{"gene":"KIAA0753","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2015,"finding":"KIAA0753/OFIP localizes to centrosomes and pericentriolar satellites in human cells and forms a ternary complex with FOR20 and OFD1; knockdown of any component of this complex causes defective recruitment of the other components to centrosomes and satellites. Additionally, KIAA0753/OFIP possesses microtubule-stabilizing activity.","method":"Co-immunoprecipitation, immunofluorescence microscopy, siRNA knockdown in RPE1 cells, microtubule stabilization assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, functional knockdown with defined cellular phenotype, multiple orthogonal methods in a single study","pmids":["26643951"],"is_preprint":false},{"year":2015,"finding":"OFD syndrome-associated KIAA0753/OFIP mutants lose their capacity to interact with FOR20 and OFD1, identifying disruption of this complex as the molecular basis of the ciliopathy defect.","method":"Co-immunoprecipitation with disease-associated mutant proteins","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with mutant protein, single lab, moderate evidence","pmids":["26643951"],"is_preprint":false},{"year":2017,"finding":"KIAA0753 mutations in Joubert syndrome patients cause defective ciliogenesis in patient-derived fibroblasts, establishing its requirement for primary cilia formation.","method":"Immunofluorescence-based ciliogenesis assay in patient fibroblasts","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in patient cells with defined cellular phenotype, single lab","pmids":["28220259"],"is_preprint":false},{"year":2021,"finding":"CEP120 directly recruits KIAA0753 to centrioles; loss of this interaction causes accumulation of granule neuron progenitors in the cerebellar germinal zone and impairs neuronal differentiation. Rescue with wild-type CEP120 restores normal differentiation, while JS-associated CEP120 mutants that cannot recruit KIAA0753 fail to rescue.","method":"Co-immunoprecipitation, in vivo loss-of-function (Cep120 depletion) with rescue by wild-type and JS-mutant CEP120, immunofluorescence in developing mouse cerebellum","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic rescue with mutagenesis, in vivo epistasis, multiple orthogonal methods","pmids":["34711653"],"is_preprint":false},{"year":2021,"finding":"Ablation of KIAA0753 in vitro blocks primary ciliogenesis and impairs Sonic Hedgehog (SHH) pathway activity; patient fibroblasts with KIAA0753 variants show deficits in primary ciliation and blunted SHH and WNT signaling responses.","method":"siRNA/shRNA knockdown, ciliogenesis assay, SHH pathway reporter assay, patient fibroblast functional assays","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 2 — KD with defined cellular phenotype and pathway readout, replicated in patient cells","pmids":["34523780"],"is_preprint":false},{"year":2024,"finding":"KIAA0753 promotes osteoblast differentiation by directly interacting with SHH, OCN, and Gli2, activating the Hedgehog signaling pathway and mitigating ubiquitination of Gli2; knockdown shortens primary cilia while overexpression rescues cilia length and osteoblast differentiation markers.","method":"Co-immunoprecipitation, shRNA knockdown, overexpression rescue, immunoblotting for differentiation markers (OCN, OPN, ALP, Gli2)","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP for interaction, KD/OE with defined phenotype, single lab","pmids":["39245790"],"is_preprint":false},{"year":2025,"finding":"KIAA0753/OFIP undergoes UFMylation catalyzed by the E3 ligase UFL1; UFL1 interacts with OFIP in vivo and in vitro, and UFL1-mediated UFMylation inhibits OFIP protein stability and maintains its proper centrosomal localization in HeLa cells (but not RPE1 cells, revealing cell-type-specific regulation).","method":"Co-immunoprecipitation, immunoblotting, RT-qPCR, immunofluorescence microscopy","journal":"Journal of clinical laboratory analysis","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP for interaction and modification, functional localization assay, single lab with multiple methods","pmids":["40059580"],"is_preprint":false},{"year":2025,"finding":"KIAA0753/OFIP (as MNR/CEP90) is part of the DISCO complex (MNR/CEP90/OFD1) that marks future appendage sites at the distal centriole; C2CD3 directly interacts with MNR and is required for DISCO complex recruitment, placing KIAA0753 within the C2CD3-dependent in-to-out architectural hub that scaffolds distal centriole appendage assembly.","method":"Ultrastructure Expansion Microscopy (U-ExM), cryo-electron tomography, C2CD3 depletion with immunofluorescence readout for DISCO complex recruitment","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 — structural methods (cryo-ET, U-ExM) plus functional depletion, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.06.17.660204"],"is_preprint":true}],"current_model":"KIAA0753/OFIP is a centrosomal and pericentriolar satellite protein that is recruited to centrioles by CEP120, forms a ternary complex with FOR20 and OFD1 (as part of the DISCO complex), stabilizes microtubules, promotes primary ciliogenesis, activates Hedgehog/SHH signaling (including direct interaction with SHH and Gli2), and is regulated by UFL1-mediated UFMylation that controls its stability and centrosomal localization; loss-of-function mutations in KIAA0753 disrupt ciliogenesis and cause ciliopathies including Joubert syndrome, OFD syndrome, and skeletal dysplasias."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing that KIAA0753 is a centrosomal/pericentriolar satellite protein that forms an obligate ternary complex with FOR20 and OFD1, where each subunit is required for the others' recruitment — this defined its core molecular context and revealed its microtubule-stabilizing activity.","evidence":"Reciprocal Co-IP, immunofluorescence, siRNA knockdown, and microtubule stabilization assays in RPE1 cells","pmids":["26643951"],"confidence":"High","gaps":["Structural basis of the ternary complex is unknown","How microtubule stabilization by KIAA0753 mechanistically supports ciliogenesis is undefined","Upstream signals controlling complex assembly were not identified"]},{"year":2015,"claim":"Disease-associated KIAA0753 mutations disrupt FOR20 and OFD1 interaction, linking OFD syndrome molecular pathology directly to ternary complex disruption.","evidence":"Co-IP with OFD syndrome-associated mutant KIAA0753 proteins","pmids":["26643951"],"confidence":"Medium","gaps":["Limited to a single lab's Co-IP data without in vivo disease model validation","Precise structural determinants of the interaction loss are unmapped","Whether partial complex disruption yields graded phenotypes is untested"]},{"year":2017,"claim":"Patient-derived evidence confirmed KIAA0753 as a bona fide ciliogenesis gene: Joubert syndrome patients carrying KIAA0753 mutations showed defective primary cilia formation in fibroblasts, bridging the molecular complex function to a human ciliopathy.","evidence":"Immunofluorescence-based ciliogenesis assay in Joubert syndrome patient fibroblasts","pmids":["28220259"],"confidence":"Medium","gaps":["No rescue experiment was performed in patient cells","Animal model phenocopying the Joubert syndrome mutations was not generated","Whether cilia initiation versus elongation is the affected step was not resolved"]},{"year":2021,"claim":"CEP120 was identified as the upstream recruiter of KIAA0753 to centrioles, and this interaction was shown to be essential for cerebellar granule neuron differentiation in vivo — establishing the recruitment hierarchy and connecting it to neurodevelopment.","evidence":"Co-IP, in vivo Cep120 depletion and rescue with WT versus JS-mutant CEP120 in developing mouse cerebellum","pmids":["34711653"],"confidence":"High","gaps":["Whether CEP120 recruits the entire KIAA0753–FOR20–OFD1 complex or KIAA0753 alone is unclear","Downstream signaling pathways affected in cerebellar neurons were not fully defined","The direct binding interface between CEP120 and KIAA0753 lacks structural characterization"]},{"year":2021,"claim":"KIAA0753 was placed functionally upstream of SHH pathway activation: its ablation blocked ciliogenesis and SHH signaling, while patient fibroblasts confirmed blunted SHH and WNT responses, expanding the gene's role beyond structural ciliogenesis to morphogenetic signal transduction.","evidence":"siRNA/shRNA knockdown, SHH pathway reporter assays, patient fibroblast functional assays","pmids":["34523780"],"confidence":"Medium","gaps":["Whether SHH signaling defects are entirely secondary to cilia loss or involve a cilia-independent function was not distinguished","WNT pathway connection was noted but mechanistic detail was absent","Single-lab finding without independent replication"]},{"year":2024,"claim":"The mechanism of Hedgehog pathway activation was deepened: KIAA0753 directly interacts with SHH and Gli2, protects Gli2 from ubiquitination, and promotes osteoblast differentiation — revealing a direct signaling role beyond its structural cilia function.","evidence":"Co-IP for SHH/Gli2 interactions, shRNA knockdown, overexpression rescue, immunoblotting for differentiation markers","pmids":["39245790"],"confidence":"Medium","gaps":["The direct interaction with SHH (a secreted ligand) at the molecular level is unusual and awaits independent confirmation","Whether Gli2 protection from ubiquitination occurs at cilia or in the cytoplasm is unresolved","Relevance to skeletal ciliopathy phenotypes in patients has not been tested in vivo"]},{"year":2025,"claim":"A post-translational regulatory mechanism was uncovered: UFL1-mediated UFMylation of KIAA0753 controls its protein stability and centrosomal localization, revealing how KIAA0753 levels are tuned — though this regulation is cell-type-specific.","evidence":"Co-IP, immunoblotting, RT-qPCR, and immunofluorescence in HeLa and RPE1 cells","pmids":["40059580"],"confidence":"Medium","gaps":["The UFMylation site(s) on KIAA0753 have not been mapped","Functional consequences for ciliogenesis upon blocking UFMylation are not established","Cell-type specificity (HeLa vs. RPE1) is unexplained"]},{"year":null,"claim":"Key open questions include: the atomic structure of the DISCO complex and how it templates appendage assembly at the distal centriole; whether KIAA0753's direct SHH/Gli2 interactions represent a cilia-independent signaling function; and how UFMylation and CEP120-mediated recruitment are coordinated to regulate KIAA0753 at the centrosome.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of the DISCO complex or KIAA0753 exists","Cilia-dependent versus cilia-independent signaling roles have not been genetically separated","Integration of UFMylation with CEP120-dependent recruitment is unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3,6]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,4,5]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,3,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2]}],"complexes":["DISCO complex (MNR/CEP90–FOR20–OFD1)"],"partners":["OFD1","FOR20","CEP120","UFL1","GLI2","SHH","C2CD3"],"other_free_text":[]},"mechanistic_narrative":"KIAA0753 (also called OFIP, MNR, or CEP90) is a centrosomal and pericentriolar satellite protein essential for primary ciliogenesis, centriole appendage assembly, and Hedgehog signaling. It forms a ternary complex with FOR20 and OFD1 (the DISCO complex) that is recruited to centrioles via CEP120, and interdependent localization of all three components is required for proper centrosome organization and microtubule stabilization [PMID:26643951, PMID:34711653]. KIAA0753 activates the Hedgehog/SHH signaling pathway by directly interacting with SHH and Gli2 and by protecting Gli2 from ubiquitin-mediated degradation, thereby linking cilia structure to downstream morphogenetic signaling [PMID:39245790, PMID:34523780]. Loss-of-function mutations in KIAA0753 cause ciliopathies including Joubert syndrome and oral-facial-digital syndrome, with patient fibroblasts exhibiting defective ciliogenesis and blunted SHH signaling [PMID:28220259, PMID:26643951]."},"prefetch_data":{"uniprot":{"accession":"Q2KHM9","full_name":"Protein moonraker","aliases":["OFD1- and FOPNL-interacting protein"],"length_aa":967,"mass_kda":109.4,"function":"Involved in centriole duplication (PubMed:24613305, PubMed:26297806). Positively regulates CEP63 centrosomal localization (PubMed:24613305, PubMed:26297806). Required for WDR62 centrosomal localization and promotes the centrosomal localization of CDK2 (PubMed:24613305, PubMed:26297806). May play a role in cilium assembly","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q2KHM9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KIAA0753","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KIAA0753","total_profiled":1310},"omim":[{"mim_id":"619479","title":"SHORT-RIB THORACIC DYSPLASIA 21 WITHOUT POLYDACTYLY; SRTD21","url":"https://www.omim.org/entry/619479"},{"mim_id":"619476","title":"JOUBERT SYNDROME 38; JBTS38","url":"https://www.omim.org/entry/619476"},{"mim_id":"617149","title":"CENTROSOMAL PROTEIN 20; CEP20","url":"https://www.omim.org/entry/617149"},{"mim_id":"617147","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 14; CCDC14","url":"https://www.omim.org/entry/617147"},{"mim_id":"617127","title":"OROFACIODIGITAL SYNDROME XV; OFD15","url":"https://www.omim.org/entry/617127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KIAA0753"},"hgnc":{"alias_symbol":["OFIP","MNR"],"prev_symbol":[]},"alphafold":{"accession":"Q2KHM9","domains":[{"cath_id":"1.20.1420","chopping":"209-379","consensus_level":"medium","plddt":81.4243,"start":209,"end":379},{"cath_id":"1.10.287","chopping":"925-967","consensus_level":"medium","plddt":88.5407,"start":925,"end":967}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2KHM9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2KHM9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2KHM9-F1-predicted_aligned_error_v6.png","plddt_mean":58.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KIAA0753","jax_strain_url":"https://www.jax.org/strain/search?query=KIAA0753"},"sequence":{"accession":"Q2KHM9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2KHM9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2KHM9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2KHM9"}},"corpus_meta":[{"pmid":"26643951","id":"PMC_26643951","title":"OFIP/KIAA0753 forms a complex with OFD1 and FOR20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral-facial-digital syndrome.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26643951","citation_count":39,"is_preprint":false},{"pmid":"28220259","id":"PMC_28220259","title":"Mutations in KIAA0753 cause Joubert syndrome associated with growth hormone deficiency.","date":"2017","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28220259","citation_count":29,"is_preprint":false},{"pmid":"29138412","id":"PMC_29138412","title":"Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29138412","citation_count":27,"is_preprint":false},{"pmid":"11328955","id":"PMC_11328955","title":"Hypoxia in fetal lambs: a study with (1)H-MNR spectroscopy of cerebrospinal fluid.","date":"2001","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/11328955","citation_count":17,"is_preprint":false},{"pmid":"366023","id":"PMC_366023","title":"Comparison of the haplotypes of the major histocompatibility complex in the rat. 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Two difficult haplotypes: H-1h (Ag-B12) in the HW strain and Ag-B13 (H-1m) in the MNR/N strain.","date":"1978","source":"Journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/366023","citation_count":16,"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":"31816441","id":"PMC_31816441","title":"A new case of KIAA0753-related variant of Jeune asphyxiating thoracic dystrophy.","date":"2019","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31816441","citation_count":7,"is_preprint":false},{"pmid":"34523780","id":"PMC_34523780","title":"Genetic and phenotypic heterogeneity in KIAA0753-related ciliopathies.","date":"2021","source":"American journal of medical genetics. 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Additionally, KIAA0753/OFIP possesses microtubule-stabilizing activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, siRNA knockdown in RPE1 cells, microtubule stabilization assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, functional knockdown with defined cellular phenotype, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"26643951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"OFD syndrome-associated KIAA0753/OFIP mutants lose their capacity to interact with FOR20 and OFD1, identifying disruption of this complex as the molecular basis of the ciliopathy defect.\",\n      \"method\": \"Co-immunoprecipitation with disease-associated mutant proteins\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with mutant protein, single lab, moderate evidence\",\n      \"pmids\": [\"26643951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KIAA0753 mutations in Joubert syndrome patients cause defective ciliogenesis in patient-derived fibroblasts, establishing its requirement for primary cilia formation.\",\n      \"method\": \"Immunofluorescence-based ciliogenesis assay in patient fibroblasts\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in patient cells with defined cellular phenotype, single lab\",\n      \"pmids\": [\"28220259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CEP120 directly recruits KIAA0753 to centrioles; loss of this interaction causes accumulation of granule neuron progenitors in the cerebellar germinal zone and impairs neuronal differentiation. Rescue with wild-type CEP120 restores normal differentiation, while JS-associated CEP120 mutants that cannot recruit KIAA0753 fail to rescue.\",\n      \"method\": \"Co-immunoprecipitation, in vivo loss-of-function (Cep120 depletion) with rescue by wild-type and JS-mutant CEP120, immunofluorescence in developing mouse cerebellum\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic rescue with mutagenesis, in vivo epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"34711653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ablation of KIAA0753 in vitro blocks primary ciliogenesis and impairs Sonic Hedgehog (SHH) pathway activity; patient fibroblasts with KIAA0753 variants show deficits in primary ciliation and blunted SHH and WNT signaling responses.\",\n      \"method\": \"siRNA/shRNA knockdown, ciliogenesis assay, SHH pathway reporter assay, patient fibroblast functional assays\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KD with defined cellular phenotype and pathway readout, replicated in patient cells\",\n      \"pmids\": [\"34523780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KIAA0753 promotes osteoblast differentiation by directly interacting with SHH, OCN, and Gli2, activating the Hedgehog signaling pathway and mitigating ubiquitination of Gli2; knockdown shortens primary cilia while overexpression rescues cilia length and osteoblast differentiation markers.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, overexpression rescue, immunoblotting for differentiation markers (OCN, OPN, ALP, Gli2)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP for interaction, KD/OE with defined phenotype, single lab\",\n      \"pmids\": [\"39245790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIAA0753/OFIP undergoes UFMylation catalyzed by the E3 ligase UFL1; UFL1 interacts with OFIP in vivo and in vitro, and UFL1-mediated UFMylation inhibits OFIP protein stability and maintains its proper centrosomal localization in HeLa cells (but not RPE1 cells, revealing cell-type-specific regulation).\",\n      \"method\": \"Co-immunoprecipitation, immunoblotting, RT-qPCR, immunofluorescence microscopy\",\n      \"journal\": \"Journal of clinical laboratory analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP for interaction and modification, functional localization assay, single lab with multiple methods\",\n      \"pmids\": [\"40059580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KIAA0753/OFIP (as MNR/CEP90) is part of the DISCO complex (MNR/CEP90/OFD1) that marks future appendage sites at the distal centriole; C2CD3 directly interacts with MNR and is required for DISCO complex recruitment, placing KIAA0753 within the C2CD3-dependent in-to-out architectural hub that scaffolds distal centriole appendage assembly.\",\n      \"method\": \"Ultrastructure Expansion Microscopy (U-ExM), cryo-electron tomography, C2CD3 depletion with immunofluorescence readout for DISCO complex recruitment\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — structural methods (cryo-ET, U-ExM) plus functional depletion, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.17.660204\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KIAA0753/OFIP is a centrosomal and pericentriolar satellite protein that is recruited to centrioles by CEP120, forms a ternary complex with FOR20 and OFD1 (as part of the DISCO complex), stabilizes microtubules, promotes primary ciliogenesis, activates Hedgehog/SHH signaling (including direct interaction with SHH and Gli2), and is regulated by UFL1-mediated UFMylation that controls its stability and centrosomal localization; loss-of-function mutations in KIAA0753 disrupt ciliogenesis and cause ciliopathies including Joubert syndrome, OFD syndrome, and skeletal dysplasias.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KIAA0753 (also called OFIP, MNR, or CEP90) is a centrosomal and pericentriolar satellite protein essential for primary ciliogenesis, centriole appendage assembly, and Hedgehog signaling. It forms a ternary complex with FOR20 and OFD1 (the DISCO complex) that is recruited to centrioles via CEP120, and interdependent localization of all three components is required for proper centrosome organization and microtubule stabilization [PMID:26643951, PMID:34711653]. KIAA0753 activates the Hedgehog/SHH signaling pathway by directly interacting with SHH and Gli2 and by protecting Gli2 from ubiquitin-mediated degradation, thereby linking cilia structure to downstream morphogenetic signaling [PMID:39245790, PMID:34523780]. Loss-of-function mutations in KIAA0753 cause ciliopathies including Joubert syndrome and oral-facial-digital syndrome, with patient fibroblasts exhibiting defective ciliogenesis and blunted SHH signaling [PMID:28220259, PMID:26643951].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that KIAA0753 is a centrosomal/pericentriolar satellite protein that forms an obligate ternary complex with FOR20 and OFD1, where each subunit is required for the others' recruitment — this defined its core molecular context and revealed its microtubule-stabilizing activity.\",\n      \"evidence\": \"Reciprocal Co-IP, immunofluorescence, siRNA knockdown, and microtubule stabilization assays in RPE1 cells\",\n      \"pmids\": [\"26643951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the ternary complex is unknown\",\n        \"How microtubule stabilization by KIAA0753 mechanistically supports ciliogenesis is undefined\",\n        \"Upstream signals controlling complex assembly were not identified\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Disease-associated KIAA0753 mutations disrupt FOR20 and OFD1 interaction, linking OFD syndrome molecular pathology directly to ternary complex disruption.\",\n      \"evidence\": \"Co-IP with OFD syndrome-associated mutant KIAA0753 proteins\",\n      \"pmids\": [\"26643951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Limited to a single lab's Co-IP data without in vivo disease model validation\",\n        \"Precise structural determinants of the interaction loss are unmapped\",\n        \"Whether partial complex disruption yields graded phenotypes is untested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Patient-derived evidence confirmed KIAA0753 as a bona fide ciliogenesis gene: Joubert syndrome patients carrying KIAA0753 mutations showed defective primary cilia formation in fibroblasts, bridging the molecular complex function to a human ciliopathy.\",\n      \"evidence\": \"Immunofluorescence-based ciliogenesis assay in Joubert syndrome patient fibroblasts\",\n      \"pmids\": [\"28220259\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No rescue experiment was performed in patient cells\",\n        \"Animal model phenocopying the Joubert syndrome mutations was not generated\",\n        \"Whether cilia initiation versus elongation is the affected step was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CEP120 was identified as the upstream recruiter of KIAA0753 to centrioles, and this interaction was shown to be essential for cerebellar granule neuron differentiation in vivo — establishing the recruitment hierarchy and connecting it to neurodevelopment.\",\n      \"evidence\": \"Co-IP, in vivo Cep120 depletion and rescue with WT versus JS-mutant CEP120 in developing mouse cerebellum\",\n      \"pmids\": [\"34711653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CEP120 recruits the entire KIAA0753–FOR20–OFD1 complex or KIAA0753 alone is unclear\",\n        \"Downstream signaling pathways affected in cerebellar neurons were not fully defined\",\n        \"The direct binding interface between CEP120 and KIAA0753 lacks structural characterization\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"KIAA0753 was placed functionally upstream of SHH pathway activation: its ablation blocked ciliogenesis and SHH signaling, while patient fibroblasts confirmed blunted SHH and WNT responses, expanding the gene's role beyond structural ciliogenesis to morphogenetic signal transduction.\",\n      \"evidence\": \"siRNA/shRNA knockdown, SHH pathway reporter assays, patient fibroblast functional assays\",\n      \"pmids\": [\"34523780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SHH signaling defects are entirely secondary to cilia loss or involve a cilia-independent function was not distinguished\",\n        \"WNT pathway connection was noted but mechanistic detail was absent\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The mechanism of Hedgehog pathway activation was deepened: KIAA0753 directly interacts with SHH and Gli2, protects Gli2 from ubiquitination, and promotes osteoblast differentiation — revealing a direct signaling role beyond its structural cilia function.\",\n      \"evidence\": \"Co-IP for SHH/Gli2 interactions, shRNA knockdown, overexpression rescue, immunoblotting for differentiation markers\",\n      \"pmids\": [\"39245790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The direct interaction with SHH (a secreted ligand) at the molecular level is unusual and awaits independent confirmation\",\n        \"Whether Gli2 protection from ubiquitination occurs at cilia or in the cytoplasm is unresolved\",\n        \"Relevance to skeletal ciliopathy phenotypes in patients has not been tested in vivo\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A post-translational regulatory mechanism was uncovered: UFL1-mediated UFMylation of KIAA0753 controls its protein stability and centrosomal localization, revealing how KIAA0753 levels are tuned — though this regulation is cell-type-specific.\",\n      \"evidence\": \"Co-IP, immunoblotting, RT-qPCR, and immunofluorescence in HeLa and RPE1 cells\",\n      \"pmids\": [\"40059580\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The UFMylation site(s) on KIAA0753 have not been mapped\",\n        \"Functional consequences for ciliogenesis upon blocking UFMylation are not established\",\n        \"Cell-type specificity (HeLa vs. RPE1) is unexplained\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the atomic structure of the DISCO complex and how it templates appendage assembly at the distal centriole; whether KIAA0753's direct SHH/Gli2 interactions represent a cilia-independent signaling function; and how UFMylation and CEP120-mediated recruitment are coordinated to regulate KIAA0753 at the centrosome.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No high-resolution structure of the DISCO complex or KIAA0753 exists\",\n        \"Cilia-dependent versus cilia-independent signaling roles have not been genetically separated\",\n        \"Integration of UFMylation with CEP120-dependent recruitment is unexplored\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 3, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"DISCO complex (MNR/CEP90–FOR20–OFD1)\"\n    ],\n    \"partners\": [\n      \"OFD1\",\n      \"FOR20\",\n      \"CEP120\",\n      \"UFL1\",\n      \"GLI2\",\n      \"SHH\",\n      \"C2CD3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}