{"gene":"OFD1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2004,"finding":"OFD1 protein is a core component of the human centrosome throughout the cell cycle, requiring coiled-coil domains (not the N-terminal LisH domain) for centrosomal targeting. During epithelial differentiation, OFD1 localizes to basal bodies at the origin of primary cilia.","method":"GFP-OFD1 deletion constructs, immunofluorescence, biochemical fractionation, overexpression in cell lines","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (deletion constructs, immunofluorescence, fractionation) with functional domain mapping","pmids":["15466260"],"is_preprint":false},{"year":2007,"finding":"OFD1 localizes to both the primary cilium and the nucleus, can self-associate via its coiled-coil-rich region, and interacts with RuvBl1 (an AAA+ ATPase). OFD1 together with RuvBl1 co-immunoprecipitates with subunits of the TIP60 histone acetyltransferase (HAT) multisubunit complex.","method":"Co-immunoprecipitation, immunofluorescence, yeast two-hybrid, subcellular fractionation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP and multiple orthogonal methods establishing binding partners and localization","pmids":["17761535"],"is_preprint":false},{"year":2009,"finding":"OFD1 interacts with LCA5-encoded lebercilin (identified by yeast two-hybrid screen of retinal cDNA library). X-linked dominant OFD1 mutations abolish lebercilin binding and cause loss of pericentriolar localization, while X-linked recessive mutations reduce but do not eliminate interaction and do not affect pericentriolar localization.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence in hTERT-RPE1 cells","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid plus cellular validation with multiple mutation classes providing mechanistic distinction","pmids":["19800048"],"is_preprint":false},{"year":2010,"finding":"Ofd1 is a component of the distal centriole that controls centriole length by stabilizing distal centriolar microtubules with normal posttranslational modifications, and is required for centriole distal appendage formation and centriolar recruitment of the intraflagellar transport protein Ift88.","method":"Mouse knockout, electron microscopy, immunofluorescence, missense allele knock-in from human OFD1 patients in embryonic stem cells","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 — loss-of-function genetics with ultrastructural analysis and patient allele reconstitution, replicated across multiple alleles","pmids":["20230748"],"is_preprint":false},{"year":2010,"finding":"Kidney-specific inactivation of Ofd1 leads to renal cystic disease with upregulation of the mTOR pathway. Primary cilia initially form and then disappear after cyst development, and rapamycin treatment significantly reduces cyst number and size.","method":"Conditional Ksp-Cre knockout mouse, immunofluorescence, western blotting, rapamycin pharmacological treatment","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with defined phenotypic readout, pathway identification confirmed by pharmacological rescue","pmids":["20444807"],"is_preprint":false},{"year":2013,"finding":"The population of OFD1 at centriolar satellites is rapidly degraded by autophagy upon serum starvation, promoting primary cilium biogenesis. In autophagy-deficient cells (Atg5 or Atg3 null), OFD1 accumulates at centriolar satellites, resulting in fewer and shorter primary cilia and defective BBS4 recruitment to cilia. OFD1 partial knockdown rescues ciliogenesis defects in autophagy-deficient cells.","method":"Autophagy-deficient mouse embryonic fibroblasts (Atg5/Atg3 null), serum starvation, siRNA knockdown, immunofluorescence, Western blotting","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with specific phenotype, epistasis confirmed by rescue experiment, highly cited","pmids":["24089205"],"is_preprint":false},{"year":2014,"finding":"OFD1 is assembled into a protein complex at the primary cilium that includes EGFR, flotillin proteins, polycystin-1, and polycystin-2. In ADPKD cells where mutant polycystin-1 fails to localize to cilia, OFD1, polycystin-2, EGFR, and flotillin-1 all concomitantly lose ciliary localization, indicating polycystins are required for assembly of this OFD1-containing ciliary signaling complex.","method":"Co-immunoprecipitation, immunofluorescence in renal epithelial cells and ADPKD patient cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with functional context from disease cells, single lab","pmids":["25180832"],"is_preprint":false},{"year":2015,"finding":"OFD1 forms a ternary complex with KIAA0753/OFIP and FOR20 at pericentriolar satellites and centrosomes. Decreased expression of any component of this complex causes defective recruitment of the others to centrosomes and satellites.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown in RPE1 cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP and reciprocal localization rescue, single lab","pmids":["26643951"],"is_preprint":false},{"year":2016,"finding":"Ofd1 plays a crucial role in forebrain development and dorso-ventral patterning through control of Sonic hedgehog (Shh) signaling. Early Ofd1 inactivation results in absence of ciliary axonemes despite presence of mature, correctly oriented and docked basal bodies, indicating Ofd1 functions after basal body docking and before axoneme elaboration.","method":"Conditional mouse knockout, immunofluorescence, ultrastructural electron microscopy, Shh pathway reporter analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO with ultrastructural analysis precisely positioning OFD1 in the ciliogenesis pathway","pmids":["23300826"],"is_preprint":false},{"year":2017,"finding":"OFD1 interacts with components of the Preinitiation complex of translation (PIC) and eIF4F complex, and cooperates with the mRNA binding protein Bicc1 to modulate translation of specific mRNA targets at the centrosome. PIC and eIF4F components also localize to the centrosome in mammalian cells.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, polysome profiling, translation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with MS and functional translation assays, single lab","pmids":["28450740"],"is_preprint":false},{"year":2017,"finding":"OFD1 can localize to chromatin, and its reduced expression causes mis-localization of TIP60. Loss of OFD1 impairs DNA double-strand break repair via homologous recombination (HRR) and adversely impacts the DSB-induced G2-M checkpoint, phenocopying TIP60 loss. OFD1-deficient cells show reduced histone acetylation.","method":"Patient-derived cell lines, siRNA knockdown, chromatin immunoprecipitation, DSB repair assays (HRR reporter), immunofluorescence, cell cycle analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays (HRR reporter, ChIP, cell cycle) in patient cells and knockdown model","pmids":["27798113"],"is_preprint":false},{"year":2017,"finding":"In Paramecium, OFD1 is recruited early during basal body assembly, localizes at the transition zone between axoneme and membrane at the level of microtubule doublets, and its depletion impairs distal basal body assembly and docking. The localizations of OFD1 and FOR20 at the basal body are interdependent.","method":"RNAi depletion in Paramecium tetraurelia, immunofluorescence, electron microscopy","journal":"Cilia","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in a ciliate model organism with ultrastructural readout, consistent with mammalian OFD1 function","pmids":["28367320"],"is_preprint":false},{"year":2020,"finding":"OFD1 acts as a bona fide selective autophagy receptor for ATG13 (a component of the ULK1 autophagy initiation complex) via direct interaction with the Atg8/LC3/GABARAP family of proteins. This OFD1-mediated selective degradation of ATG13 constitutes a negative feedback mechanism limiting autophagosome biogenesis. Genetic inhibition of autophagy in an Ofd1 mouse model significantly ameliorates polycystic kidney disease.","method":"Co-immunoprecipitation, in vitro binding assays, LC3-interaction domain mutagenesis, conditional mouse model, autophagy flux assays, patient cell analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assay with mutagenesis, in vivo rescue experiment, multiple orthogonal methods","pmids":["33368531"],"is_preprint":false},{"year":2020,"finding":"OFD1 displays a dynamic distribution during the cell cycle, and Ofd1-depleted fibroblasts exhibit impaired cell cycle progression, centrosome accumulation, nuclear abnormalities, aneuploidy, and an abnormal microtubule network, indicating OFD1 contributes to MTOC function and cell cycle control.","method":"Immunofluorescence, high-content microscopy, siRNA knockdown, cell proliferation assays","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with specific phenotypic readouts but no pathway placement beyond MTOC","pmids":["32473706"],"is_preprint":false},{"year":2020,"finding":"TRAPPC8 and TRAPPC12 (TRAPPIII-specific subunits) interact with OFD1. TRAPPC8 is necessary for association of OFD1 with PCM1 at centriolar satellites. The TRAPPC8-OFD1 interaction inhibits the OFD1-TRAPPC12 interaction, and TRAPPC12 is required for cilia disassembly.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence in hTERT-RPE1 cells","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with competitive interaction data and KD phenotypes, single lab","pmids":["32258032"],"is_preprint":false},{"year":2021,"finding":"TBC1D31 assembles a centrosomal complex containing praja2 (E3 ubiquitin ligase), PKA, and OFD1. Upon GPCR-cAMP stimulation, PKA phosphorylates OFD1 at Ser735, promoting OFD1 proteolysis through the praja2-ubiquitin-proteasome system (UPS). This pathway is required for ciliogenesis; a non-phosphorylatable OFD1-S735A mutant dramatically impairs cilium morphology.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (S735A), ubiquitylation assay, immunofluorescence, in vivo Medaka fish model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay, phosphorylation-site mutagenesis, UPS assay, and in vivo validation in Medaka","pmids":["33934390"],"is_preprint":false},{"year":2021,"finding":"Myosin VI interacts with OFD1 and regulates OFD1 localization at centrioles; myosin VI depletion causes aberrant OFD1 distribution along centriolar walls due to a reduction in the OFD1 mobile fraction, impairs Cep164 (distal appendage protein) recruitment, and causes severe ciliogenesis defects partly through impairment of autophagic removal of OFD1 from satellites.","method":"Co-immunoprecipitation, FRAP, immunofluorescence, siRNA knockdown, live imaging","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 — Co-IP, FRAP measuring mobility, KD with defined phenotypes across multiple readouts","pmids":["34957672"],"is_preprint":false},{"year":2022,"finding":"CEP90, FOPNL, and OFD1 form an evolutionarily conserved functional module (DISCO complex) that localizes at the distal end of centrioles/basal bodies. OFD1 is recruited to procentrioles early during centriole duplication and is required for distal appendage assembly and basal body docking, downstream of MNR.","method":"Ultrastructure expansion microscopy (U-ExM), immunofluorescence, siRNA knockdown, functional rescue in mammalian cells and Paramecium","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 — U-ExM structural localization, functional knockdown in two model systems, epistasis establishing MNR→OFD1 hierarchy","pmids":["36070319"],"is_preprint":false},{"year":2023,"finding":"OFD1 (residues 601-1012) interacts with paxillin independently of its ciliogenic function (residues 1-601). OFD1 knockdown reduces paxillin expression, inhibits melanocyte adhesion to ECM, and induces melanocyte apoptosis; this phenotype is not reproduced by IFT88 or RPGRIP1L knockdown and is rescued by paxillin overexpression.","method":"siRNA knockdown, domain-mapping co-immunoprecipitation, overexpression rescue, adhesion assays, apoptosis assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain-mapping Co-IP, rescue experiment, but single lab single study","pmids":["38139355"],"is_preprint":false},{"year":2025,"finding":"OFD1 interacts with E2F4 in the cytosol to prevent assembly of the transcriptional repressor DREAM complex at the BRCA1 promoter. OFD1 depletion promotes E2F4 nuclear translocation and DREAM complex formation, suppressing BRCA1 expression and causing homologous recombination repair deficiency (BRCAness), conferring sensitivity to PARP inhibitors.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, nuclear fractionation, HRR reporter assays, xenograft mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal mechanistic methods (Co-IP, ChIP, fractionation, functional HRR assay) plus in vivo validation","pmids":["40764600"],"is_preprint":false},{"year":2025,"finding":"CCHCR1 interacts with OFD1 via its C-terminal coiled-coil domain, and the centrosomal localization of CCHCR1 is determined by OFD1 and PCM1. CCHCR1 also recruits P-body proteins (via EDC4) to the centrosome and is required for ciliogenesis.","method":"BioID mass spectrometry, co-immunoprecipitation, GST pull-down, AB-FRET, siRNA knockdown, CRISPR-Cas9 knockout, immunofluorescence","journal":"Cellular & molecular biology letters","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal interaction methods (BioID, Co-IP, GST pull-down, FRET) with functional KO/KD readouts","pmids":["40883668"],"is_preprint":false}],"current_model":"OFD1 is a multifunctional centrosomal/basal body scaffold protein that (1) controls distal centriole length, microtubule stability, distal appendage formation, and axoneme elaboration downstream of basal body docking; (2) is regulated at centriolar satellites by autophagy (via LC3/GABARAP interaction) and by PKA-dependent phosphorylation at Ser735 followed by praja2-UPS-mediated proteolysis, both of which are required for ciliogenesis; (3) acts as a selective autophagy receptor for ATG13, providing negative feedback on autophagosome biogenesis; (4) interacts with the TIP60 histone acetyltransferase complex and localizes to chromatin to support DNA double-strand break repair via homologous recombination; (5) interacts with translation initiation factors (PIC/eIF4F) at the centrosome to regulate local mRNA translation; and (6) sequesters E2F4 in the cytosol to prevent DREAM complex assembly and maintain BRCA1 transcription."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that OFD1 is a constitutive centrosomal protein resolved its subcellular site of action and showed that coiled-coil domains, not the LisH domain, mediate centrosomal targeting.","evidence":"GFP-deletion constructs, immunofluorescence, and biochemical fractionation in cell lines","pmids":["15466260"],"confidence":"High","gaps":["Centrosomal function of OFD1 not yet defined","Mechanism of coiled-coil-mediated targeting unresolved"]},{"year":2007,"claim":"Identifying OFD1 self-association and its interaction with RuvBl1 within the TIP60 HAT complex revealed a previously unsuspected nuclear/chromatin function beyond centrosome biology.","evidence":"Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation","pmids":["17761535"],"confidence":"High","gaps":["Functional consequence of TIP60 complex association unknown","Relative importance of nuclear vs. centrosomal OFD1 pools unclear"]},{"year":2010,"claim":"Mouse knockout and ultrastructural analysis established that OFD1 controls distal centriole length, microtubule stability, and distal appendage formation, placing it as a structural organizer of the distal centriole required for IFT88 recruitment and ciliogenesis.","evidence":"Ofd1 knockout mice, electron microscopy, patient missense allele knock-in in ES cells","pmids":["20230748"],"confidence":"High","gaps":["Whether OFD1 acts as a scaffold or an enzymatic regulator at centrioles unknown","Protein partners at the distal centriole not identified"]},{"year":2010,"claim":"Kidney-specific Ofd1 knockout revealed that loss of OFD1 causes renal cystic disease with mTOR upregulation, and rapamycin rescue demonstrated pathway-level disease mechanism.","evidence":"Conditional Ksp-Cre knockout mouse, rapamycin treatment","pmids":["20444807"],"confidence":"High","gaps":["How OFD1 loss activates mTOR not determined","Whether cilia loss or a cilia-independent function drives mTOR activation unclear"]},{"year":2013,"claim":"The discovery that autophagy selectively degrades the centriolar satellite pool of OFD1 to promote ciliogenesis established autophagy as a direct regulator of cilium biogenesis and identified OFD1 as the key substrate linking these two processes.","evidence":"Atg5/Atg3-null MEFs, serum starvation, OFD1 knockdown rescue of ciliogenesis","pmids":["24089205"],"confidence":"High","gaps":["Autophagy receptor mediating OFD1 satellite clearance not identified","Whether centriolar and satellite OFD1 pools are functionally distinct unknown"]},{"year":2016,"claim":"Conditional brain knockout demonstrated OFD1 is required for axoneme elaboration after basal body docking and maturation, precisely positioning its function in the ciliogenesis pathway and linking it to Shh-dependent forebrain patterning.","evidence":"Conditional mouse knockout, electron microscopy, Shh reporter","pmids":["23300826"],"confidence":"High","gaps":["Molecular mechanism by which OFD1 enables axoneme extension unknown","Whether OFD1 directly participates in transition zone assembly unclear"]},{"year":2017,"claim":"Demonstrating that OFD1 localizes to chromatin and is required for TIP60-dependent histone acetylation, homologous recombination repair, and the G2-M DNA damage checkpoint established a cilia-independent genome maintenance role for OFD1.","evidence":"Patient-derived cells, siRNA, ChIP, HRR reporter, cell cycle analysis","pmids":["27798113"],"confidence":"High","gaps":["How OFD1 recruits or stabilizes TIP60 on chromatin not defined","Whether DNA repair defects contribute to OFD1-associated disease phenotypes unknown"]},{"year":2017,"claim":"Interaction of OFD1 with translation initiation complexes (PIC/eIF4F) at the centrosome suggested a role in local mRNA translation control, expanding OFD1 function beyond structural scaffolding.","evidence":"Co-IP, mass spectrometry, polysome profiling","pmids":["28450740"],"confidence":"Medium","gaps":["Specific mRNA targets regulated by OFD1-dependent translation not comprehensively identified","In vivo relevance of centrosomal translation regulation not demonstrated"]},{"year":2020,"claim":"Identification of OFD1 as a selective autophagy receptor for ATG13 via LC3/GABARAP interaction revealed a negative feedback loop limiting autophagosome biogenesis, and genetic inhibition of autophagy ameliorated Ofd1-associated polycystic kidney disease in mice.","evidence":"In vitro binding, LIR mutagenesis, conditional mouse model, autophagy flux assays","pmids":["33368531"],"confidence":"High","gaps":["Structural basis of OFD1-ATG13 recognition unknown","Whether OFD1 autophagy receptor function operates in all tissues or is context-specific"]},{"year":2021,"claim":"Discovery that PKA phosphorylates OFD1 at Ser735 downstream of GPCR-cAMP signaling, promoting praja2-mediated proteasomal degradation required for ciliogenesis, established a UPS-dependent regulatory axis complementary to autophagic control of OFD1 levels.","evidence":"In vitro kinase assay, S735A mutagenesis, ubiquitylation assay, Medaka fish model","pmids":["33934390"],"confidence":"High","gaps":["How UPS and autophagy pathways are coordinated for OFD1 turnover unclear","Whether additional phosphorylation sites regulate OFD1 stability unknown"]},{"year":2022,"claim":"Identification of the DISCO complex (CEP90-FOPNL-OFD1) by expansion microscopy resolved OFD1's structural position at the distal centriole and placed it downstream of MNR in distal appendage assembly hierarchy.","evidence":"U-ExM, siRNA, functional rescue in mammalian cells and Paramecium","pmids":["36070319"],"confidence":"High","gaps":["Atomic-resolution structure of the DISCO complex not available","How MNR recruits OFD1 molecularly not defined"]},{"year":2025,"claim":"Demonstrating that OFD1 sequesters E2F4 in the cytosol to prevent DREAM complex assembly at the BRCA1 promoter revealed a mechanism connecting OFD1 loss to HR deficiency (BRCAness) and PARP inhibitor sensitivity, linking ciliopathy biology to cancer therapeutic vulnerability.","evidence":"Co-IP, ChIP, nuclear fractionation, HRR reporter, xenograft models","pmids":["40764600"],"confidence":"High","gaps":["Whether E2F4 sequestration is relevant in OFD1-mutant ciliopathy patients unknown","Full transcriptional program controlled by OFD1-E2F4 axis not mapped"]},{"year":null,"claim":"A unified structural model explaining how OFD1 integrates its centrosomal scaffold, autophagy receptor, chromatin-associated, and cytosolic sequestration functions—and how disease mutations differentially disrupt each—remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length OFD1 or its complexes","Genotype-phenotype correlations across OFD1 functional domains not systematically resolved","Relative contributions of cilia-dependent versus cilia-independent functions to disease unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,17]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[12]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[19]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,3,7,13,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,10]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[10]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,8,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[19]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[3,5,8,15,17]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[10,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,15]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[1,10]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[13]}],"complexes":["DISCO complex (CEP90-FOPNL-OFD1)","TIP60 HAT complex","OFD1-KIAA0753/OFIP-FOR20 satellite complex"],"partners":["CEP90","FOPNL","RUVBL1","KIAA0753","FOR20","E2F4","PRAJA2","MYO6"],"other_free_text":[]},"mechanistic_narrative":"OFD1 is a centrosomal and basal body scaffold protein that organizes centriole distal structures, regulates ciliogenesis, and participates in genome maintenance through chromatin-associated functions. At centrioles, OFD1 forms the evolutionarily conserved DISCO complex with CEP90 and FOPNL, controlling distal centriole length, microtubule stability, distal appendage assembly (Cep164 recruitment), and axoneme elaboration downstream of basal body docking [PMID:20230748, PMID:36070319, PMID:23300826]. The centriolar satellite pool of OFD1 is removed by autophagy upon serum starvation to permit ciliogenesis, and OFD1 itself functions as a selective autophagy receptor that targets ATG13 for degradation, providing negative feedback on autophagosome biogenesis; additionally, PKA-dependent phosphorylation at Ser735 triggers praja2-mediated proteasomal degradation of OFD1, a pathway also required for cilium formation [PMID:24089205, PMID:33368531, PMID:33934390]. Beyond cilia, OFD1 localizes to chromatin where it supports TIP60-dependent histone acetylation and homologous recombination repair of DNA double-strand breaks, and it sequesters E2F4 in the cytosol to prevent DREAM complex–mediated repression of BRCA1 transcription, thereby maintaining HR competence [PMID:27798113, PMID:40764600]."},"prefetch_data":{"uniprot":{"accession":"O75665","full_name":"Centriole and centriolar satellite protein OFD1","aliases":["Oral-facial-digital syndrome 1 protein","Protein 71-7A"],"length_aa":1012,"mass_kda":116.7,"function":"Component of the centrioles controlling mother and daughter centrioles length. Recruits to the centriole IFT88 and centriole distal appendage-specific proteins including CEP164 (By similarity). Involved in the biogenesis of the cilium, a centriole-associated function. The cilium is a cell surface projection found in many vertebrate cells required to transduce signals important for development and tissue homeostasis (PubMed:33934390). Plays an important role in development by regulating Wnt signaling and the specification of the left-right axis. Only OFD1 localized at the centriolar satellites is removed by autophagy, which is an important step in the ciliogenesis regulation (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cytoplasm, cytoskeleton, cilium basal body; Nucleus; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite","url":"https://www.uniprot.org/uniprotkb/O75665/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OFD1","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":[{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/OFD1","total_profiled":1310},"omim":[{"mim_id":"621444","title":"TBC1 DOMAIN FAMILY, MEMBER 31; TBC1D31","url":"https://www.omim.org/entry/621444"},{"mim_id":"620718","title":"OROFACIODIGITAL SYNDROME XX; OFD20","url":"https://www.omim.org/entry/620718"},{"mim_id":"619341","title":"PRAJA RING FINGER UBIQUITIN LIGASE 2; PJA2","url":"https://www.omim.org/entry/619341"},{"mim_id":"617149","title":"CENTROSOMAL PROTEIN 20; CEP20","url":"https://www.omim.org/entry/617149"},{"mim_id":"617127","title":"OROFACIODIGITAL SYNDROME XV; OFD15","url":"https://www.omim.org/entry/617127"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Microtubules","reliability":"Uncertain"},{"location":"Primary cilium","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OFD1"},"hgnc":{"alias_symbol":["71-7A","JBTS10"],"prev_symbol":["CXorf5","RP23"]},"alphafold":{"accession":"O75665","domains":[{"cath_id":"-","chopping":"67-151","consensus_level":"medium","plddt":79.9087,"start":67,"end":151},{"cath_id":"-","chopping":"248-435","consensus_level":"medium","plddt":95.9003,"start":248,"end":435},{"cath_id":"1.20.5","chopping":"20-51","consensus_level":"medium","plddt":82.4209,"start":20,"end":51}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75665","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75665-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75665-F1-predicted_aligned_error_v6.png","plddt_mean":67.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OFD1","jax_strain_url":"https://www.jax.org/strain/search?query=OFD1"},"sequence":{"accession":"O75665","fasta_url":"https://rest.uniprot.org/uniprotkb/O75665.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75665/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75665"}},"corpus_meta":[{"pmid":"24089205","id":"PMC_24089205","title":"Autophagy 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During epithelial differentiation, OFD1 localizes to basal bodies at the origin of primary cilia.\",\n      \"method\": \"GFP-OFD1 deletion constructs, immunofluorescence, biochemical fractionation, overexpression in cell lines\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (deletion constructs, immunofluorescence, fractionation) with functional domain mapping\",\n      \"pmids\": [\"15466260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"OFD1 localizes to both the primary cilium and the nucleus, can self-associate via its coiled-coil-rich region, and interacts with RuvBl1 (an AAA+ ATPase). OFD1 together with RuvBl1 co-immunoprecipitates with subunits of the TIP60 histone acetyltransferase (HAT) multisubunit complex.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, yeast two-hybrid, subcellular fractionation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and multiple orthogonal methods establishing binding partners and localization\",\n      \"pmids\": [\"17761535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OFD1 interacts with LCA5-encoded lebercilin (identified by yeast two-hybrid screen of retinal cDNA library). X-linked dominant OFD1 mutations abolish lebercilin binding and cause loss of pericentriolar localization, while X-linked recessive mutations reduce but do not eliminate interaction and do not affect pericentriolar localization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence in hTERT-RPE1 cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid plus cellular validation with multiple mutation classes providing mechanistic distinction\",\n      \"pmids\": [\"19800048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ofd1 is a component of the distal centriole that controls centriole length by stabilizing distal centriolar microtubules with normal posttranslational modifications, and is required for centriole distal appendage formation and centriolar recruitment of the intraflagellar transport protein Ift88.\",\n      \"method\": \"Mouse knockout, electron microscopy, immunofluorescence, missense allele knock-in from human OFD1 patients in embryonic stem cells\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — loss-of-function genetics with ultrastructural analysis and patient allele reconstitution, replicated across multiple alleles\",\n      \"pmids\": [\"20230748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Kidney-specific inactivation of Ofd1 leads to renal cystic disease with upregulation of the mTOR pathway. Primary cilia initially form and then disappear after cyst development, and rapamycin treatment significantly reduces cyst number and size.\",\n      \"method\": \"Conditional Ksp-Cre knockout mouse, immunofluorescence, western blotting, rapamycin pharmacological treatment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with defined phenotypic readout, pathway identification confirmed by pharmacological rescue\",\n      \"pmids\": [\"20444807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The population of OFD1 at centriolar satellites is rapidly degraded by autophagy upon serum starvation, promoting primary cilium biogenesis. In autophagy-deficient cells (Atg5 or Atg3 null), OFD1 accumulates at centriolar satellites, resulting in fewer and shorter primary cilia and defective BBS4 recruitment to cilia. OFD1 partial knockdown rescues ciliogenesis defects in autophagy-deficient cells.\",\n      \"method\": \"Autophagy-deficient mouse embryonic fibroblasts (Atg5/Atg3 null), serum starvation, siRNA knockdown, immunofluorescence, Western blotting\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with specific phenotype, epistasis confirmed by rescue experiment, highly cited\",\n      \"pmids\": [\"24089205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"OFD1 is assembled into a protein complex at the primary cilium that includes EGFR, flotillin proteins, polycystin-1, and polycystin-2. In ADPKD cells where mutant polycystin-1 fails to localize to cilia, OFD1, polycystin-2, EGFR, and flotillin-1 all concomitantly lose ciliary localization, indicating polycystins are required for assembly of this OFD1-containing ciliary signaling complex.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence in renal epithelial cells and ADPKD patient cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with functional context from disease cells, single lab\",\n      \"pmids\": [\"25180832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"OFD1 forms a ternary complex with KIAA0753/OFIP and FOR20 at pericentriolar satellites and centrosomes. Decreased expression of any component of this complex causes defective recruitment of the others to centrosomes and satellites.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown in RPE1 cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP and reciprocal localization rescue, single lab\",\n      \"pmids\": [\"26643951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ofd1 plays a crucial role in forebrain development and dorso-ventral patterning through control of Sonic hedgehog (Shh) signaling. Early Ofd1 inactivation results in absence of ciliary axonemes despite presence of mature, correctly oriented and docked basal bodies, indicating Ofd1 functions after basal body docking and before axoneme elaboration.\",\n      \"method\": \"Conditional mouse knockout, immunofluorescence, ultrastructural electron microscopy, Shh pathway reporter analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO with ultrastructural analysis precisely positioning OFD1 in the ciliogenesis pathway\",\n      \"pmids\": [\"23300826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OFD1 interacts with components of the Preinitiation complex of translation (PIC) and eIF4F complex, and cooperates with the mRNA binding protein Bicc1 to modulate translation of specific mRNA targets at the centrosome. PIC and eIF4F components also localize to the centrosome in mammalian cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, polysome profiling, translation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with MS and functional translation assays, single lab\",\n      \"pmids\": [\"28450740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OFD1 can localize to chromatin, and its reduced expression causes mis-localization of TIP60. Loss of OFD1 impairs DNA double-strand break repair via homologous recombination (HRR) and adversely impacts the DSB-induced G2-M checkpoint, phenocopying TIP60 loss. OFD1-deficient cells show reduced histone acetylation.\",\n      \"method\": \"Patient-derived cell lines, siRNA knockdown, chromatin immunoprecipitation, DSB repair assays (HRR reporter), immunofluorescence, cell cycle analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays (HRR reporter, ChIP, cell cycle) in patient cells and knockdown model\",\n      \"pmids\": [\"27798113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Paramecium, OFD1 is recruited early during basal body assembly, localizes at the transition zone between axoneme and membrane at the level of microtubule doublets, and its depletion impairs distal basal body assembly and docking. The localizations of OFD1 and FOR20 at the basal body are interdependent.\",\n      \"method\": \"RNAi depletion in Paramecium tetraurelia, immunofluorescence, electron microscopy\",\n      \"journal\": \"Cilia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in a ciliate model organism with ultrastructural readout, consistent with mammalian OFD1 function\",\n      \"pmids\": [\"28367320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OFD1 acts as a bona fide selective autophagy receptor for ATG13 (a component of the ULK1 autophagy initiation complex) via direct interaction with the Atg8/LC3/GABARAP family of proteins. This OFD1-mediated selective degradation of ATG13 constitutes a negative feedback mechanism limiting autophagosome biogenesis. Genetic inhibition of autophagy in an Ofd1 mouse model significantly ameliorates polycystic kidney disease.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assays, LC3-interaction domain mutagenesis, conditional mouse model, autophagy flux assays, patient cell analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assay with mutagenesis, in vivo rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"33368531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OFD1 displays a dynamic distribution during the cell cycle, and Ofd1-depleted fibroblasts exhibit impaired cell cycle progression, centrosome accumulation, nuclear abnormalities, aneuploidy, and an abnormal microtubule network, indicating OFD1 contributes to MTOC function and cell cycle control.\",\n      \"method\": \"Immunofluorescence, high-content microscopy, siRNA knockdown, cell proliferation assays\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with specific phenotypic readouts but no pathway placement beyond MTOC\",\n      \"pmids\": [\"32473706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRAPPC8 and TRAPPC12 (TRAPPIII-specific subunits) interact with OFD1. TRAPPC8 is necessary for association of OFD1 with PCM1 at centriolar satellites. The TRAPPC8-OFD1 interaction inhibits the OFD1-TRAPPC12 interaction, and TRAPPC12 is required for cilia disassembly.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence in hTERT-RPE1 cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with competitive interaction data and KD phenotypes, single lab\",\n      \"pmids\": [\"32258032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TBC1D31 assembles a centrosomal complex containing praja2 (E3 ubiquitin ligase), PKA, and OFD1. Upon GPCR-cAMP stimulation, PKA phosphorylates OFD1 at Ser735, promoting OFD1 proteolysis through the praja2-ubiquitin-proteasome system (UPS). This pathway is required for ciliogenesis; a non-phosphorylatable OFD1-S735A mutant dramatically impairs cilium morphology.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (S735A), ubiquitylation assay, immunofluorescence, in vivo Medaka fish model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay, phosphorylation-site mutagenesis, UPS assay, and in vivo validation in Medaka\",\n      \"pmids\": [\"33934390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Myosin VI interacts with OFD1 and regulates OFD1 localization at centrioles; myosin VI depletion causes aberrant OFD1 distribution along centriolar walls due to a reduction in the OFD1 mobile fraction, impairs Cep164 (distal appendage protein) recruitment, and causes severe ciliogenesis defects partly through impairment of autophagic removal of OFD1 from satellites.\",\n      \"method\": \"Co-immunoprecipitation, FRAP, immunofluorescence, siRNA knockdown, live imaging\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, FRAP measuring mobility, KD with defined phenotypes across multiple readouts\",\n      \"pmids\": [\"34957672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEP90, FOPNL, and OFD1 form an evolutionarily conserved functional module (DISCO complex) that localizes at the distal end of centrioles/basal bodies. OFD1 is recruited to procentrioles early during centriole duplication and is required for distal appendage assembly and basal body docking, downstream of MNR.\",\n      \"method\": \"Ultrastructure expansion microscopy (U-ExM), immunofluorescence, siRNA knockdown, functional rescue in mammalian cells and Paramecium\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — U-ExM structural localization, functional knockdown in two model systems, epistasis establishing MNR→OFD1 hierarchy\",\n      \"pmids\": [\"36070319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OFD1 (residues 601-1012) interacts with paxillin independently of its ciliogenic function (residues 1-601). OFD1 knockdown reduces paxillin expression, inhibits melanocyte adhesion to ECM, and induces melanocyte apoptosis; this phenotype is not reproduced by IFT88 or RPGRIP1L knockdown and is rescued by paxillin overexpression.\",\n      \"method\": \"siRNA knockdown, domain-mapping co-immunoprecipitation, overexpression rescue, adhesion assays, apoptosis assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain-mapping Co-IP, rescue experiment, but single lab single study\",\n      \"pmids\": [\"38139355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"OFD1 interacts with E2F4 in the cytosol to prevent assembly of the transcriptional repressor DREAM complex at the BRCA1 promoter. OFD1 depletion promotes E2F4 nuclear translocation and DREAM complex formation, suppressing BRCA1 expression and causing homologous recombination repair deficiency (BRCAness), conferring sensitivity to PARP inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, nuclear fractionation, HRR reporter assays, xenograft mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal mechanistic methods (Co-IP, ChIP, fractionation, functional HRR assay) plus in vivo validation\",\n      \"pmids\": [\"40764600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCHCR1 interacts with OFD1 via its C-terminal coiled-coil domain, and the centrosomal localization of CCHCR1 is determined by OFD1 and PCM1. CCHCR1 also recruits P-body proteins (via EDC4) to the centrosome and is required for ciliogenesis.\",\n      \"method\": \"BioID mass spectrometry, co-immunoprecipitation, GST pull-down, AB-FRET, siRNA knockdown, CRISPR-Cas9 knockout, immunofluorescence\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal interaction methods (BioID, Co-IP, GST pull-down, FRET) with functional KO/KD readouts\",\n      \"pmids\": [\"40883668\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OFD1 is a multifunctional centrosomal/basal body scaffold protein that (1) controls distal centriole length, microtubule stability, distal appendage formation, and axoneme elaboration downstream of basal body docking; (2) is regulated at centriolar satellites by autophagy (via LC3/GABARAP interaction) and by PKA-dependent phosphorylation at Ser735 followed by praja2-UPS-mediated proteolysis, both of which are required for ciliogenesis; (3) acts as a selective autophagy receptor for ATG13, providing negative feedback on autophagosome biogenesis; (4) interacts with the TIP60 histone acetyltransferase complex and localizes to chromatin to support DNA double-strand break repair via homologous recombination; (5) interacts with translation initiation factors (PIC/eIF4F) at the centrosome to regulate local mRNA translation; and (6) sequesters E2F4 in the cytosol to prevent DREAM complex assembly and maintain BRCA1 transcription.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OFD1 is a centrosomal and basal body scaffold protein that organizes centriole distal structures, regulates ciliogenesis, and participates in genome maintenance through chromatin-associated functions. At centrioles, OFD1 forms the evolutionarily conserved DISCO complex with CEP90 and FOPNL, controlling distal centriole length, microtubule stability, distal appendage assembly (Cep164 recruitment), and axoneme elaboration downstream of basal body docking [PMID:20230748, PMID:36070319, PMID:23300826]. The centriolar satellite pool of OFD1 is removed by autophagy upon serum starvation to permit ciliogenesis, and OFD1 itself functions as a selective autophagy receptor that targets ATG13 for degradation, providing negative feedback on autophagosome biogenesis; additionally, PKA-dependent phosphorylation at Ser735 triggers praja2-mediated proteasomal degradation of OFD1, a pathway also required for cilium formation [PMID:24089205, PMID:33368531, PMID:33934390]. Beyond cilia, OFD1 localizes to chromatin where it supports TIP60-dependent histone acetylation and homologous recombination repair of DNA double-strand breaks, and it sequesters E2F4 in the cytosol to prevent DREAM complex–mediated repression of BRCA1 transcription, thereby maintaining HR competence [PMID:27798113, PMID:40764600].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that OFD1 is a constitutive centrosomal protein resolved its subcellular site of action and showed that coiled-coil domains, not the LisH domain, mediate centrosomal targeting.\",\n      \"evidence\": \"GFP-deletion constructs, immunofluorescence, and biochemical fractionation in cell lines\",\n      \"pmids\": [\"15466260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Centrosomal function of OFD1 not yet defined\", \"Mechanism of coiled-coil-mediated targeting unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying OFD1 self-association and its interaction with RuvBl1 within the TIP60 HAT complex revealed a previously unsuspected nuclear/chromatin function beyond centrosome biology.\",\n      \"evidence\": \"Co-immunoprecipitation, yeast two-hybrid, subcellular fractionation\",\n      \"pmids\": [\"17761535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of TIP60 complex association unknown\", \"Relative importance of nuclear vs. centrosomal OFD1 pools unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mouse knockout and ultrastructural analysis established that OFD1 controls distal centriole length, microtubule stability, and distal appendage formation, placing it as a structural organizer of the distal centriole required for IFT88 recruitment and ciliogenesis.\",\n      \"evidence\": \"Ofd1 knockout mice, electron microscopy, patient missense allele knock-in in ES cells\",\n      \"pmids\": [\"20230748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether OFD1 acts as a scaffold or an enzymatic regulator at centrioles unknown\", \"Protein partners at the distal centriole not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Kidney-specific Ofd1 knockout revealed that loss of OFD1 causes renal cystic disease with mTOR upregulation, and rapamycin rescue demonstrated pathway-level disease mechanism.\",\n      \"evidence\": \"Conditional Ksp-Cre knockout mouse, rapamycin treatment\",\n      \"pmids\": [\"20444807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How OFD1 loss activates mTOR not determined\", \"Whether cilia loss or a cilia-independent function drives mTOR activation unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The discovery that autophagy selectively degrades the centriolar satellite pool of OFD1 to promote ciliogenesis established autophagy as a direct regulator of cilium biogenesis and identified OFD1 as the key substrate linking these two processes.\",\n      \"evidence\": \"Atg5/Atg3-null MEFs, serum starvation, OFD1 knockdown rescue of ciliogenesis\",\n      \"pmids\": [\"24089205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Autophagy receptor mediating OFD1 satellite clearance not identified\", \"Whether centriolar and satellite OFD1 pools are functionally distinct unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Conditional brain knockout demonstrated OFD1 is required for axoneme elaboration after basal body docking and maturation, precisely positioning its function in the ciliogenesis pathway and linking it to Shh-dependent forebrain patterning.\",\n      \"evidence\": \"Conditional mouse knockout, electron microscopy, Shh reporter\",\n      \"pmids\": [\"23300826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which OFD1 enables axoneme extension unknown\", \"Whether OFD1 directly participates in transition zone assembly unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that OFD1 localizes to chromatin and is required for TIP60-dependent histone acetylation, homologous recombination repair, and the G2-M DNA damage checkpoint established a cilia-independent genome maintenance role for OFD1.\",\n      \"evidence\": \"Patient-derived cells, siRNA, ChIP, HRR reporter, cell cycle analysis\",\n      \"pmids\": [\"27798113\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How OFD1 recruits or stabilizes TIP60 on chromatin not defined\", \"Whether DNA repair defects contribute to OFD1-associated disease phenotypes unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Interaction of OFD1 with translation initiation complexes (PIC/eIF4F) at the centrosome suggested a role in local mRNA translation control, expanding OFD1 function beyond structural scaffolding.\",\n      \"evidence\": \"Co-IP, mass spectrometry, polysome profiling\",\n      \"pmids\": [\"28450740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific mRNA targets regulated by OFD1-dependent translation not comprehensively identified\", \"In vivo relevance of centrosomal translation regulation not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of OFD1 as a selective autophagy receptor for ATG13 via LC3/GABARAP interaction revealed a negative feedback loop limiting autophagosome biogenesis, and genetic inhibition of autophagy ameliorated Ofd1-associated polycystic kidney disease in mice.\",\n      \"evidence\": \"In vitro binding, LIR mutagenesis, conditional mouse model, autophagy flux assays\",\n      \"pmids\": [\"33368531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of OFD1-ATG13 recognition unknown\", \"Whether OFD1 autophagy receptor function operates in all tissues or is context-specific\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that PKA phosphorylates OFD1 at Ser735 downstream of GPCR-cAMP signaling, promoting praja2-mediated proteasomal degradation required for ciliogenesis, established a UPS-dependent regulatory axis complementary to autophagic control of OFD1 levels.\",\n      \"evidence\": \"In vitro kinase assay, S735A mutagenesis, ubiquitylation assay, Medaka fish model\",\n      \"pmids\": [\"33934390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How UPS and autophagy pathways are coordinated for OFD1 turnover unclear\", \"Whether additional phosphorylation sites regulate OFD1 stability unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of the DISCO complex (CEP90-FOPNL-OFD1) by expansion microscopy resolved OFD1's structural position at the distal centriole and placed it downstream of MNR in distal appendage assembly hierarchy.\",\n      \"evidence\": \"U-ExM, siRNA, functional rescue in mammalian cells and Paramecium\",\n      \"pmids\": [\"36070319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the DISCO complex not available\", \"How MNR recruits OFD1 molecularly not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that OFD1 sequesters E2F4 in the cytosol to prevent DREAM complex assembly at the BRCA1 promoter revealed a mechanism connecting OFD1 loss to HR deficiency (BRCAness) and PARP inhibitor sensitivity, linking ciliopathy biology to cancer therapeutic vulnerability.\",\n      \"evidence\": \"Co-IP, ChIP, nuclear fractionation, HRR reporter, xenograft models\",\n      \"pmids\": [\"40764600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether E2F4 sequestration is relevant in OFD1-mutant ciliopathy patients unknown\", \"Full transcriptional program controlled by OFD1-E2F4 axis not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural model explaining how OFD1 integrates its centrosomal scaffold, autophagy receptor, chromatin-associated, and cytosolic sequestration functions—and how disease mutations differentially disrupt each—remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length OFD1 or its complexes\", \"Genotype-phenotype correlations across OFD1 functional domains not systematically resolved\", \"Relative contributions of cilia-dependent versus cilia-independent functions to disease unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 17]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 3, 7, 13, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 8, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 5, 8, 15, 17]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 15]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"DISCO complex (CEP90-FOPNL-OFD1)\",\n      \"TIP60 HAT complex\",\n      \"OFD1-KIAA0753/OFIP-FOR20 satellite complex\"\n    ],\n    \"partners\": [\n      \"CEP90\",\n      \"FOPNL\",\n      \"RUVBL1\",\n      \"KIAA0753\",\n      \"FOR20\",\n      \"E2F4\",\n      \"PRAJA2\",\n      \"MYO6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}