{"gene":"OFD1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2004,"finding":"OFD1 protein is a core component of the human centrosome throughout the cell cycle; coiled-coil domains (at least two) are required for centrosomal targeting, while the N-terminal LisH domain is not required. During acquisition of epithelial polarity in kidney development, OFD1 localizes to the apical zone of nephron precursor cells and then to basal bodies at the origin of primary cilia.","method":"GFP-OFD1 deletion constructs, immunofluorescence, immunoprobing of human metanephroi and kidney epithelial lines","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments with deletion constructs identifying required domains, single lab with multiple orthogonal methods","pmids":["15466260"],"is_preprint":false},{"year":2007,"finding":"OFD1 localizes both to the primary cilium and to the nucleus. OFD1 self-associates via its coiled-coil-rich region. OFD1 interacts with RuvBL1 (an AAA+ ATPase) and co-immunoprecipitates with subunits of the human TIP60 histone acetyltransferase (HAT) multisubunit complex.","method":"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and immunofluorescence from single lab, multiple binding partners identified","pmids":["17761535"],"is_preprint":false},{"year":2008,"finding":"Ofd1 morpholino knockdown in zebrafish causes convergent extension (CE) defects, shorter cilia with disrupted axonemes, and perturbed fluid flow in Kupffer's vesicle leading to laterality randomization. CE defects are enhanced by simultaneous loss of Slb/Wnt11 or Tri/Vangl2 (non-canonical Wnt/PCP pathway components), placing Ofd1 in the PCP pathway.","method":"Antisense morpholino knockdown in zebrafish, genetic epistasis with Wnt/PCP mutants, live imaging","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and morpholino KD in zebrafish with defined phenotypic readouts, single lab","pmids":["18971206"],"is_preprint":false},{"year":2009,"finding":"OFD1 interacts with LCA5-encoded lebercilin (identified by yeast two-hybrid screen of a retinal cDNA library). X-linked recessive OFD1 mutations reduce but do not eliminate this interaction, while dominant OFD1 mutations completely abolish binding. Dominant mutations also cause loss of pericentriolar localization of OFD1, whereas recessive mutations do not affect localization.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence in hTERT-RPE1 cells","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus localization studies, single lab with multiple orthogonal methods","pmids":["19800048"],"is_preprint":false},{"year":2010,"finding":"Ofd1 is a component of the distal centriole that controls centriole length. In absence of Ofd1, distal regions of centrioles (but not procentrioles) elongate abnormally with destabilized microtubules and abnormal post-translational modifications. Ofd1 is required for centriole distal appendage formation and centriolar recruitment of the intraflagellar transport protein Ift88. Disease-associated OFD1 missense alleles cause different degrees of excessive or decreased centriole elongation, all associated with diminished ciliogenesis.","method":"Conditional knockout mouse ES cells, electron microscopy, immunofluorescence, disease allele knock-in","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined ultrastructural readouts, multiple disease alleles tested, replicated mechanistic conclusions","pmids":["20230748"],"is_preprint":false},{"year":2010,"finding":"Kidney-specific inactivation of Ofd1 (using Ksp-Cre) leads to renal cystic disease with upregulation of the mTOR pathway in both dilated and non-dilated renal structures. Treatment with rapamycin (mTOR inhibitor) significantly reduces cyst number and size, demonstrating mTOR pathway dysregulation is causally linked to cyst development downstream of Ofd1 loss.","method":"Conditional knockout mouse model, immunofluorescence, western blotting, rapamycin treatment","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with pharmacological rescue, western blot pathway analysis, multiple readouts","pmids":["20444807"],"is_preprint":false},{"year":2012,"finding":"Ofd1 plays a crucial role in forebrain dorso-ventral patterning and early corticogenesis. Early Ofd1 inactivation results in absence of ciliary axonemes despite the presence of mature, correctly oriented and docked basal bodies, placing Ofd1 function after basal body docking but before axoneme elaboration. Abnormal activation of Sonic hedgehog (Shh) signaling is observed in mutant brains.","method":"Conditional mouse knockout, ultrastructural electron microscopy, immunofluorescence, in vivo pathway analysis","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ultrastructural analysis precisely positioning Ofd1 in ciliogenesis pathway, multiple readouts","pmids":["23300826"],"is_preprint":false},{"year":2013,"finding":"OFD1 at centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient (Atg5 or Atg3 null) mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, causing fewer and shorter primary cilia and defective recruitment of BBS4 to cilia. OFD1 partial knockdown fully rescues ciliogenesis defects in autophagy-deficient cells. OFD1 depletion at centriolar satellites promotes cilia formation even in normally non-ciliated MCF7 cancer cells.","method":"Autophagy-deficient mouse embryonic fibroblasts (Atg5/Atg3 KO), siRNA knockdown, immunofluorescence, rescue experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with rescue experiments across multiple cell types, replicated with two different autophagy-deficient genotypes","pmids":["24089205"],"is_preprint":false},{"year":2014,"finding":"OFD1 is assembled into a protein complex at the primary cilium containing EGFR, flotillin proteins, polycystin-1, and polycystin-2. In human ADPKD cells where mutant polycystin-1 fails to localize to cilia, OFD1, polycystin-2, EGFR, and flotillin-1 also lose ciliary localization, indicating polycystins are required for assembly of this OFD1-containing ciliary signaling complex.","method":"Co-immunoprecipitation, immunofluorescence in renal epithelia and ADPKD patient cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP and immunofluorescence, single lab, disease cell model used as functional validation","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 ternary complex causes defective recruitment of the other components onto centrosomes and satellites. The OFD1/SGBS2 disease-associated KIAA0753 mutant loses interaction with FOR20 and OFD1.","method":"Co-immunoprecipitation, immunofluorescence, siRNA knockdown in RPE1 cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional depletion experiments, single lab, interdependence of complex components demonstrated","pmids":["26643951"],"is_preprint":false},{"year":2016,"finding":"OFD1 localizes to the outer segments of rat retina photoreceptors. Knockdown of Ofd1 in retinal cell lines results in shorter and fewer cilia, and reduced cell viability. Ofd1 overexpression partially attenuates MNU-induced toxicity by reducing reactive oxygen species levels and mitigating apoptosis.","method":"Immunofluorescence, siRNA knockdown, overexpression in 661W and R28 cells, DCFH-DA ROS assay, FACS apoptosis analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined mechanistic readouts (ROS, apoptosis, cilia length), single lab","pmids":["27196396"],"is_preprint":false},{"year":2017,"finding":"OFD1 interacts with components of the Preinitiation complex of translation (PIC) and the eIF4F complex. OFD1 cooperates with the mRNA binding protein Bicc1 to modulate translation of specific mRNA targets at the centrosome, where PIC and eIF4F components also localize. Selected translational targets accumulate in two models of inherited renal cystic disease.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, translation assays in kidney cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with MS identification plus functional translation assays, single lab with multiple methods","pmids":["28450740"],"is_preprint":false},{"year":2017,"finding":"OFD1 localizes to chromatin. Reduced OFD1 expression causes mis-localization of TIP60 in patient-derived cell lines, reduced histone acetylation, altered chromatin dynamics in response to DNA double-strand breaks, and impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also impairs the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest, phenocopying loss of TIP60.","method":"Chromatin fractionation, immunofluorescence, DSB repair assays, checkpoint analysis in OFD1 patient-derived cell lines","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient-derived cell lines with multiple orthogonal assays (HRR assay, checkpoint, chromatin dynamics), single lab","pmids":["27798113"],"is_preprint":false},{"year":2017,"finding":"In Paramecium tetraurelia, OFD1 depletion impairs basal body docking and causes defective assembly of the basal body distal part. OFD1 is recruited early during basal body assembly and localizes at the transition zone at the level of microtubule doublets. The localizations of OFD1 and FOR20 at the basal body are interdependent.","method":"RNAi knockdown in Paramecium, immunofluorescence, electron microscopy","journal":"Cilia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi KD with ultrastructural analysis in ciliate model, demonstrates conservation of 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 constitutes a negative feedback mechanism limiting autophagosome biogenesis. OFD1-mutant patients display excessive autophagy, and genetic inhibition of autophagy in a conditional mouse model significantly ameliorates polycystic kidney disease.","method":"Co-immunoprecipitation, direct binding assays, conditional mouse model, autophagy flux assays, patient cell analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated (OFD1 as autophagy receptor), confirmed in patient cells and mouse model with disease rescue, multiple orthogonal methods","pmids":["33368531"],"is_preprint":false},{"year":2020,"finding":"OFD1 interacts with TRAPPC8 and TRAPPC12 (TRAPPIII-specific subunits). TRAPPC8 is required for association of OFD1 with pericentriolar material 1 (PCM1). The interaction between TRAPPC8 and OFD1 inhibits the interaction between OFD1 and TRAPPC12, suggesting competitive binding that differentially regulates cilium assembly and disassembly.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence in hTERT-RPE1 cells","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus KD with functional readouts, single lab, competitive binding shown","pmids":["32258032"],"is_preprint":false},{"year":2020,"finding":"OFD1 has a dynamic distribution during the cell cycle. Ofd1 depletion in fibroblasts causes centrosome accumulation, nuclear abnormalities, aneuploidy, and an abnormal microtubule network, resulting in impaired cell cycle progression.","method":"High-content microscopy, immunofluorescence, cell proliferation assays, siRNA knockdown","journal":"Tissue & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple cellular readouts identifying MTOC function, single lab","pmids":["32473706"],"is_preprint":false},{"year":2021,"finding":"TBC1D31 assembles a centrosomal complex including the E3 ubiquitin ligase praja2, PKA, and OFD1. Upon GPCR-cAMP stimulation, PKA phosphorylates OFD1 at Ser735, promoting OFD1 proteolysis via the praja2-ubiquitin-proteasome system. This phosphorylation-dependent proteolysis is required for ciliogenesis; a non-phosphorylatable OFD1 mutant dramatically impairs cilium morphology. Disruption of this axis impairs ciliogenesis in vivo in Medaka fish.","method":"Co-immunoprecipitation, mass spectrometry, site-directed mutagenesis, ubiquitylation assays, GPCR stimulation, in vivo Medaka model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — phosphorylation site identified by MS, mutagenesis confirms mechanism, in vivo validation in fish model, multiple orthogonal methods","pmids":["33934390"],"is_preprint":false},{"year":2021,"finding":"Myosin VI interacts with OFD1 and regulates its localization at centrioles. Myosin VI depletion causes aberrant OFD1 localization along centriolar walls (due to reduced OFD1 mobile fraction), impairs recruitment of the distal appendage protein Cep164, and causes severe ciliogenesis defects that are at least partially due to impaired autophagic removal of OFD1 from satellites.","method":"Co-immunoprecipitation, FRAP, immunofluorescence, siRNA knockdown in non-tumoural cell lines","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, FRAP mobility assay, and functional KD with mechanistic readouts, single lab","pmids":["34957672"],"is_preprint":false},{"year":2022,"finding":"CEP90, FOPNL, and OFD1 form a functional module (DISCO complex) that localizes at the distal end of centrioles/basal bodies. These proteins are recruited early during centriole duplication on the external surface of the procentriole. OFD1 (along with FOPNL and CEP90) requires MNR for its recruitment, and in turn recruits distal appendage proteins CEP83, CEP89, and CEP164. Functional loss of these proteins in both Paramecium and mammalian cells impairs distal appendage assembly and basal body docking.","method":"Ultrastructure expansion microscopy (U-ExM), RNAi in Paramecium, siRNA in mammalian cells, immunofluorescence","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — super-resolution imaging plus functional KD in two model systems, hierarchical recruitment order established","pmids":["36070319"],"is_preprint":false},{"year":2023,"finding":"OFD1 amino acid residues 601-1012 interact with paxillin (a cell-ECM adhesion protein), while residues 1-601 are responsible for ciliogenesis. OFD1 knockdown, but not IFT88 or RPGRIP1L knockdown, reduces paxillin expression, inhibits melanocyte adhesion to the ECM, and induces melanocyte apoptosis, establishing a cilia-independent OFD1 function in cell survival via ECM adhesion.","method":"Co-immunoprecipitation, domain mapping, siRNA knockdown, cell adhesion assays, apoptosis assays, paxillin overexpression rescue","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping combined with KD/rescue experiments establishing distinct cilia-independent function, single lab","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 impairing homologous recombination repair (HRR), conferring synthetic lethality with PARP inhibitors.","method":"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, chromatin immunoprecipitation, BRCA1 promoter reporter assays, xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic pathway dissected with co-IP, fractionation, ChIP, and multiple in vivo models; multiple orthogonal methods establishing OFD1-E2F4-DREAM-BRCA1 axis","pmids":["40764600"],"is_preprint":false}],"current_model":"OFD1 is a multifunctional centrosomal/basal body scaffold protein required for centriole length control, distal appendage formation, and ciliogenesis; it is degraded at centriolar satellites by selective autophagy (promoting cilia formation) and at the centrosome by PKA-phosphorylation (Ser735)-driven praja2-UPS proteolysis downstream of GPCR-cAMP signaling; it acts as a selective autophagy receptor for ATG13 to limit autophagosome biogenesis; it regulates BRCA1 transcription by sequestering E2F4 in the cytosol to prevent DREAM complex formation; and it participates in nuclear chromatin remodeling via the TIP60 complex and in centrosome-based translational control via the eIF4F/PIC machinery."},"narrative":{"mechanistic_narrative":"OFD1 is a centrosomal and basal-body scaffold protein required for centriole length control, distal appendage formation, and primary ciliogenesis [PMID:15466260, PMID:20230748]. At the distal centriole it controls distal-region elongation and microtubule stability, recruits IFT88, and is essential for distal appendage assembly; disease-associated alleles produce excessive or decreased centriole elongation, all coupled to diminished ciliogenesis [PMID:20230748]. OFD1 functions as part of a hierarchical distal-centriole module (with CEP90 and FOPNL) that is recruited early during centriole duplication and in turn recruits the distal appendage proteins CEP83, CEP89, and CEP164, enabling basal body docking [PMID:36070319]. Its abundance at distinct compartments is set by two degradation routes: a satellite pool is cleared by selective autophagy to permit cilium formation, such that autophagy-deficient cells accumulate OFD1 and fail to ciliate [PMID:24089205], and a centrosomal pool is degraded downstream of GPCR-cAMP signaling, where PKA phosphorylates OFD1 at Ser735 to trigger praja2-ubiquitin-proteasome proteolysis required for ciliogenesis [PMID:33934390]. OFD1 also acts as a selective autophagy receptor for ATG13, binding Atg8/LC3/GABARAP proteins to limit autophagosome biogenesis, and excess autophagy in OFD1-mutant settings contributes to polycystic kidney disease that is ameliorated by autophagy inhibition [PMID:33368531]. Loss of Ofd1 drives renal cystic disease through mTOR pathway dysregulation, reversible by rapamycin [PMID:20444807]. Beyond the cilium, OFD1 has nuclear and cytosolic functions: it associates with the TIP60 histone acetyltransferase complex and is required for histone acetylation, chromatin dynamics, and homologous recombination repair of double-strand breaks [PMID:17761535, PMID:27798113], and it sequesters E2F4 in the cytosol to block DREAM complex assembly at the BRCA1 promoter, sustaining BRCA1 expression and HRR [PMID:40764600]. It additionally cooperates with the centrosomal translation machinery to control localized mRNA translation [PMID:28450740].","teleology":[{"year":2004,"claim":"Established OFD1 as a constitutive centrosomal component and identified which domains target it there, framing it as a structural scaffold rather than a transient visitor.","evidence":"GFP-OFD1 deletion constructs and immunofluorescence in kidney epithelial lines and human metanephroi","pmids":["15466260"],"confidence":"Medium","gaps":["Did not define a molecular activity for OFD1","No partners identified at this stage"]},{"year":2007,"claim":"Revealed a nuclear pool of OFD1 and its physical association with chromatin-modifying machinery, the first hint of a function beyond the centrosome.","evidence":"Co-immunoprecipitation and yeast two-hybrid identifying RuvBL1 and TIP60 complex subunits","pmids":["17761535"],"confidence":"Medium","gaps":["Co-IP without reciprocal or endogenous validation","Functional consequence of TIP60 association not tested here"]},{"year":2008,"claim":"Placed OFD1 in ciliary signaling physiology by linking it to non-canonical Wnt/PCP-dependent cilia and left-right patterning.","evidence":"Morpholino knockdown and genetic epistasis with Wnt/PCP mutants in zebrafish","pmids":["18971206"],"confidence":"Medium","gaps":["Morpholino-based; off-target effects not excluded","Molecular link between OFD1 and PCP components undefined"]},{"year":2009,"claim":"Connected OFD1 genotype to a ciliary interaction and localization phenotype, showing dominant versus recessive mutations differ in disrupting lebercilin binding and pericentriolar targeting.","evidence":"Yeast two-hybrid, co-IP, and immunofluorescence of disease alleles in RPE1 cells","pmids":["19800048"],"confidence":"Medium","gaps":["Functional role of OFD1-lebercilin complex in cilia not established","Structural basis of binding unknown"]},{"year":2010,"claim":"Defined the core molecular function of OFD1 as a distal-centriole protein controlling centriole length and distal appendage formation, the mechanistic anchor of its ciliogenesis role.","evidence":"Conditional knockout ES cells, electron microscopy, and disease-allele knock-in","pmids":["20230748"],"confidence":"High","gaps":["Mechanism of microtubule length control not resolved at molecular detail","How distal appendage recruitment is achieved not yet mapped"]},{"year":2010,"claim":"Linked OFD1 loss to renal cystic disease through mTOR dysregulation and demonstrated pharmacological reversibility, establishing a druggable downstream pathway.","evidence":"Kidney-specific conditional knockout mouse with rapamycin rescue and western blot pathway analysis","pmids":["20444807"],"confidence":"High","gaps":["Direct molecular link between OFD1 and mTOR activation not defined","Whether mTOR effect is cilia-dependent unresolved"]},{"year":2013,"claim":"Discovered that selective autophagy degrades the satellite pool of OFD1 to license ciliogenesis, recasting OFD1 turnover as a regulatory switch for cilium formation.","evidence":"Atg5/Atg3-null MEFs, siRNA rescue, and immunofluorescence across multiple cell types","pmids":["24089205"],"confidence":"High","gaps":["Recognition mechanism marking satellite OFD1 for autophagy not defined here","Distinction between satellite and centrosomal pools not molecularly resolved"]},{"year":2014,"claim":"Positioned OFD1 within a polycystin-dependent ciliary signaling complex, linking it to ADPKD-relevant membrane receptor assemblies.","evidence":"Co-IP and immunofluorescence in renal epithelia and ADPKD patient cells","pmids":["25180832"],"confidence":"Medium","gaps":["Direct versus indirect associations within the complex not separated","Functional output of the OFD1-polycystin complex not measured"]},{"year":2015,"claim":"Defined an interdependent OFD1/KIAA0753/FOR20 ternary module governing mutual recruitment to satellites and centrosomes, clarifying how OFD1 is positioned in the centriolar protein network.","evidence":"Co-IP and siRNA interdependence assays in RPE1 cells","pmids":["26643951"],"confidence":"Medium","gaps":["Stoichiometry and direct contacts within the ternary complex unresolved","Order of assembly not established"]},{"year":2016,"claim":"Extended OFD1 function to photoreceptor cilia and implicated it in cell survival via control of reactive oxygen species and apoptosis.","evidence":"siRNA knockdown and overexpression in retinal cell lines with ROS and apoptosis assays","pmids":["27196396"],"confidence":"Medium","gaps":["Mechanism linking OFD1 to ROS levels not defined","Whether survival effect is cilia-dependent unclear"]},{"year":2017,"claim":"Identified a centrosome-based translational control function, with OFD1 cooperating with Bicc1 and the PIC/eIF4F machinery to regulate specific mRNAs relevant to cystic disease.","evidence":"Co-IP with mass spectrometry and translation assays in kidney cells","pmids":["28450740"],"confidence":"Medium","gaps":["Direct RNA-binding by OFD1 not demonstrated","Specific target mRNAs and selection mechanism incompletely defined"]},{"year":2017,"claim":"Established a nuclear genome-maintenance role, showing OFD1 supports TIP60 localization, histone acetylation, and homologous-recombination DSB repair, with loss phenocopying TIP60 deficiency.","evidence":"Chromatin fractionation, DSB repair assays, and checkpoint analysis in patient-derived cells","pmids":["27798113"],"confidence":"Medium","gaps":["Whether OFD1 directly stabilizes TIP60 or acts indirectly unresolved","How a centrosomal protein partitions to chromatin not defined"]},{"year":2017,"claim":"Demonstrated evolutionary conservation of OFD1's basal-body docking and distal-assembly function and its transition-zone localization in a ciliate.","evidence":"RNAi knockdown, immunofluorescence, and electron microscopy in Paramecium","pmids":["28367320"],"confidence":"Medium","gaps":["Mapping of conserved domains to specific functions not done","Relationship to mammalian distal appendage hierarchy not yet integrated"]},{"year":2020,"claim":"Showed OFD1 is itself a selective autophagy receptor for ATG13 that limits autophagosome biogenesis, and that excess autophagy underlies OFD1-related polycystic kidney disease rescuable by autophagy inhibition.","evidence":"Direct binding assays, conditional mouse model, autophagy flux, and patient cell analysis","pmids":["33368531"],"confidence":"High","gaps":["How the autophagy-receptor role is spatially separated from being an autophagy substrate not fully resolved","Regulation of OFD1-ATG13 binding not mapped"]},{"year":2020,"claim":"Identified TRAPPIII subunits as competitive OFD1 partners controlling its association with PCM1, providing a switch between cilium assembly and disassembly states.","evidence":"Co-IP and siRNA with functional readouts in RPE1 cells","pmids":["32258032"],"confidence":"Medium","gaps":["Structural basis of competitive binding unresolved","Physiological trigger that biases binding not defined"]},{"year":2020,"claim":"Connected OFD1 to cell-cycle progression and genome stability, with depletion causing centrosome accumulation, aneuploidy, and microtubule network defects.","evidence":"High-content microscopy and proliferation assays after siRNA in fibroblasts","pmids":["32473706"],"confidence":"Medium","gaps":["Whether defects are secondary to centrosome amplification not separated","Direct cell-cycle effector role undefined"]},{"year":2021,"claim":"Defined a GPCR-cAMP-PKA signaling axis that controls centrosomal OFD1 levels, identifying Ser735 phosphorylation and praja2-mediated proteasomal degradation as required for ciliogenesis.","evidence":"Mass spectrometry, site-directed mutagenesis, ubiquitylation assays, and in vivo Medaka model","pmids":["33934390"],"confidence":"High","gaps":["How this proteasomal route is coordinated with autophagic turnover unresolved","Upstream receptors that engage this axis not enumerated"]},{"year":2021,"claim":"Showed Myosin VI regulates OFD1 mobility and localization at centrioles, coupling motor activity to distal appendage protein recruitment and autophagic clearance of OFD1.","evidence":"Co-IP, FRAP, and siRNA in non-tumoral cell lines","pmids":["34957672"],"confidence":"Medium","gaps":["Direct versus adaptor-mediated Myosin VI-OFD1 contact not resolved","Mechanism by which mobility controls satellite autophagy unclear"]},{"year":2022,"claim":"Resolved the hierarchical recruitment order of a distal-centriole module (DISCO: CEP90/FOPNL/OFD1) downstream of MNR and upstream of CEP83/CEP89/CEP164, mechanistically explaining OFD1's role in distal appendage assembly and basal body docking.","evidence":"Ultrastructure expansion microscopy and RNAi/siRNA in Paramecium and mammalian cells","pmids":["36070319"],"confidence":"High","gaps":["Direct biochemical contacts within DISCO not mapped","How module assembly is timed during duplication not defined"]},{"year":2023,"claim":"Separated a cilia-independent OFD1 function in cell survival, mapping a paxillin-binding domain that supports ECM adhesion distinct from the ciliogenesis domain.","evidence":"Domain mapping, co-IP, adhesion and apoptosis assays with paxillin rescue in melanocytes","pmids":["38139355"],"confidence":"Medium","gaps":["Whether OFD1-paxillin acts at adhesion sites or remotely not established","Mechanism by which OFD1 controls paxillin expression undefined"]},{"year":2025,"claim":"Defined a cytosolic OFD1-E2F4-DREAM-BRCA1 axis in which OFD1 sequesters E2F4 to prevent DREAM-mediated BRCA1 repression, sustaining HRR and creating synthetic lethality with PARP inhibitors.","evidence":"Co-IP, nuclear/cytoplasmic fractionation, ChIP, promoter reporters, and xenograft models","pmids":["40764600"],"confidence":"High","gaps":["How OFD1's cytosolic sequestration pool is regulated unknown","Integration with OFD1's TIP60-dependent HRR role not reconciled"]},{"year":null,"claim":"How OFD1 partitions among its centrosomal, satellite, nuclear/chromatin, and cytosolic functional pools, and how the competing autophagic and proteasomal degradation routes are spatially and temporally coordinated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of pool partitioning","Structural basis of OFD1 scaffolding interactions largely undetermined","Relationship between ciliary and nuclear DSB-repair functions not mechanistically linked"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,19]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14,21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[21]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,4,9,16]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,6,8,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[21]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,19]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,14]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[12,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[16]}],"complexes":["TIP60 histone acetyltransferase complex","OFD1/KIAA0753/FOR20 ternary complex","DISCO complex (CEP90/FOPNL/OFD1)","TBC1D31-praja2-PKA centrosomal complex"],"partners":["RUVBL1","LCA5","KIAA0753","FOR20","ATG13","TRAPPC8","E2F4","MYO6"],"other_free_text":[]}},"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 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/32677760","citation_count":0,"is_preprint":false},{"pmid":"40883668","id":"PMC_40883668","title":"CCHCR1 links P-body proteins to the centrosome and is required for ciliogenesis through interacting with OFD1 and PCM1.","date":"2025","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/40883668","citation_count":0,"is_preprint":false},{"pmid":"41064626","id":"PMC_41064626","title":"Novel OFD1 Mutation Results in Unusually Early-Onset Polycystic Kidney Disease.","date":"2025","source":"Case reports in nephrology and dialysis","url":"https://pubmed.ncbi.nlm.nih.gov/41064626","citation_count":0,"is_preprint":false},{"pmid":"40763968","id":"PMC_40763968","title":"[Analysis of OFD1 gene variant in a child with Oral-facial-digital syndrome].","date":"2025","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40763968","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.17.660204","title":"The Luminal Ring Protein C2CD3 Acts as a Radial In-to-Out Organizer of the Distal Centriole and Appendages","date":"2025-06-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.17.660204","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.10.632335","title":"Wnt/LRP6 signaling imbalance impairs ciliogenesis in human retina epithelial cells","date":"2025-01-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.10.632335","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.30.602578","title":"Ciliary biology intersects autism and congenital heart disease","date":"2024-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.30.602578","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.17.665435","title":"DirectContacts2: A network of direct physical protein interactions derived from high-throughput mass spectrometry experiments","date":"2025-07-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.17.665435","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.18.24310640","title":"Chromosome X-Wide Common Variant Association Study (XWAS) in Autism Spectrum Disorder","date":"2024-07-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.18.24310640","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37640,"output_tokens":5677,"usd":0.099038,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14133,"output_tokens":6150,"usd":0.112208,"stage2_stop_reason":"end_turn"},"total_usd":0.211246,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"OFD1 protein is a core component of the human centrosome throughout the cell cycle; coiled-coil domains (at least two) are required for centrosomal targeting, while the N-terminal LisH domain is not required. During acquisition of epithelial polarity in kidney development, OFD1 localizes to the apical zone of nephron precursor cells and then to basal bodies at the origin of primary cilia.\",\n      \"method\": \"GFP-OFD1 deletion constructs, immunofluorescence, immunoprobing of human metanephroi and kidney epithelial lines\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments with deletion constructs identifying required domains, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15466260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"OFD1 localizes both to the primary cilium and to the nucleus. OFD1 self-associates via its coiled-coil-rich region. OFD1 interacts with RuvBL1 (an AAA+ ATPase) and co-immunoprecipitates with subunits of the human TIP60 histone acetyltransferase (HAT) multisubunit complex.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and immunofluorescence from single lab, multiple binding partners identified\",\n      \"pmids\": [\"17761535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ofd1 morpholino knockdown in zebrafish causes convergent extension (CE) defects, shorter cilia with disrupted axonemes, and perturbed fluid flow in Kupffer's vesicle leading to laterality randomization. CE defects are enhanced by simultaneous loss of Slb/Wnt11 or Tri/Vangl2 (non-canonical Wnt/PCP pathway components), placing Ofd1 in the PCP pathway.\",\n      \"method\": \"Antisense morpholino knockdown in zebrafish, genetic epistasis with Wnt/PCP mutants, live imaging\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and morpholino KD in zebrafish with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"18971206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"OFD1 interacts with LCA5-encoded lebercilin (identified by yeast two-hybrid screen of a retinal cDNA library). X-linked recessive OFD1 mutations reduce but do not eliminate this interaction, while dominant OFD1 mutations completely abolish binding. Dominant mutations also cause loss of pericentriolar localization of OFD1, whereas recessive mutations do not affect localization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence in hTERT-RPE1 cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-IP plus localization studies, single lab with multiple orthogonal methods\",\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. In absence of Ofd1, distal regions of centrioles (but not procentrioles) elongate abnormally with destabilized microtubules and abnormal post-translational modifications. Ofd1 is required for centriole distal appendage formation and centriolar recruitment of the intraflagellar transport protein Ift88. Disease-associated OFD1 missense alleles cause different degrees of excessive or decreased centriole elongation, all associated with diminished ciliogenesis.\",\n      \"method\": \"Conditional knockout mouse ES cells, electron microscopy, immunofluorescence, disease allele knock-in\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined ultrastructural readouts, multiple disease alleles tested, replicated mechanistic conclusions\",\n      \"pmids\": [\"20230748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Kidney-specific inactivation of Ofd1 (using Ksp-Cre) leads to renal cystic disease with upregulation of the mTOR pathway in both dilated and non-dilated renal structures. Treatment with rapamycin (mTOR inhibitor) significantly reduces cyst number and size, demonstrating mTOR pathway dysregulation is causally linked to cyst development downstream of Ofd1 loss.\",\n      \"method\": \"Conditional knockout mouse model, immunofluorescence, western blotting, rapamycin treatment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with pharmacological rescue, western blot pathway analysis, multiple readouts\",\n      \"pmids\": [\"20444807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Ofd1 plays a crucial role in forebrain dorso-ventral patterning and early corticogenesis. Early Ofd1 inactivation results in absence of ciliary axonemes despite the presence of mature, correctly oriented and docked basal bodies, placing Ofd1 function after basal body docking but before axoneme elaboration. Abnormal activation of Sonic hedgehog (Shh) signaling is observed in mutant brains.\",\n      \"method\": \"Conditional mouse knockout, ultrastructural electron microscopy, immunofluorescence, in vivo pathway analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ultrastructural analysis precisely positioning Ofd1 in ciliogenesis pathway, multiple readouts\",\n      \"pmids\": [\"23300826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"OFD1 at centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient (Atg5 or Atg3 null) mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, causing fewer and shorter primary cilia and defective recruitment of BBS4 to cilia. OFD1 partial knockdown fully rescues ciliogenesis defects in autophagy-deficient cells. OFD1 depletion at centriolar satellites promotes cilia formation even in normally non-ciliated MCF7 cancer cells.\",\n      \"method\": \"Autophagy-deficient mouse embryonic fibroblasts (Atg5/Atg3 KO), siRNA knockdown, immunofluorescence, rescue experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with rescue experiments across multiple cell types, replicated with two different autophagy-deficient genotypes\",\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 containing EGFR, flotillin proteins, polycystin-1, and polycystin-2. In human ADPKD cells where mutant polycystin-1 fails to localize to cilia, OFD1, polycystin-2, EGFR, and flotillin-1 also lose ciliary localization, indicating polycystins are required for assembly of this OFD1-containing ciliary signaling complex.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence in renal epithelia and ADPKD patient cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP and immunofluorescence, single lab, disease cell model used as functional validation\",\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 ternary complex causes defective recruitment of the other components onto centrosomes and satellites. The OFD1/SGBS2 disease-associated KIAA0753 mutant loses interaction with FOR20 and OFD1.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, siRNA knockdown in RPE1 cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional depletion experiments, single lab, interdependence of complex components demonstrated\",\n      \"pmids\": [\"26643951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"OFD1 localizes to the outer segments of rat retina photoreceptors. Knockdown of Ofd1 in retinal cell lines results in shorter and fewer cilia, and reduced cell viability. Ofd1 overexpression partially attenuates MNU-induced toxicity by reducing reactive oxygen species levels and mitigating apoptosis.\",\n      \"method\": \"Immunofluorescence, siRNA knockdown, overexpression in 661W and R28 cells, DCFH-DA ROS assay, FACS apoptosis analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined mechanistic readouts (ROS, apoptosis, cilia length), single lab\",\n      \"pmids\": [\"27196396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OFD1 interacts with components of the Preinitiation complex of translation (PIC) and the eIF4F complex. OFD1 cooperates with the mRNA binding protein Bicc1 to modulate translation of specific mRNA targets at the centrosome, where PIC and eIF4F components also localize. Selected translational targets accumulate in two models of inherited renal cystic disease.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, translation assays in kidney cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with MS identification plus functional translation assays, single lab with multiple methods\",\n      \"pmids\": [\"28450740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"OFD1 localizes to chromatin. Reduced OFD1 expression causes mis-localization of TIP60 in patient-derived cell lines, reduced histone acetylation, altered chromatin dynamics in response to DNA double-strand breaks, and impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also impairs the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest, phenocopying loss of TIP60.\",\n      \"method\": \"Chromatin fractionation, immunofluorescence, DSB repair assays, checkpoint analysis in OFD1 patient-derived cell lines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived cell lines with multiple orthogonal assays (HRR assay, checkpoint, chromatin dynamics), single lab\",\n      \"pmids\": [\"27798113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Paramecium tetraurelia, OFD1 depletion impairs basal body docking and causes defective assembly of the basal body distal part. OFD1 is recruited early during basal body assembly and localizes at the transition zone at the level of microtubule doublets. The localizations of OFD1 and FOR20 at the basal body are interdependent.\",\n      \"method\": \"RNAi knockdown in Paramecium, immunofluorescence, electron microscopy\",\n      \"journal\": \"Cilia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi KD with ultrastructural analysis in ciliate model, demonstrates conservation of 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 constitutes a negative feedback mechanism limiting autophagosome biogenesis. OFD1-mutant patients display excessive autophagy, and genetic inhibition of autophagy in a conditional mouse model significantly ameliorates polycystic kidney disease.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assays, conditional mouse model, autophagy flux assays, patient cell analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding demonstrated (OFD1 as autophagy receptor), confirmed in patient cells and mouse model with disease rescue, multiple orthogonal methods\",\n      \"pmids\": [\"33368531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OFD1 interacts with TRAPPC8 and TRAPPC12 (TRAPPIII-specific subunits). TRAPPC8 is required for association of OFD1 with pericentriolar material 1 (PCM1). The interaction between TRAPPC8 and OFD1 inhibits the interaction between OFD1 and TRAPPC12, suggesting competitive binding that differentially regulates cilium assembly and 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 3 / Moderate — co-IP plus KD with functional readouts, single lab, competitive binding shown\",\n      \"pmids\": [\"32258032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"OFD1 has a dynamic distribution during the cell cycle. Ofd1 depletion in fibroblasts causes centrosome accumulation, nuclear abnormalities, aneuploidy, and an abnormal microtubule network, resulting in impaired cell cycle progression.\",\n      \"method\": \"High-content microscopy, immunofluorescence, cell proliferation assays, siRNA knockdown\",\n      \"journal\": \"Tissue & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple cellular readouts identifying MTOC function, single lab\",\n      \"pmids\": [\"32473706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TBC1D31 assembles a centrosomal complex including the E3 ubiquitin ligase praja2, PKA, and OFD1. Upon GPCR-cAMP stimulation, PKA phosphorylates OFD1 at Ser735, promoting OFD1 proteolysis via the praja2-ubiquitin-proteasome system. This phosphorylation-dependent proteolysis is required for ciliogenesis; a non-phosphorylatable OFD1 mutant dramatically impairs cilium morphology. Disruption of this axis impairs ciliogenesis in vivo in Medaka fish.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, site-directed mutagenesis, ubiquitylation assays, GPCR stimulation, in vivo Medaka model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — phosphorylation site identified by MS, mutagenesis confirms mechanism, in vivo validation in fish model, multiple orthogonal methods\",\n      \"pmids\": [\"33934390\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Myosin VI interacts with OFD1 and regulates its localization at centrioles. Myosin VI depletion causes aberrant OFD1 localization along centriolar walls (due to reduced OFD1 mobile fraction), impairs recruitment of the distal appendage protein Cep164, and causes severe ciliogenesis defects that are at least partially due to impaired autophagic removal of OFD1 from satellites.\",\n      \"method\": \"Co-immunoprecipitation, FRAP, immunofluorescence, siRNA knockdown in non-tumoural cell lines\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, FRAP mobility assay, and functional KD with mechanistic readouts, single lab\",\n      \"pmids\": [\"34957672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CEP90, FOPNL, and OFD1 form a functional module (DISCO complex) that localizes at the distal end of centrioles/basal bodies. These proteins are recruited early during centriole duplication on the external surface of the procentriole. OFD1 (along with FOPNL and CEP90) requires MNR for its recruitment, and in turn recruits distal appendage proteins CEP83, CEP89, and CEP164. Functional loss of these proteins in both Paramecium and mammalian cells impairs distal appendage assembly and basal body docking.\",\n      \"method\": \"Ultrastructure expansion microscopy (U-ExM), RNAi in Paramecium, siRNA in mammalian cells, immunofluorescence\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — super-resolution imaging plus functional KD in two model systems, hierarchical recruitment order established\",\n      \"pmids\": [\"36070319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"OFD1 amino acid residues 601-1012 interact with paxillin (a cell-ECM adhesion protein), while residues 1-601 are responsible for ciliogenesis. OFD1 knockdown, but not IFT88 or RPGRIP1L knockdown, reduces paxillin expression, inhibits melanocyte adhesion to the ECM, and induces melanocyte apoptosis, establishing a cilia-independent OFD1 function in cell survival via ECM adhesion.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, siRNA knockdown, cell adhesion assays, apoptosis assays, paxillin overexpression rescue\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping combined with KD/rescue experiments establishing distinct cilia-independent function, single lab\",\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 impairing homologous recombination repair (HRR), conferring synthetic lethality with PARP inhibitors.\",\n      \"method\": \"Co-immunoprecipitation, nuclear/cytoplasmic fractionation, chromatin immunoprecipitation, BRCA1 promoter reporter assays, xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic pathway dissected with co-IP, fractionation, ChIP, and multiple in vivo models; multiple orthogonal methods establishing OFD1-E2F4-DREAM-BRCA1 axis\",\n      \"pmids\": [\"40764600\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OFD1 is a multifunctional centrosomal/basal body scaffold protein required for centriole length control, distal appendage formation, and ciliogenesis; it is degraded at centriolar satellites by selective autophagy (promoting cilia formation) and at the centrosome by PKA-phosphorylation (Ser735)-driven praja2-UPS proteolysis downstream of GPCR-cAMP signaling; it acts as a selective autophagy receptor for ATG13 to limit autophagosome biogenesis; it regulates BRCA1 transcription by sequestering E2F4 in the cytosol to prevent DREAM complex formation; and it participates in nuclear chromatin remodeling via the TIP60 complex and in centrosome-based translational control via the eIF4F/PIC machinery.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"OFD1 is a centrosomal and basal-body scaffold protein required for centriole length control, distal appendage formation, and primary ciliogenesis [#0, #4]. At the distal centriole it controls distal-region elongation and microtubule stability, recruits IFT88, and is essential for distal appendage assembly; disease-associated alleles produce excessive or decreased centriole elongation, all coupled to diminished ciliogenesis [#4]. OFD1 functions as part of a hierarchical distal-centriole module (with CEP90 and FOPNL) that is recruited early during centriole duplication and in turn recruits the distal appendage proteins CEP83, CEP89, and CEP164, enabling basal body docking [#19]. Its abundance at distinct compartments is set by two degradation routes: a satellite pool is cleared by selective autophagy to permit cilium formation, such that autophagy-deficient cells accumulate OFD1 and fail to ciliate [#7], and a centrosomal pool is degraded downstream of GPCR-cAMP signaling, where PKA phosphorylates OFD1 at Ser735 to trigger praja2-ubiquitin-proteasome proteolysis required for ciliogenesis [#17]. OFD1 also acts as a selective autophagy receptor for ATG13, binding Atg8/LC3/GABARAP proteins to limit autophagosome biogenesis, and excess autophagy in OFD1-mutant settings contributes to polycystic kidney disease that is ameliorated by autophagy inhibition [#14]. Loss of Ofd1 drives renal cystic disease through mTOR pathway dysregulation, reversible by rapamycin [#5]. Beyond the cilium, OFD1 has nuclear and cytosolic functions: it associates with the TIP60 histone acetyltransferase complex and is required for histone acetylation, chromatin dynamics, and homologous recombination repair of double-strand breaks [#1, #12], and it sequesters E2F4 in the cytosol to block DREAM complex assembly at the BRCA1 promoter, sustaining BRCA1 expression and HRR [#21]. It additionally cooperates with the centrosomal translation machinery to control localized mRNA translation [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established OFD1 as a constitutive centrosomal component and identified which domains target it there, framing it as a structural scaffold rather than a transient visitor.\",\n      \"evidence\": \"GFP-OFD1 deletion constructs and immunofluorescence in kidney epithelial lines and human metanephroi\",\n      \"pmids\": [\"15466260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define a molecular activity for OFD1\", \"No partners identified at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed a nuclear pool of OFD1 and its physical association with chromatin-modifying machinery, the first hint of a function beyond the centrosome.\",\n      \"evidence\": \"Co-immunoprecipitation and yeast two-hybrid identifying RuvBL1 and TIP60 complex subunits\",\n      \"pmids\": [\"17761535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP without reciprocal or endogenous validation\", \"Functional consequence of TIP60 association not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed OFD1 in ciliary signaling physiology by linking it to non-canonical Wnt/PCP-dependent cilia and left-right patterning.\",\n      \"evidence\": \"Morpholino knockdown and genetic epistasis with Wnt/PCP mutants in zebrafish\",\n      \"pmids\": [\"18971206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino-based; off-target effects not excluded\", \"Molecular link between OFD1 and PCP components undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected OFD1 genotype to a ciliary interaction and localization phenotype, showing dominant versus recessive mutations differ in disrupting lebercilin binding and pericentriolar targeting.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, and immunofluorescence of disease alleles in RPE1 cells\",\n      \"pmids\": [\"19800048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of OFD1-lebercilin complex in cilia not established\", \"Structural basis of binding unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the core molecular function of OFD1 as a distal-centriole protein controlling centriole length and distal appendage formation, the mechanistic anchor of its ciliogenesis role.\",\n      \"evidence\": \"Conditional knockout ES cells, electron microscopy, and disease-allele knock-in\",\n      \"pmids\": [\"20230748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of microtubule length control not resolved at molecular detail\", \"How distal appendage recruitment is achieved not yet mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked OFD1 loss to renal cystic disease through mTOR dysregulation and demonstrated pharmacological reversibility, establishing a druggable downstream pathway.\",\n      \"evidence\": \"Kidney-specific conditional knockout mouse with rapamycin rescue and western blot pathway analysis\",\n      \"pmids\": [\"20444807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between OFD1 and mTOR activation not defined\", \"Whether mTOR effect is cilia-dependent unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovered that selective autophagy degrades the satellite pool of OFD1 to license ciliogenesis, recasting OFD1 turnover as a regulatory switch for cilium formation.\",\n      \"evidence\": \"Atg5/Atg3-null MEFs, siRNA rescue, and immunofluorescence across multiple cell types\",\n      \"pmids\": [\"24089205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recognition mechanism marking satellite OFD1 for autophagy not defined here\", \"Distinction between satellite and centrosomal pools not molecularly resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Positioned OFD1 within a polycystin-dependent ciliary signaling complex, linking it to ADPKD-relevant membrane receptor assemblies.\",\n      \"evidence\": \"Co-IP and immunofluorescence in renal epithelia and ADPKD patient cells\",\n      \"pmids\": [\"25180832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect associations within the complex not separated\", \"Functional output of the OFD1-polycystin complex not measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined an interdependent OFD1/KIAA0753/FOR20 ternary module governing mutual recruitment to satellites and centrosomes, clarifying how OFD1 is positioned in the centriolar protein network.\",\n      \"evidence\": \"Co-IP and siRNA interdependence assays in RPE1 cells\",\n      \"pmids\": [\"26643951\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and direct contacts within the ternary complex unresolved\", \"Order of assembly not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended OFD1 function to photoreceptor cilia and implicated it in cell survival via control of reactive oxygen species and apoptosis.\",\n      \"evidence\": \"siRNA knockdown and overexpression in retinal cell lines with ROS and apoptosis assays\",\n      \"pmids\": [\"27196396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking OFD1 to ROS levels not defined\", \"Whether survival effect is cilia-dependent unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a centrosome-based translational control function, with OFD1 cooperating with Bicc1 and the PIC/eIF4F machinery to regulate specific mRNAs relevant to cystic disease.\",\n      \"evidence\": \"Co-IP with mass spectrometry and translation assays in kidney cells\",\n      \"pmids\": [\"28450740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RNA-binding by OFD1 not demonstrated\", \"Specific target mRNAs and selection mechanism incompletely defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established a nuclear genome-maintenance role, showing OFD1 supports TIP60 localization, histone acetylation, and homologous-recombination DSB repair, with loss phenocopying TIP60 deficiency.\",\n      \"evidence\": \"Chromatin fractionation, DSB repair assays, and checkpoint analysis in patient-derived cells\",\n      \"pmids\": [\"27798113\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OFD1 directly stabilizes TIP60 or acts indirectly unresolved\", \"How a centrosomal protein partitions to chromatin not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated evolutionary conservation of OFD1's basal-body docking and distal-assembly function and its transition-zone localization in a ciliate.\",\n      \"evidence\": \"RNAi knockdown, immunofluorescence, and electron microscopy in Paramecium\",\n      \"pmids\": [\"28367320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mapping of conserved domains to specific functions not done\", \"Relationship to mammalian distal appendage hierarchy not yet integrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed OFD1 is itself a selective autophagy receptor for ATG13 that limits autophagosome biogenesis, and that excess autophagy underlies OFD1-related polycystic kidney disease rescuable by autophagy inhibition.\",\n      \"evidence\": \"Direct binding assays, conditional mouse model, autophagy flux, and patient cell analysis\",\n      \"pmids\": [\"33368531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the autophagy-receptor role is spatially separated from being an autophagy substrate not fully resolved\", \"Regulation of OFD1-ATG13 binding not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified TRAPPIII subunits as competitive OFD1 partners controlling its association with PCM1, providing a switch between cilium assembly and disassembly states.\",\n      \"evidence\": \"Co-IP and siRNA with functional readouts in RPE1 cells\",\n      \"pmids\": [\"32258032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of competitive binding unresolved\", \"Physiological trigger that biases binding not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected OFD1 to cell-cycle progression and genome stability, with depletion causing centrosome accumulation, aneuploidy, and microtubule network defects.\",\n      \"evidence\": \"High-content microscopy and proliferation assays after siRNA in fibroblasts\",\n      \"pmids\": [\"32473706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether defects are secondary to centrosome amplification not separated\", \"Direct cell-cycle effector role undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a GPCR-cAMP-PKA signaling axis that controls centrosomal OFD1 levels, identifying Ser735 phosphorylation and praja2-mediated proteasomal degradation as required for ciliogenesis.\",\n      \"evidence\": \"Mass spectrometry, site-directed mutagenesis, ubiquitylation assays, and in vivo Medaka model\",\n      \"pmids\": [\"33934390\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How this proteasomal route is coordinated with autophagic turnover unresolved\", \"Upstream receptors that engage this axis not enumerated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed Myosin VI regulates OFD1 mobility and localization at centrioles, coupling motor activity to distal appendage protein recruitment and autophagic clearance of OFD1.\",\n      \"evidence\": \"Co-IP, FRAP, and siRNA in non-tumoral cell lines\",\n      \"pmids\": [\"34957672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus adaptor-mediated Myosin VI-OFD1 contact not resolved\", \"Mechanism by which mobility controls satellite autophagy unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the hierarchical recruitment order of a distal-centriole module (DISCO: CEP90/FOPNL/OFD1) downstream of MNR and upstream of CEP83/CEP89/CEP164, mechanistically explaining OFD1's role in distal appendage assembly and basal body docking.\",\n      \"evidence\": \"Ultrastructure expansion microscopy and RNAi/siRNA in Paramecium and mammalian cells\",\n      \"pmids\": [\"36070319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical contacts within DISCO not mapped\", \"How module assembly is timed during duplication not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Separated a cilia-independent OFD1 function in cell survival, mapping a paxillin-binding domain that supports ECM adhesion distinct from the ciliogenesis domain.\",\n      \"evidence\": \"Domain mapping, co-IP, adhesion and apoptosis assays with paxillin rescue in melanocytes\",\n      \"pmids\": [\"38139355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether OFD1-paxillin acts at adhesion sites or remotely not established\", \"Mechanism by which OFD1 controls paxillin expression undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a cytosolic OFD1-E2F4-DREAM-BRCA1 axis in which OFD1 sequesters E2F4 to prevent DREAM-mediated BRCA1 repression, sustaining HRR and creating synthetic lethality with PARP inhibitors.\",\n      \"evidence\": \"Co-IP, nuclear/cytoplasmic fractionation, ChIP, promoter reporters, and xenograft models\",\n      \"pmids\": [\"40764600\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How OFD1's cytosolic sequestration pool is regulated unknown\", \"Integration with OFD1's TIP60-dependent HRR role not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How OFD1 partitions among its centrosomal, satellite, nuclear/chromatin, and cytosolic functional pools, and how the competing autophagic and proteasomal degradation routes are spatially and temporally coordinated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of pool partitioning\", \"Structural basis of OFD1 scaffolding interactions largely undetermined\", \"Relationship between ciliary and nuclear DSB-repair functions not mechanistically linked\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 19]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14, 21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 4, 9, 16]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 6, 8, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 19]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [12, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"TIP60 histone acetyltransferase complex\",\n      \"OFD1/KIAA0753/FOR20 ternary complex\",\n      \"DISCO complex (CEP90/FOPNL/OFD1)\",\n      \"TBC1D31-praja2-PKA centrosomal complex\"\n    ],\n    \"partners\": [\n      \"RuvBL1\",\n      \"LCA5\",\n      \"KIAA0753\",\n      \"FOR20\",\n      \"ATG13\",\n      \"TRAPPC8\",\n      \"E2F4\",\n      \"MYO6\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}