{"gene":"CEP120","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"CEP120 (Cep120) localizes to centrosomes, interacts with TACC (transforming acidic coiled-coil) proteins, and is required for interkinetic nuclear migration (INM) and neural progenitor self-renewal in the developing neocortex; silencing Cep120 or TACCs impairs both INM and progenitor self-renewal.","method":"In utero electroporation-mediated shRNA knockdown in mouse neocortex; co-immunoprecipitation of Cep120 with TACCs; immunofluorescence for centrosomal localization","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus loss-of-function with defined cellular phenotype, replicated with multiple shRNAs and rescue","pmids":["17920017"],"is_preprint":false},{"year":2010,"finding":"Cep120 (Ccdc100) is asymmetrically localized to the daughter centriole in cycling cells, with this asymmetry relieved upon new centriole assembly; it is required for centriole duplication in cycling cells, centriole amplification in multiciliated cells (MTECs), and centriole overduplication in S-phase-arrested cells. FRAP revealed two kinetically distinct pools of Cep120 at the centriole.","method":"Immunofluorescence, siRNA knockdown, FRAP (fluorescence recovery after photobleaching) in cycling cells and mouse tracheal epithelial cells (MTECs)","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct localization by immunofluorescence with functional consequence via KD, FRAP dynamics, and multiple cell-type contexts","pmids":["20956381"],"is_preprint":false},{"year":2013,"finding":"CEP120 directly interacts with CPAP and positively regulates centriole elongation; CEP120 levels are cell-cycle regulated (peak at S/G2/M). Overexpression of either CEP120 or CPAP induces overly long centrioles; depletion of CEP120 inhibits CPAP-induced elongation and vice versa. CEP120 contains an N-terminal microtubule-binding domain (disrupted by K76A mutation), a C-terminal dimerization domain, and a centriolar localization domain; the K76A microtubule-binding mutant suppresses elongated centriole formation.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, mutagenesis (CEP120-K76A), immunofluorescence, cell-cycle synchronization","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — direct interaction confirmed by Co-IP, domain-specific mutagenesis with functional readout, reciprocal depletion epistasis","pmids":["23857771"],"is_preprint":false},{"year":2014,"finding":"Cep120 interacts with Talpid3 (Ta3), and this interaction mediates asymmetric localization of Cep120 to the daughter centriole. Conditional knockout of Cep120 in the CNS causes failed centriole duplication, loss of ciliogenesis, impaired Hedgehog pathway activity in cerebellar granule neuron progenitors (GNPs), hydrocephalus, and cerebellar hypoplasia.","method":"Co-immunoprecipitation of Cep120 with Talpid3; conditional Cep120 knockout in mouse CNS; immunofluorescence for centriole and cilia markers; Hedgehog signaling assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — Co-IP binding partner identified plus in vivo conditional KO with defined cellular and signaling phenotype","pmids":["25251415"],"is_preprint":false},{"year":2018,"finding":"CEP120 contains three consecutive C2 domains (C2A, C2B, C2C) followed by a coiled-coil dimerization domain. The N-terminal C2A domain binds tubulin and microtubules and promotes microtubule formation; a conserved positively charged surface patch on C2A mediates this interaction. C2 domains lack classical calcium- and phospholipid-binding activities.","method":"X-ray crystallography; in vitro tubulin/microtubule binding assays; mutagenesis of positively charged residues; microtubule polymerization assay","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro biochemical reconstitution and mutagenesis in single study","pmids":["29398280"],"is_preprint":false},{"year":2018,"finding":"X-ray crystallography confirmed that CEP120 contains three C2 domains; ciliopathy point mutations V194A (Joubert syndrome) and A199P (Jeune JATD) reduce thermostability of the second C2 domain (C2B) by targeting hydrophobic core residues. Genome-engineered cells homozygous for these mutations show reduced CEP120 protein levels, compromised recruitment of distal centriole markers, and deficient cilia formation, with largely normal centriole numbers.","method":"X-ray crystallography; thermal shift/stability assays; CRISPR/Cas9 genome engineering of disease mutations; immunofluorescence for distal centriole and cilia markers","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis plus genome-engineered cell phenotyping in single study","pmids":["29847808"],"is_preprint":false},{"year":2018,"finding":"In quiescent cells, Cep120 plays a critical inhibitory role at daughter centrioles to prevent premature PCM accumulation (pericentrin, Cdk5Rap2, ninein, Cep170). Depletion of Cep120 in quiescent cells causes elevated PCM, increased microtubule-nucleation activity, aberrant dynein-dependent trafficking of centrosomal proteins, dispersal of centriolar satellites, and defective cilia assembly and signaling.","method":"siRNA knockdown in quiescent mouse and human cells; immunofluorescence for PCM components; microtubule nucleation assays; ciliogenesis assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — clean KD with multiple defined cellular phenotypes, multiple orthogonal readouts in two species","pmids":["29741480"],"is_preprint":false},{"year":2019,"finding":"CEP120 interacts with C2CD3 and Talpid3 and is required for recruitment of these proteins to the distal ends of centrioles for centriole appendage assembly and ciliogenesis. CEP120 knockout produces short centrioles lacking distal and subdistal appendages. The disease-associated mutant CEP120-I975S has reduced affinity for C2CD3 binding, perturbing cilia assembly.","method":"CRISPR/Cas9 knockout in p53-deficient RPE1 cells; co-immunoprecipitation; immunofluorescence for appendage markers (C2CD3, Talpid3); ciliogenesis assay; binding affinity assessment of I975S mutant","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, clean KO with appendage assembly phenotype, disease-mutant binding analysis","pmids":["30988386"],"is_preprint":false},{"year":2020,"finding":"A CEP120 variant (rs2303720, p.Arg947His) impairs spindle microtubule nucleation efficiency and increases aneuploidy incidence in mouse oocytes undergoing meiotic maturation, linking CEP120 to meiotic spindle function.","method":"Ectopic expression of CEP120:p.Arg947His in mouse oocytes; spindle microtubule nucleation assays; aneuploidy scoring","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay in oocytes, but single lab, single variant, mouse model only","pmids":["32772081"],"is_preprint":false},{"year":2021,"finding":"CEP120 recruits KIAA0753 (a Joubert syndrome-associated protein) to centrioles; loss of this interaction leads to accumulation of granule neuron progenitors (GNPs) in the cerebellar germinal zone and impaired neuronal differentiation. JS-associated CEP120 mutants that hinder KIAA0753 recruitment fail to rescue this defect.","method":"Co-immunoprecipitation of CEP120 with KIAA0753; in vivo Cep120 depletion; rescue experiments with wild-type vs. JS-associated CEP120 mutants; immunofluorescence and cell cycle exit analyses","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — Co-IP binding partner, in vivo KD phenotype, mutant rescue epistasis in single study","pmids":["34711653"],"is_preprint":false},{"year":2023,"finding":"Conditional deletion of Cep120 in kidney stromal mesenchyme causes delayed mitosis, activation of the mitotic surveillance pathway leading to apoptosis, and altered Wnt and Hedgehog signaling, resulting in reduction of interstitial lineages (pericytes, fibroblasts, mesangial cells), hypoplastic kidneys, and sensitization to fibrosis via enhanced TGF-β/Smad3-Gli2 signaling after renal injury.","method":"Conditional Cep120 knockout in mouse stromal mesenchyme; immunofluorescence and flow cytometry for lineage markers; signaling pathway analysis (Wnt, Hh, TGF-β/Smad3-Gli2); mitotic surveillance assay","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — in vivo conditional KO with multiple defined cellular and signaling phenotypes","pmids":["38177914"],"is_preprint":false}],"current_model":"CEP120 is a daughter centriole-enriched protein that contains three C2 domains (C2A binds tubulin/microtubules) and a coiled-coil dimerization domain; it directly interacts with CPAP, TACCs, Talpid3, C2CD3, and KIAA0753 to drive centriole elongation, centriole appendage assembly, and ciliogenesis, while also inhibiting premature PCM accumulation at daughter centrioles in quiescent cells, and mutations that destabilize its C2B domain or disrupt key interactions cause ciliopathies including Joubert syndrome and Jeune asphyxiating thoracic dystrophy."},"narrative":{"teleology":[{"year":2007,"claim":"Identifying CEP120 as a centrosomal protein that interacts with TACCs and is functionally required for interkinetic nuclear migration and neural progenitor self-renewal established its role in centrosome-dependent processes during brain development.","evidence":"In utero electroporation shRNA knockdown in mouse neocortex with Co-IP of Cep120–TACC interaction","pmids":["17920017"],"confidence":"High","gaps":["Mechanism by which CEP120–TACC interaction supports INM not resolved","Role in centriole biogenesis not yet tested"]},{"year":2010,"claim":"Demonstrating that CEP120 is asymmetrically enriched on the daughter centriole and required for centriole duplication in cycling and multiciliated cells positioned it as a core centriole biogenesis factor rather than a general centrosome component.","evidence":"Immunofluorescence, siRNA knockdown, and FRAP in cycling cells and mouse tracheal epithelial cells","pmids":["20956381"],"confidence":"High","gaps":["Molecular basis of daughter-centriole targeting unknown","Direct binding partners for duplication function not identified"]},{"year":2013,"claim":"Showing that CEP120 directly interacts with CPAP and that both are required for centriole elongation—with the N-terminal microtubule-binding domain essential for this activity—revealed the molecular mechanism through which CEP120 promotes centriole length control.","evidence":"Co-IP, reciprocal siRNA epistasis, overexpression-induced elongation, and K76A microtubule-binding mutant analysis","pmids":["23857771"],"confidence":"High","gaps":["Structural basis of CEP120–CPAP interaction not determined","How elongation is limited to prevent over-elongation in vivo unclear"]},{"year":2014,"claim":"Identifying Talpid3 as a binding partner that mediates CEP120 daughter-centriole asymmetry, and showing that conditional Cep120 knockout in the CNS ablates centriole duplication, ciliogenesis, and Hedgehog signaling, linked CEP120 to ciliary signaling in vivo.","evidence":"Co-IP of Cep120–Talpid3; conditional Cep120 knockout in mouse CNS with Hedgehog pathway readouts","pmids":["25251415"],"confidence":"High","gaps":["How Talpid3 directs CEP120 asymmetry at the molecular level not resolved","Whether Hedgehog defects are solely secondary to cilia loss not distinguished"]},{"year":2018,"claim":"Crystal structures revealed three consecutive C2 domains whose C2A domain binds tubulin/microtubules through a positively charged patch, while ciliopathy mutations in C2B destabilize the protein and compromise centriole maturation and cilia formation, providing the structural basis for CEP120 function and disease.","evidence":"X-ray crystallography; in vitro tubulin binding and microtubule polymerization assays; thermal stability assays of V194A/A199P; CRISPR knock-in of disease mutations in human cells","pmids":["29398280","29847808"],"confidence":"High","gaps":["Functional roles of C2C domain unknown","Whether C2A–tubulin binding is calcium-independent in all contexts not fully tested"]},{"year":2018,"claim":"Discovering that CEP120 actively suppresses PCM accumulation at daughter centrioles in quiescent cells revealed a regulatory function distinct from its pro-duplication role in cycling cells, explaining how daughter-centriole identity is maintained.","evidence":"siRNA knockdown in quiescent mouse and human cells; PCM component quantification; microtubule nucleation and ciliogenesis assays","pmids":["29741480"],"confidence":"High","gaps":["Molecular mechanism of PCM inhibition not identified","Whether this function operates through the same domains as elongation activity unknown"]},{"year":2019,"claim":"Establishing that CEP120 recruits C2CD3 and Talpid3 to distal centrioles for appendage assembly, and that the disease mutation I975S weakens C2CD3 binding, defined CEP120 as a scaffold for distal centriole maturation upstream of appendage formation.","evidence":"CRISPR KO in RPE1 cells; Co-IP; appendage marker analysis; binding affinity of I975S mutant","pmids":["30988386"],"confidence":"High","gaps":["Order of recruitment between C2CD3 and Talpid3 not fully resolved","Whether CEP120 scaffolding is direct or involves additional intermediaries"]},{"year":2021,"claim":"Showing that CEP120 recruits KIAA0753 to centrioles and that Joubert-syndrome-associated CEP120 mutants failing in this recruitment cause impaired granule neuron differentiation connected CEP120-KIAA0753 to the neuropathology of Joubert syndrome.","evidence":"Co-IP; in vivo Cep120 depletion with mutant rescue in cerebellar granule neuron progenitors","pmids":["34711653"],"confidence":"High","gaps":["Which CEP120 domain mediates KIAA0753 binding not mapped","Whether KIAA0753 recruitment is required in non-neural tissues unknown"]},{"year":2023,"claim":"Conditional deletion of Cep120 in kidney stromal mesenchyme causing mitotic delay, apoptosis via mitotic surveillance, and altered Wnt/Hh/TGF-β signaling extended CEP120's in vivo importance to renal interstitial lineage specification and fibrosis susceptibility.","evidence":"Conditional KO in mouse kidney stromal mesenchyme; lineage tracing; signaling pathway analysis after injury","pmids":["38177914"],"confidence":"High","gaps":["Whether renal phenotype is cilia-dependent or reflects centrosome-intrinsic mitotic defects not distinguished","Relevance to human kidney disease not established"]},{"year":null,"claim":"The mechanism by which CEP120 inhibits PCM accumulation at daughter centrioles, the functional role of the C2C domain, and how disease mutations differentially affect centriole elongation versus appendage assembly versus ciliogenesis remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstitution of PCM-inhibitory activity","C2C domain function untested by mutagenesis or structure-guided experiments","No systematic genotype–phenotype correlation across all known CEP120 disease mutations"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,7]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,1,2,6,7]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,7]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,10]}],"complexes":[],"partners":["CPAP","TACC3","KIAA1081","C2CD3","KIAA0753"],"other_free_text":[]},"mechanistic_narrative":"CEP120 is a daughter-centriole-enriched protein that governs centriole elongation, appendage assembly, ciliogenesis, and pericentriolar material homeostasis. It contains three tandem C2 domains—of which C2A binds tubulin and microtubules via a conserved positively charged surface patch—and a C-terminal coiled-coil dimerization domain; it directly interacts with CPAP to drive centriole elongation, with Talpid3 and C2CD3 for distal appendage assembly, and with KIAA0753 for cerebellar granule neuron differentiation [PMID:23857771, PMID:29398280, PMID:30988386, PMID:34711653]. In quiescent cells CEP120 restrains premature PCM accumulation at daughter centrioles, thereby preventing aberrant microtubule nucleation and ensuring proper cilia formation and Hedgehog signaling [PMID:29741480, PMID:25251415]. Destabilizing mutations in the C2B domain (V194A, A199P) cause Joubert syndrome and Jeune asphyxiating thoracic dystrophy by reducing protein levels and compromising distal centriole maturation and ciliogenesis [PMID:29847808]."},"prefetch_data":{"uniprot":{"accession":"Q8N960","full_name":"Centrosomal protein of 120 kDa","aliases":["Coiled-coil domain-containing protein 100"],"length_aa":986,"mass_kda":112.6,"function":"Plays a role in the microtubule-dependent coupling of the nucleus and the centrosome. Involved in the processes that regulate centrosome-mediated interkinetic nuclear migration (INM) of neural progenitors and for proper positioning of neurons during brain development. Also implicated in the migration and selfrenewal of neural progenitors. Required for centriole duplication and maturation during mitosis and subsequent ciliogenesis (By similarity). Required for the recruitment of CEP295 to the proximal end of new-born centrioles at the centriolar microtubule wall during early S phase in a PLK4-dependent manner (PubMed:27185865)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q8N960/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CEP120","classification":"Not Classified","n_dependent_lines":44,"n_total_lines":1208,"dependency_fraction":0.03642384105960265},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CEP120","total_profiled":1310},"omim":[{"mim_id":"617761","title":"JOUBERT SYNDROME 31; JBTS31","url":"https://www.omim.org/entry/617761"},{"mim_id":"617728","title":"CENTROSOMAL PROTEIN, 295-KD; CEP295","url":"https://www.omim.org/entry/617728"},{"mim_id":"616300","title":"SHORT-RIB THORACIC DYSPLASIA 13 WITH OR WITHOUT POLYDACTYLY; SRTD13","url":"https://www.omim.org/entry/616300"},{"mim_id":"613447","title":"SPINDLE- AND CENTRIOLE-ASSOCIATED PROTEIN 1; SPICE1","url":"https://www.omim.org/entry/613447"},{"mim_id":"613446","title":"CENTROSOMAL PROTEIN, 120-KD; CEP120","url":"https://www.omim.org/entry/613446"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Microtubules","reliability":"Uncertain"},{"location":"Flagellar centriole","reliability":"Uncertain"},{"location":"Annulus","reliability":"Uncertain"},{"location":"Mitotic spindle","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CEP120"},"hgnc":{"alias_symbol":["FLJ36090"],"prev_symbol":["CCDC100"]},"alphafold":{"accession":"Q8N960","domains":[{"cath_id":"2.60.40.150","chopping":"8-135","consensus_level":"high","plddt":91.8444,"start":8,"end":135},{"cath_id":"2.60.40.150","chopping":"165-341","consensus_level":"high","plddt":87.7806,"start":165,"end":341},{"cath_id":"2.60.40.150","chopping":"453-608","consensus_level":"high","plddt":92.6085,"start":453,"end":608}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N960","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N960-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N960-F1-predicted_aligned_error_v6.png","plddt_mean":78.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CEP120","jax_strain_url":"https://www.jax.org/strain/search?query=CEP120"},"sequence":{"accession":"Q8N960","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N960.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N960/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N960"}},"corpus_meta":[{"pmid":"17920017","id":"PMC_17920017","title":"Cep120 and TACCs control interkinetic nuclear migration and the neural progenitor pool.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/17920017","citation_count":146,"is_preprint":false},{"pmid":"23857771","id":"PMC_23857771","title":"CEP120 interacts with CPAP and positively regulates centriole elongation.","date":"2013","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23857771","citation_count":99,"is_preprint":false},{"pmid":"20956381","id":"PMC_20956381","title":"Cep120 is asymmetrically localized to the daughter centriole and is essential for centriole assembly.","date":"2010","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20956381","citation_count":98,"is_preprint":false},{"pmid":"25361962","id":"PMC_25361962","title":"A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25361962","citation_count":63,"is_preprint":false},{"pmid":"27208211","id":"PMC_27208211","title":"Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes.","date":"2016","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27208211","citation_count":52,"is_preprint":false},{"pmid":"25251415","id":"PMC_25251415","title":"Talpid3-binding centrosomal protein Cep120 is required for centriole duplication and proliferation of cerebellar granule neuron progenitors.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25251415","citation_count":40,"is_preprint":false},{"pmid":"30988386","id":"PMC_30988386","title":"CEP120 interacts with C2CD3 and Talpid3 and is required for centriole appendage assembly and ciliogenesis.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30988386","citation_count":34,"is_preprint":false},{"pmid":"32772081","id":"PMC_32772081","title":"Exome sequencing links CEP120 mutation to maternally derived aneuploid conception risk.","date":"2020","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32772081","citation_count":20,"is_preprint":false},{"pmid":"29741480","id":"PMC_29741480","title":"A novel Cep120-dependent mechanism inhibits centriole maturation in quiescent cells.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29741480","citation_count":20,"is_preprint":false},{"pmid":"29847808","id":"PMC_29847808","title":"Disease-Associated Mutations in CEP120 Destabilize the Protein and Impair Ciliogenesis.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29847808","citation_count":17,"is_preprint":false},{"pmid":"33486889","id":"PMC_33486889","title":"Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33486889","citation_count":12,"is_preprint":false},{"pmid":"17920006","id":"PMC_17920006","title":"The ups and downs of neural progenitors: Cep120 and TACCs control interkinetic nuclear migration.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/17920006","citation_count":11,"is_preprint":false},{"pmid":"29398280","id":"PMC_29398280","title":"Cep120 promotes microtubule formation through a unique tubulin binding C2 domain.","date":"2018","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/29398280","citation_count":11,"is_preprint":false},{"pmid":"34711653","id":"PMC_34711653","title":"CEP120-mediated KIAA0753 recruitment onto centrioles is required for timely neuronal differentiation and germinal zone exit in the developing cerebellum.","date":"2021","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/34711653","citation_count":7,"is_preprint":false},{"pmid":"38177914","id":"PMC_38177914","title":"Cep120 is essential for kidney stromal progenitor cell growth and differentiation.","date":"2023","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/38177914","citation_count":6,"is_preprint":false},{"pmid":"33297941","id":"PMC_33297941","title":"Expression patterns of ciliopathy genes ARL3 and CEP120 reveal roles in multisystem development.","date":"2020","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33297941","citation_count":5,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.03.24317221","title":"Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing","date":"2024-12-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.03.24317221","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8884,"output_tokens":3016,"usd":0.035946},"stage2":{"model":"claude-opus-4-6","input_tokens":6350,"output_tokens":2424,"usd":0.138525},"total_usd":0.174471,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"CEP120 (Cep120) localizes to centrosomes, interacts with TACC (transforming acidic coiled-coil) proteins, and is required for interkinetic nuclear migration (INM) and neural progenitor self-renewal in the developing neocortex; silencing Cep120 or TACCs impairs both INM and progenitor self-renewal.\",\n      \"method\": \"In utero electroporation-mediated shRNA knockdown in mouse neocortex; co-immunoprecipitation of Cep120 with TACCs; immunofluorescence for centrosomal localization\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus loss-of-function with defined cellular phenotype, replicated with multiple shRNAs and rescue\",\n      \"pmids\": [\"17920017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cep120 (Ccdc100) is asymmetrically localized to the daughter centriole in cycling cells, with this asymmetry relieved upon new centriole assembly; it is required for centriole duplication in cycling cells, centriole amplification in multiciliated cells (MTECs), and centriole overduplication in S-phase-arrested cells. FRAP revealed two kinetically distinct pools of Cep120 at the centriole.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown, FRAP (fluorescence recovery after photobleaching) in cycling cells and mouse tracheal epithelial cells (MTECs)\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by immunofluorescence with functional consequence via KD, FRAP dynamics, and multiple cell-type contexts\",\n      \"pmids\": [\"20956381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CEP120 directly interacts with CPAP and positively regulates centriole elongation; CEP120 levels are cell-cycle regulated (peak at S/G2/M). Overexpression of either CEP120 or CPAP induces overly long centrioles; depletion of CEP120 inhibits CPAP-induced elongation and vice versa. CEP120 contains an N-terminal microtubule-binding domain (disrupted by K76A mutation), a C-terminal dimerization domain, and a centriolar localization domain; the K76A microtubule-binding mutant suppresses elongated centriole formation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, mutagenesis (CEP120-K76A), immunofluorescence, cell-cycle synchronization\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct interaction confirmed by Co-IP, domain-specific mutagenesis with functional readout, reciprocal depletion epistasis\",\n      \"pmids\": [\"23857771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cep120 interacts with Talpid3 (Ta3), and this interaction mediates asymmetric localization of Cep120 to the daughter centriole. Conditional knockout of Cep120 in the CNS causes failed centriole duplication, loss of ciliogenesis, impaired Hedgehog pathway activity in cerebellar granule neuron progenitors (GNPs), hydrocephalus, and cerebellar hypoplasia.\",\n      \"method\": \"Co-immunoprecipitation of Cep120 with Talpid3; conditional Cep120 knockout in mouse CNS; immunofluorescence for centriole and cilia markers; Hedgehog signaling assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP binding partner identified plus in vivo conditional KO with defined cellular and signaling phenotype\",\n      \"pmids\": [\"25251415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CEP120 contains three consecutive C2 domains (C2A, C2B, C2C) followed by a coiled-coil dimerization domain. The N-terminal C2A domain binds tubulin and microtubules and promotes microtubule formation; a conserved positively charged surface patch on C2A mediates this interaction. C2 domains lack classical calcium- and phospholipid-binding activities.\",\n      \"method\": \"X-ray crystallography; in vitro tubulin/microtubule binding assays; mutagenesis of positively charged residues; microtubule polymerization assay\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro biochemical reconstitution and mutagenesis in single study\",\n      \"pmids\": [\"29398280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"X-ray crystallography confirmed that CEP120 contains three C2 domains; ciliopathy point mutations V194A (Joubert syndrome) and A199P (Jeune JATD) reduce thermostability of the second C2 domain (C2B) by targeting hydrophobic core residues. Genome-engineered cells homozygous for these mutations show reduced CEP120 protein levels, compromised recruitment of distal centriole markers, and deficient cilia formation, with largely normal centriole numbers.\",\n      \"method\": \"X-ray crystallography; thermal shift/stability assays; CRISPR/Cas9 genome engineering of disease mutations; immunofluorescence for distal centriole and cilia markers\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis plus genome-engineered cell phenotyping in single study\",\n      \"pmids\": [\"29847808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In quiescent cells, Cep120 plays a critical inhibitory role at daughter centrioles to prevent premature PCM accumulation (pericentrin, Cdk5Rap2, ninein, Cep170). Depletion of Cep120 in quiescent cells causes elevated PCM, increased microtubule-nucleation activity, aberrant dynein-dependent trafficking of centrosomal proteins, dispersal of centriolar satellites, and defective cilia assembly and signaling.\",\n      \"method\": \"siRNA knockdown in quiescent mouse and human cells; immunofluorescence for PCM components; microtubule nucleation assays; ciliogenesis assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple defined cellular phenotypes, multiple orthogonal readouts in two species\",\n      \"pmids\": [\"29741480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEP120 interacts with C2CD3 and Talpid3 and is required for recruitment of these proteins to the distal ends of centrioles for centriole appendage assembly and ciliogenesis. CEP120 knockout produces short centrioles lacking distal and subdistal appendages. The disease-associated mutant CEP120-I975S has reduced affinity for C2CD3 binding, perturbing cilia assembly.\",\n      \"method\": \"CRISPR/Cas9 knockout in p53-deficient RPE1 cells; co-immunoprecipitation; immunofluorescence for appendage markers (C2CD3, Talpid3); ciliogenesis assay; binding affinity assessment of I975S mutant\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, clean KO with appendage assembly phenotype, disease-mutant binding analysis\",\n      \"pmids\": [\"30988386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A CEP120 variant (rs2303720, p.Arg947His) impairs spindle microtubule nucleation efficiency and increases aneuploidy incidence in mouse oocytes undergoing meiotic maturation, linking CEP120 to meiotic spindle function.\",\n      \"method\": \"Ectopic expression of CEP120:p.Arg947His in mouse oocytes; spindle microtubule nucleation assays; aneuploidy scoring\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay in oocytes, but single lab, single variant, mouse model only\",\n      \"pmids\": [\"32772081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEP120 recruits KIAA0753 (a Joubert syndrome-associated protein) to centrioles; loss of this interaction leads to accumulation of granule neuron progenitors (GNPs) in the cerebellar germinal zone and impaired neuronal differentiation. JS-associated CEP120 mutants that hinder KIAA0753 recruitment fail to rescue this defect.\",\n      \"method\": \"Co-immunoprecipitation of CEP120 with KIAA0753; in vivo Cep120 depletion; rescue experiments with wild-type vs. JS-associated CEP120 mutants; immunofluorescence and cell cycle exit analyses\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP binding partner, in vivo KD phenotype, mutant rescue epistasis in single study\",\n      \"pmids\": [\"34711653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Conditional deletion of Cep120 in kidney stromal mesenchyme causes delayed mitosis, activation of the mitotic surveillance pathway leading to apoptosis, and altered Wnt and Hedgehog signaling, resulting in reduction of interstitial lineages (pericytes, fibroblasts, mesangial cells), hypoplastic kidneys, and sensitization to fibrosis via enhanced TGF-β/Smad3-Gli2 signaling after renal injury.\",\n      \"method\": \"Conditional Cep120 knockout in mouse stromal mesenchyme; immunofluorescence and flow cytometry for lineage markers; signaling pathway analysis (Wnt, Hh, TGF-β/Smad3-Gli2); mitotic surveillance assay\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo conditional KO with multiple defined cellular and signaling phenotypes\",\n      \"pmids\": [\"38177914\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CEP120 is a daughter centriole-enriched protein that contains three C2 domains (C2A binds tubulin/microtubules) and a coiled-coil dimerization domain; it directly interacts with CPAP, TACCs, Talpid3, C2CD3, and KIAA0753 to drive centriole elongation, centriole appendage assembly, and ciliogenesis, while also inhibiting premature PCM accumulation at daughter centrioles in quiescent cells, and mutations that destabilize its C2B domain or disrupt key interactions cause ciliopathies including Joubert syndrome and Jeune asphyxiating thoracic dystrophy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CEP120 is a daughter-centriole-enriched protein that governs centriole elongation, appendage assembly, ciliogenesis, and pericentriolar material homeostasis. It contains three tandem C2 domains—of which C2A binds tubulin and microtubules via a conserved positively charged surface patch—and a C-terminal coiled-coil dimerization domain; it directly interacts with CPAP to drive centriole elongation, with Talpid3 and C2CD3 for distal appendage assembly, and with KIAA0753 for cerebellar granule neuron differentiation [PMID:23857771, PMID:29398280, PMID:30988386, PMID:34711653]. In quiescent cells CEP120 restrains premature PCM accumulation at daughter centrioles, thereby preventing aberrant microtubule nucleation and ensuring proper cilia formation and Hedgehog signaling [PMID:29741480, PMID:25251415]. Destabilizing mutations in the C2B domain (V194A, A199P) cause Joubert syndrome and Jeune asphyxiating thoracic dystrophy by reducing protein levels and compromising distal centriole maturation and ciliogenesis [PMID:29847808].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying CEP120 as a centrosomal protein that interacts with TACCs and is functionally required for interkinetic nuclear migration and neural progenitor self-renewal established its role in centrosome-dependent processes during brain development.\",\n      \"evidence\": \"In utero electroporation shRNA knockdown in mouse neocortex with Co-IP of Cep120–TACC interaction\",\n      \"pmids\": [\"17920017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CEP120–TACC interaction supports INM not resolved\", \"Role in centriole biogenesis not yet tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that CEP120 is asymmetrically enriched on the daughter centriole and required for centriole duplication in cycling and multiciliated cells positioned it as a core centriole biogenesis factor rather than a general centrosome component.\",\n      \"evidence\": \"Immunofluorescence, siRNA knockdown, and FRAP in cycling cells and mouse tracheal epithelial cells\",\n      \"pmids\": [\"20956381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of daughter-centriole targeting unknown\", \"Direct binding partners for duplication function not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that CEP120 directly interacts with CPAP and that both are required for centriole elongation—with the N-terminal microtubule-binding domain essential for this activity—revealed the molecular mechanism through which CEP120 promotes centriole length control.\",\n      \"evidence\": \"Co-IP, reciprocal siRNA epistasis, overexpression-induced elongation, and K76A microtubule-binding mutant analysis\",\n      \"pmids\": [\"23857771\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CEP120–CPAP interaction not determined\", \"How elongation is limited to prevent over-elongation in vivo unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying Talpid3 as a binding partner that mediates CEP120 daughter-centriole asymmetry, and showing that conditional Cep120 knockout in the CNS ablates centriole duplication, ciliogenesis, and Hedgehog signaling, linked CEP120 to ciliary signaling in vivo.\",\n      \"evidence\": \"Co-IP of Cep120–Talpid3; conditional Cep120 knockout in mouse CNS with Hedgehog pathway readouts\",\n      \"pmids\": [\"25251415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Talpid3 directs CEP120 asymmetry at the molecular level not resolved\", \"Whether Hedgehog defects are solely secondary to cilia loss not distinguished\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Crystal structures revealed three consecutive C2 domains whose C2A domain binds tubulin/microtubules through a positively charged patch, while ciliopathy mutations in C2B destabilize the protein and compromise centriole maturation and cilia formation, providing the structural basis for CEP120 function and disease.\",\n      \"evidence\": \"X-ray crystallography; in vitro tubulin binding and microtubule polymerization assays; thermal stability assays of V194A/A199P; CRISPR knock-in of disease mutations in human cells\",\n      \"pmids\": [\"29398280\", \"29847808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional roles of C2C domain unknown\", \"Whether C2A–tubulin binding is calcium-independent in all contexts not fully tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovering that CEP120 actively suppresses PCM accumulation at daughter centrioles in quiescent cells revealed a regulatory function distinct from its pro-duplication role in cycling cells, explaining how daughter-centriole identity is maintained.\",\n      \"evidence\": \"siRNA knockdown in quiescent mouse and human cells; PCM component quantification; microtubule nucleation and ciliogenesis assays\",\n      \"pmids\": [\"29741480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of PCM inhibition not identified\", \"Whether this function operates through the same domains as elongation activity unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that CEP120 recruits C2CD3 and Talpid3 to distal centrioles for appendage assembly, and that the disease mutation I975S weakens C2CD3 binding, defined CEP120 as a scaffold for distal centriole maturation upstream of appendage formation.\",\n      \"evidence\": \"CRISPR KO in RPE1 cells; Co-IP; appendage marker analysis; binding affinity of I975S mutant\",\n      \"pmids\": [\"30988386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of recruitment between C2CD3 and Talpid3 not fully resolved\", \"Whether CEP120 scaffolding is direct or involves additional intermediaries\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that CEP120 recruits KIAA0753 to centrioles and that Joubert-syndrome-associated CEP120 mutants failing in this recruitment cause impaired granule neuron differentiation connected CEP120-KIAA0753 to the neuropathology of Joubert syndrome.\",\n      \"evidence\": \"Co-IP; in vivo Cep120 depletion with mutant rescue in cerebellar granule neuron progenitors\",\n      \"pmids\": [\"34711653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which CEP120 domain mediates KIAA0753 binding not mapped\", \"Whether KIAA0753 recruitment is required in non-neural tissues unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Conditional deletion of Cep120 in kidney stromal mesenchyme causing mitotic delay, apoptosis via mitotic surveillance, and altered Wnt/Hh/TGF-β signaling extended CEP120's in vivo importance to renal interstitial lineage specification and fibrosis susceptibility.\",\n      \"evidence\": \"Conditional KO in mouse kidney stromal mesenchyme; lineage tracing; signaling pathway analysis after injury\",\n      \"pmids\": [\"38177914\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether renal phenotype is cilia-dependent or reflects centrosome-intrinsic mitotic defects not distinguished\", \"Relevance to human kidney disease not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which CEP120 inhibits PCM accumulation at daughter centrioles, the functional role of the C2C domain, and how disease mutations differentially affect centriole elongation versus appendage assembly versus ciliogenesis remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No reconstitution of PCM-inhibitory activity\", \"C2C domain function untested by mutagenesis or structure-guided experiments\", \"No systematic genotype–phenotype correlation across all known CEP120 disease mutations\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 1, 2, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CPAP\", \"TACC3\", \"KIAA1081\", \"C2CD3\", \"KIAA0753\"],\n    \"other_free_text\": []\n  }\n}\n```"}