":["Coiled-coil domain-containing protein 41","Renal carcinoma antigen NY-REN-58"],"length_aa":701,"mass_kda":82.9,"function":"Component of the distal appendage region of the centriole involved in the initiation of primary cilium assembly. May collaborate with IFT20 in the trafficking of ciliary membrane proteins from the Golgi complex to the cilium during the initiation of primary cilium assembly","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole","url":"https://www.uniprot.org/uniprotkb/Q9Y592/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP83","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/CEP83","total_profiled":1310},"omim":[{"mim_id":"621312","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 45; LRRC45","url":"https://www.omim.org/entry/621312"},{"mim_id":"615944","title":"C2 CALCIUM-DEPENDENT DOMAIN-CONTAINING PROTEIN 3; C2CD3","url":"https://www.omim.org/entry/615944"},{"mim_id":"615862","title":"NEPHRONOPHTHISIS 18; NPHP18","url":"https://www.omim.org/entry/615862"},{"mim_id":"615847","title":"CENTROSOMAL PROTEIN, 83-KD; CEP83","url":"https://www.omim.org/entry/615847"},{"mim_id":"611399","title":"SODIUM CHANNEL AND CLATHRIN LINKER 1; SCLT1","url":"https://www.omim.org/entry/611399"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Golgi apparatus","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Uncertain"},{"location":"Primary cilium","reliability":"Uncertain"},{"location":"Primary cilium transition zone","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEP83"},"hgnc":{"alias_symbol":["NY-REN-58","NPHP18"],"prev_symbol":["CCDC41"]},"alphafold":{"accession":"Q9Y592","domains":[{"cath_id":"-","chopping":"111-197_216-355","consensus_level":"medium","plddt":91.8618,"start":111,"end":355},{"cath_id":"-","chopping":"406-601","consensus_level":"medium","plddt":88.6497,"start":406,"end":601}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y592","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y592-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y592-F1-predicted_aligned_error_v6.png","plddt_mean":81.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP83","jax_strain_url":"https://www.jax.org/strain/search?query=CEP83"},"sequence":{"accession":"Q9Y592","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y592.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y592/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y592"}},"corpus_meta":[{"pmid":"18199800","id":"PMC_18199800","title":"NEK8 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/39219159","citation_count":0,"is_preprint":false},{"pmid":"39696441","id":"PMC_39696441","title":"Distinct roles of centriole distal appendage proteins in ciliary assembly and disassembly.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39696441","citation_count":0,"is_preprint":false},{"pmid":"37164540","id":"PMC_37164540","title":"Multi-color live-cell fluorescence imaging of primary ciliary membrane assembly and dynamics.","date":"2023","source":"Methods in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/37164540","citation_count":0,"is_preprint":false},{"pmid":"40581359","id":"PMC_40581359","title":"TTBK2 affects sperm quality by regulating the expression of centrosomal proteins and flagellar transporters during spermiogenesis in mice.","date":"2025","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/40581359","citation_count":0,"is_preprint":false},{"pmid":"42094407","id":"PMC_42094407","title":"Development of Potent and Cell Active 5-Azaindole-Based Tau Tubulin Kinase Inhibitors.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42094407","citation_count":0,"is_preprint":false},{"pmid":"41917816","id":"PMC_41917816","title":"Expression and regulation of lncRNAs in the testes of Yili geese with high and low sperm motility.","date":"2026","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41917816","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16898,"output_tokens":3802,"usd":0.053862,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11589,"output_tokens":3341,"usd":0.070735,"stage2_stop_reason":"end_turn"},"total_usd":0.124597,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"CCDC41 (CEP83) localizes specifically to the distal end of the mother centriole and interacts with CEP164, a distal appendage component. A pool of CCDC41 colocalizes with IFT20 at the Golgi complex. Knockdown of CCDC41 inhibits recruitment of IFT20 to the centrosome and blocks ciliogenesis at the ciliary vesicle docking step.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, electron microscopy\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, siRNA knockdown with defined cellular phenotype, multiple orthogonal methods, replicated in subsequent studies\",\n      \"pmids\": [\"23530209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Biallelic mutations in CEP83 cause altered distal appendage (DAP) composition and ciliary defects in patient fibroblasts and tubular renal cells, establishing CEP83 as a key component of distal appendages required for ciliogenesis.\",\n      \"method\": \"Patient fibroblast and renal cell analysis, immunofluorescence of distal appendage markers, targeted exon sequencing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in patient cells with defined ciliary phenotype, single study with two orthogonal cellular readouts\",\n      \"pmids\": [\"24882706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CEP83, as a distal appendage protein, is required for the mother centriole to contact the plasma membrane at the immunological synapse in cytotoxic T lymphocytes (CTLs). siRNA knockdown of CEP83 impairs CTL secretion, demonstrating a role in centrosome docking without full ciliogenesis.\",\n      \"method\": \"siRNA knockdown, high-resolution TEM tomography, functional secretion assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined functional phenotype (impaired secretion) and structural imaging, single lab\",\n      \"pmids\": [\"26670998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEP83 and SCLT1 are core distal appendage proteins that recruit LRRC45 to the mother centriole, placing CEP83 upstream of LRRC45 in the distal appendage assembly hierarchy.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, epistasis analysis of protein recruitment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by knockdown showing recruitment dependency, single lab with clear pathway placement\",\n      \"pmids\": [\"30131441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TTBK2 phosphorylates CEP83 at four specific phosphorylation sites. CEP164-dependent TTBK2 recruitment to distal appendages is required for CEP83 phosphorylation. TTBK2-dependent CEP83 phosphorylation is important for ciliary vesicle docking and CP110 removal during early ciliogenesis.\",\n      \"method\": \"Biochemical phosphorylation assays, mass spectrometry, superresolution microscopy, site-directed mutagenesis of phosphorylation sites, knockdown/rescue\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis of specific sites, functional ciliogenesis readouts, superresolution microscopy, replicated by independent study (PMID:32129703)\",\n      \"pmids\": [\"31455668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RABL2 recruitment to the mother centriole is dependent on the distal appendage proteins CEP164 and CEP83, placing CEP83 upstream of RABL2 in the pathway controlling ciliary GPCR trafficking.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown, epistasis analysis of protein recruitment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown epistasis showing CEP83-dependent RABL2 recruitment, single lab\",\n      \"pmids\": [\"30578315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEP83 (FBF1) and distal appendage proteins are required for GFP-Rabin8 centrosomal accumulation, supporting a role for CEP83 in tethering preciliary vesicles to the mother centriole via the TRAPPII complex pathway.\",\n      \"method\": \"siRNA knockdown, live-cell fluorescence imaging of GFP-Rabin8, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined molecular phenotype (loss of Rabin8 centrosomal recruitment), single lab\",\n      \"pmids\": [\"31467083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CEP83 is a substrate of TTBK2 kinase in vitro and in vivo, with specific phosphosites characterized. TTBK2-induced phosphorylations of CEP83 are part of a broader substrate set including CEP89, CCDC92, Rabin8, and DVL3 that regulate ciliogenesis.\",\n      \"method\": \"In vitro kinase assay, mass spectrometry phosphosite mapping, cell-based phosphorylation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus in vivo phosphosite characterization, independently confirms PMID:31455668\",\n      \"pmids\": [\"32129703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Selective removal of CEP83 in mouse radial glial progenitors (RGPs) eliminates distal appendages and disrupts centrosome anchorage to the apical membrane, resulting in microtubule disorganization, apical membrane stiffening, YAP activation, excessive RGP proliferation, overproduction of intermediate progenitor cells, and cortical enlargement with abnormal folding. Simultaneous elimination of YAP suppresses these cortical phenotypes.\",\n      \"method\": \"Conditional knockout mouse, genetic epistasis (CEP83 KO + YAP KO), electron microscopy, live imaging, mechanical measurements, immunofluorescence\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined cellular and tissue phenotype, genetic epistasis with YAP, multiple orthogonal methods including structural EM and mechanical measurements\",\n      \"pmids\": [\"32238932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEP90, FOPNL, and OFD1, recruited by MNR (Moonraker), are required upstream of CEP83, CEP89, and CEP164 for distal appendage assembly. CEP83 localization to the distal centriole depends on this upstream module.\",\n      \"method\": \"CRISPR-Cas9 knockouts, ultrastructure expansion microscopy, epistasis analysis of protein recruitment in mammalian cells and Paramecium\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO epistasis demonstrating CEP83 recruitment dependency, replicated across two model systems (mammalian and Paramecium)\",\n      \"pmids\": [\"36070319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEP83 inactivation in human iPSCs causes absent or elongated primary cilia in induced mesodermal cells and perturbs differentiation toward intermediate mesoderm (IM) progenitors, with decreased expression of IM genes (PAX8, EYA1, HOXB7) and aberrant induction of lateral plate mesoderm markers, leading to failure to generate kidney cell types in organoid culture.\",\n      \"method\": \"CRISPR-Cas9 inactivating deletions in hiPSCs, single-cell and bulk transcriptomics, organoid culture, immunofluorescence of cilia\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined differentiation phenotype and transcriptomic characterization, single lab\",\n      \"pmids\": [\"36222666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CEP83 and SCLT1 form a critical module for structural assembly of distal appendages. Deletion of CEP83-SCLT1-CEP164-TTBK2 severely compromises all four steps of cilium formation: preciliary vesicle recruitment, IFT recruitment, IFT initiation, and CP110 removal. CEP83 knockout disrupts recruitment of downstream distal appendage proteins in a hierarchical manner.\",\n      \"method\": \"CRISPR-Cas9 knockouts, superresolution microscopy, functional ciliogenesis assays (preprint version of PMID:39882846)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple functional readouts; preprint later published as peer-reviewed paper\",\n      \"pmids\": [\"36711481\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CEP83 belongs to a functional subgroup of distal appendage proteins (with SCLT1 and CEP164) primarily essential for ciliary assembly and centriole docking, distinct from CEP89/FBF1 which regulate ciliary disassembly. siRNA-mediated depletion of CEP83 impairs ciliogenesis but does not affect Aurora A kinase-mediated ciliary disassembly.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, kinetics of ciliation/deciliation assays, Aurora A kinase localization analysis\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined functional categorization across assembly and disassembly, single lab\",\n      \"pmids\": [\"39696441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Comprehensive CRISPR-Cas9 analysis confirms CEP83-SCLT1 as one of two critical modules for distal appendage structural assembly. CEP83 deletion severely compromises all four steps of cilium formation (RAB34+ vesicle recruitment, IFT recruitment, IFT initiation, CP110 removal) and disrupts recruitment of multiple downstream distal appendage proteins.\",\n      \"method\": \"CRISPR-Cas9 knockouts, superresolution microscopy, functional ciliogenesis assays for four distinct steps, epistasis analysis of 12+ proteins\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — comprehensive CRISPR KO panel with multiple orthogonal functional assays across 12+ proteins, peer-reviewed publication confirming preprint findings\",\n      \"pmids\": [\"39882846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In zebrafish RGPs, Pcm1 is asymmetrically associated with Cep83 as a mother centrosome marker. CEP83 is used as a marker distinguishing mother from daughter centrioles, with conserved PARD3-PCM1-CEP83-RAB11 associations detected in human cortical brain organoids.\",\n      \"method\": \"In vivo time-lapse imaging, nanoscale expansion microscopy, co-localization analysis in zebrafish and human brain organoids\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CEP83 used as a marker rather than subject of mechanistic investigation; association with PCM1 reported by co-localization without biochemical validation of direct interaction\",\n      \"pmids\": [\"41315244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Complete biallelic loss-of-function of CEP83 (abrogating CEP83 mRNA and protein expression) results in aberrantly long (elongated) primary cilia in patient fibroblasts, in contrast to the shorter/absent cilia phenotype seen with partial loss-of-function mutations, suggesting a dosage-dependent mechanism in cilia length regulation.\",\n      \"method\": \"Patient fibroblast analysis, whole genome sequencing, RT-PCR, Western blot, immunofluorescence of cilia\",\n      \"journal\": \"NPJ genomic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct measurement of cilia phenotype in patient cells with confirmed absent protein expression, single study\",\n      \"pmids\": [\"41073425\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP83 is a core structural component of the distal appendages (DAPs) of the mother centriole that acts as an early and essential organizer of ciliogenesis: it interacts with CEP164 and forms a CEP83-SCLT1 module critical for DAP structural assembly, recruits downstream proteins (LRRC45, RABL2, IFT20) to the centrosome, and is phosphorylated by TTBK2 (recruited by CEP164) at four sites to drive ciliary vesicle docking and CP110 removal; in neural progenitors, CEP83-mediated centrosome anchoring to the apical membrane controls mechanical properties of the cell and suppresses YAP-driven proliferation, and in iPSC differentiation CEP83 is required for proper intermediate mesoderm specification via primary cilia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CEP83 is a core structural component of the distal appendages (DAPs) of the mother centriole and functions as an early, essential organizer of ciliogenesis and centriole docking to the plasma membrane [#0, #13]. It localizes to the distal end of the mother centriole, where its own positioning depends on an upstream CEP90/FOPNL/OFD1 module, and together with SCLT1 it constitutes one of the two critical modules for DAP structural assembly, hierarchically recruiting downstream appendage proteins including LRRC45 and RABL2 [#3, #5, #9, #13]. Through these appendages CEP83 tethers preciliary/ciliary vesicles to the mother centriole and coordinates IFT recruitment — interacting with and recruiting IFT20 and supporting Rabin8/TRAPPII-dependent vesicle accumulation — and its loss compromises all four steps of cilium formation: vesicle recruitment, IFT recruitment, IFT initiation, and CP110 removal [#0, #6, #13]. CEP83 is a direct substrate of TTBK2, which is recruited to appendages in a CEP164-dependent manner and phosphorylates CEP83 at four sites to drive ciliary vesicle docking and CP110 removal [#4, #7]. Functionally, CEP83 distinguishes a ciliary-assembly subgroup of DAP proteins distinct from disassembly regulators, mediates mother-centriole contact with the plasma membrane in non-ciliary contexts such as the immunological synapse in cytotoxic T lymphocytes, and in radial glial progenitors anchors the centrosome to the apical membrane to set cell mechanical properties and suppress YAP-driven proliferation [#2, #8, #12]. Biallelic CEP83 mutations cause altered distal appendage composition and ciliary defects in patients, and CEP83 is required for primary cilia-dependent intermediate mesoderm specification during iPSC differentiation [#1, #10, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established CEP83 as a distal-appendage protein physically linked to the ciliogenesis machinery, answering where it acts and what step it controls.\",\n      \"evidence\": \"Immunofluorescence, reciprocal co-IP with CEP164, siRNA knockdown and EM in human cells\",\n      \"pmids\": [\"23530209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding interface with CEP164 not mapped\", \"Mechanism of IFT20 recruitment not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked CEP83 loss-of-function to human disease, establishing that altered DAP composition underlies patient ciliary defects.\",\n      \"evidence\": \"Patient fibroblast/renal cell analysis with DAP marker immunofluorescence and targeted sequencing\",\n      \"pmids\": [\"24882706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genotype-phenotype relationship of specific alleles not dissected\", \"Tissue specificity of phenotype unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CEP83 mediates centrosome docking to the plasma membrane beyond ciliogenesis, generalizing its appendage-tethering function.\",\n      \"evidence\": \"siRNA knockdown, TEM tomography and secretion assays at the immunological synapse in CTLs\",\n      \"pmids\": [\"26670998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular partners for plasma-membrane docking in CTLs not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed CEP83 upstream in the DAP assembly hierarchy by defining LRRC45 recruitment dependency.\",\n      \"evidence\": \"siRNA knockdown and epistasis of protein recruitment by immunofluorescence\",\n      \"pmids\": [\"30131441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect recruitment of LRRC45 unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified CEP83 as a TTBK2 substrate phosphorylated at four sites and extended its role to RABL2/Rabin8-dependent vesicle tethering, connecting kinase regulation to vesicle docking and CP110 removal.\",\n      \"evidence\": \"In vitro kinase assays, mass spectrometry phosphosite mapping, site-directed mutagenesis, knockdown/rescue, and live imaging of Rabin8/RABL2\",\n      \"pmids\": [\"31455668\", \"30578315\", \"31467083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional contribution of each individual phosphosite not separated\", \"Direct CEP83-RABL2/Rabin8 binding not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Independently confirmed CEP83 as a TTBK2 substrate within a broader phosphorylation network and defined the centrosome-anchoring/YAP mechanotransduction role in neural progenitors.\",\n      \"evidence\": \"In vitro/in vivo kinase and phosphosite assays; conditional knockout mouse with CEP83/YAP epistasis, EM, and mechanical measurements\",\n      \"pmids\": [\"32129703\", \"32238932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How appendage loss leads to apical membrane stiffening mechanically not fully resolved\", \"Link between phosphorylation and the in vivo progenitor phenotype not connected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the module upstream of CEP83 (CEP90/FOPNL/OFD1) and showed CEP83 is required for cilia-dependent intermediate mesoderm specification, extending its role to lineage differentiation.\",\n      \"evidence\": \"CRISPR knockouts with expansion microscopy epistasis; hiPSC inactivation with single-cell/bulk transcriptomics and kidney organoids\",\n      \"pmids\": [\"36070319\", \"36222666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cilia-dependent signaling pathway driving IM gene expression not identified\", \"Direct interactions within the upstream module not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comprehensive CRISPR analysis established CEP83-SCLT1 as a critical DAP assembly module controlling all four ciliogenesis steps, and functionally separated it from disassembly regulators.\",\n      \"evidence\": \"CRISPR-Cas9 knockout panels, superresolution microscopy, four-step ciliogenesis assays and epistasis across 12+ proteins; ciliation/deciliation kinetics with Aurora A analysis\",\n      \"pmids\": [\"39882846\", \"39696441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CEP83-SCLT1 module not solved\", \"Mechanism distinguishing assembly from disassembly roles not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed dosage-dependent control of cilia length, with complete loss producing elongated cilia versus shorter/absent cilia from partial loss.\",\n      \"evidence\": \"Patient fibroblast analysis with whole genome sequencing, RT-PCR, Western blot and cilia immunofluorescence\",\n      \"pmids\": [\"41073425\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of dosage-dependent length regulation unknown\", \"Single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CEP83 mechanically integrates appendage assembly, vesicle docking, TTBK2 phosphorylation, and downstream cilia-dependent signaling into tissue-level outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of CEP83 or the CEP83-SCLT1 module\", \"Direct physical partners largely inferred from recruitment epistasis rather than biochemistry\", \"Causal chain from phosphosites to in vivo phenotypes incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 5, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3, 9, 13]},\n      {\"term_id\": \"GO:0005814\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 10, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [8, 10]}\n    ],\n    \"complexes\": [\"distal appendage\", \"CEP83-SCLT1 module\"],\n    \"partners\": [\"CEP164\", \"SCLT1\", \"IFT20\", \"LRRC45\", \"RABL2\", \"TTBK2\", \"PCM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}