{"gene":"WDR73","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2014,"finding":"WDR73 protein localizes diffusely in the cytoplasm during interphase but relocalizes to spindle poles and astral microtubules during mitosis, and its depletion in podocytes causes abnormal nuclear morphology, low cell viability, and alterations of the microtubule network.","method":"Immunofluorescence localization in cells, fibroblast analysis from affected patient, WDR73-depleted podocyte experiments","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence (nuclear morphology, cell viability, microtubule network alterations), single lab, two orthogonal approaches (patient fibroblasts + knockdown podocytes)","pmids":["25466283"],"is_preprint":false},{"year":2015,"finding":"WDR73 protein physically interacts with α-, β-, and γ-tubulin, HSP-70, HSP-90, and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase (CAD) multi-enzyme complex at mitotic microtubules. Truncated/loss-of-function mutant WDR73 proteins (p.Phe296Leufs*26 and p.Arg256Profs*18) are unstable and show increased interaction with α- and β-tubulin and HSP-70/HSP-90.","method":"Co-immunoprecipitation/interaction assays with recombinant truncated proteins; fibroblast proliferation assays","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — identified multiple binding partners by interaction assay with recombinant proteins including mutant forms, single lab, multiple partners tested","pmids":["26070982"],"is_preprint":false},{"year":2015,"finding":"Loss of WDR73 function in zebrafish (wdr73 morpholino knockdown) causes significant brain growth and morphogenesis defects, resulting in a poorly differentiated midbrain and cerebellum, establishing a direct role for WDR73 in brain development.","method":"Morpholino knockdown in zebrafish with morphological phenotypic readout","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean loss-of-function in a vertebrate model with defined cellular phenotype, single lab, single method","pmids":["25873735"],"is_preprint":false},{"year":2021,"finding":"WDR73 physically interacts with the INTS9 and INTS11 subunits of the Integrator complex, and WDR73 suppression disrupts two Integrator-regulated pathways: processing of uridylate-rich small nuclear RNAs (UsnRNA) and the transcriptional response to EGF stimulation. WDR73 loss also leads to altered expression of genes encoding cell cycle regulatory proteins.","method":"Co-immunoprecipitation (interaction with INTS9 and INTS11), snRNA processing assays, transcriptional response assays, transcriptomic analysis of WDR73-suppressed cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal/direct interaction with Integrator subunits combined with functional pathway assays (snRNA processing, EGF transcriptional response), single lab, multiple orthogonal methods","pmids":["33686175"],"is_preprint":false},{"year":2022,"finding":"WDR73 physically interacts with PIP4K2C (a phospholipid kinase) as validated by protein microarray and GST pulldown. WDR73 regulates PIP4K2C protein stability through the autophagy-lysosomal pathway. WDR73 knockout reduces PIP4K2C levels, leading to decreased PIP2 and impaired focal adhesion (FA) formation. Podocyte-specific Wdr73 conditional knockout mice show albuminuria and podocyte foot process injury with impaired FA formation in primary podocytes.","method":"Protein microarray, GST pulldown, WDR73 KO HEK293 cells, conditional knockout mouse model with ADR-induced nephropathy, primary podocyte culture, FA assays","journal":"Biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — GST pulldown plus in vivo KO mouse model with defined molecular mechanism (autophagy-lysosomal pathway degradation of PIP4K2C, PIP2 reduction, FA impairment) and functional renal phenotype, single lab, multiple orthogonal methods","pmids":["36290302"],"is_preprint":false}],"current_model":"WDR73 is a WD40-repeat protein that localizes to the cytoplasm during interphase and relocalizes to spindle poles and astral microtubules during mitosis, where it interacts with α/β/γ-tubulin, HSP-70/90, and the CAD multi-enzyme complex; it also associates with the Integrator complex subunits INTS9/INTS11 to regulate UsnRNA processing and EGF-stimulated transcription, and stabilizes the phospholipid kinase PIP4K2C via the autophagy-lysosomal pathway to sustain focal adhesion formation—collectively maintaining cell architecture, cell cycle progression, and survival in neurons and podocytes."},"narrative":{"mechanistic_narrative":"WDR73 is a WD40-repeat protein required for the maintenance of cell architecture, cell cycle progression, and survival in neurons and podocytes [PMID:25466283, PMID:25873735]. It localizes diffusely in the cytoplasm during interphase and relocalizes to spindle poles and astral microtubules in mitosis, where it physically associates with α-, β-, and γ-tubulin, HSP-70/HSP-90, and the CAD multi-enzyme complex; its depletion disrupts the microtubule network, distorts nuclear morphology, and reduces cell viability [PMID:25466283, PMID:26070982]. Disease-associated truncating mutants are unstable and bind tubulin and the chaperones more avidly, indicating loss of normal WDR73 stability and microtubule association [PMID:26070982]. Beyond the mitotic cytoskeleton, WDR73 interacts with the Integrator complex subunits INTS9 and INTS11 and is required for Integrator-dependent UsnRNA processing and the EGF-stimulated transcriptional response, with its loss perturbing cell-cycle regulatory gene expression [PMID:33686175]. WDR73 also binds the phospholipid kinase PIP4K2C and stabilizes it against autophagy-lysosomal degradation, sustaining PIP2 levels and focal adhesion formation; podocyte-specific Wdr73 knockout mice develop albuminuria and foot-process injury [PMID:36290302]. Loss of WDR73 in zebrafish causes brain growth and morphogenesis defects, establishing a developmental requirement consistent with its podocyte and neuronal roles [PMID:25873735].","teleology":[{"year":2014,"claim":"Established that WDR73 is a cell-cycle-regulated cytoskeletal protein whose loss compromises cell integrity, framing it as more than a static structural component.","evidence":"Immunofluorescence localization across cell cycle, patient fibroblast analysis, and WDR73-depleted podocyte assays","pmids":["25466283"],"confidence":"Medium","gaps":["Direct binding partners at the spindle not yet identified","Mechanism linking microtubule association to nuclear morphology unresolved"]},{"year":2015,"claim":"Defined the molecular interactome of WDR73 at mitotic microtubules and showed disease mutants are unstable, connecting protein destabilization to aberrant tubulin/chaperone binding.","evidence":"Co-immunoprecipitation/interaction assays with recombinant wild-type and truncated proteins; fibroblast proliferation assays","pmids":["26070982"],"confidence":"Medium","gaps":["Functional consequence of CAD complex association not established","Whether tubulin binding is direct or chaperone-mediated unclear"]},{"year":2015,"claim":"Demonstrated an organismal requirement for WDR73 in vertebrate brain development, linking molecular dysfunction to the neurological phenotype.","evidence":"Morpholino knockdown in zebrafish with morphological readout of midbrain/cerebellum","pmids":["25873735"],"confidence":"Medium","gaps":["Cell-type and molecular basis of brain defect not dissected","Morpholino specificity not cross-validated by mutant"]},{"year":2021,"claim":"Revealed a nuclear/transcriptional axis for WDR73 through the Integrator complex, expanding its role beyond the cytoskeleton to RNA processing and signal-responsive transcription.","evidence":"Co-immunoprecipitation with INTS9/INTS11, snRNA processing assays, EGF transcriptional assays, and transcriptomics of suppressed cells","pmids":["33686175"],"confidence":"Medium","gaps":["How WDR73 mechanistically contributes to Integrator activity unknown","Relationship between cytoplasmic and Integrator-associated pools unresolved"]},{"year":2022,"claim":"Identified a substrate-stabilization mechanism whereby WDR73 protects PIP4K2C from autophagy-lysosomal degradation to maintain PIP2 and focal adhesions, providing a molecular route to the podocyte phenotype in vivo.","evidence":"Protein microarray and GST pulldown, WDR73 KO HEK293 cells, conditional knockout mice with ADR nephropathy, and primary podocyte focal adhesion assays","pmids":["36290302"],"confidence":"High","gaps":["How WDR73 shields PIP4K2C from autophagic turnover at the molecular level unknown","Integration of the PIP4K2C/FA axis with the mitotic and Integrator functions not established"]},{"year":null,"claim":"It remains unknown how WDR73's distinct activities — mitotic microtubule association, Integrator-dependent RNA/transcription regulation, and PIP4K2C stabilization — are coordinated into a single unifying biochemical function.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of WDR73 or its complexes","No defined catalytic or scaffolding mechanism unifying the three pathways","Causal hierarchy among the phenotypes not determined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4]}],"complexes":[],"partners":["TUBA1A","TUBB","TUBG1","HSPA8","HSP90AA1","INTS9","INTS11","PIP4K2C"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P4I2","full_name":"Integrator complex assembly factor WDR73","aliases":["WD repeat-containing protein 73"],"length_aa":378,"mass_kda":41.7,"function":"Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex (PubMed:39032489). Associates with INTS9 and INTS11 in the cytoplasm, stabilizing the INTS9-INTS11 heterodimer and blocking the active site of INTS11 (PubMed:39032489). BRAT1 then joins the complex and plugs the active site of INTS11, leading to WDR73 release and nuclear import of INTS9 and INTS11 (PubMed:39032489)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, spindle; Cytoplasm, cytoskeleton, spindle pole; Cleavage furrow","url":"https://www.uniprot.org/uniprotkb/Q6P4I2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR73","classification":"Not Classified","n_dependent_lines":664,"n_total_lines":1208,"dependency_fraction":0.5496688741721855},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WDR73","total_profiled":1310},"omim":[{"mim_id":"616144","title":"WD REPEAT-CONTAINING PROTEIN 73; WDR73","url":"https://www.omim.org/entry/616144"},{"mim_id":"613624","title":"ZINC FINGER PROTEIN 592; ZNF592","url":"https://www.omim.org/entry/613624"},{"mim_id":"251300","title":"GALLOWAY-MOWAT SYNDROME 1; GAMOS1","url":"https://www.omim.org/entry/251300"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR73"},"hgnc":{"alias_symbol":["FLJ14888","HSPC264"],"prev_symbol":[]},"alphafold":{"accession":"Q6P4I2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P4I2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P4I2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P4I2-F1-predicted_aligned_error_v6.png","plddt_mean":87.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR73","jax_strain_url":"https://www.jax.org/strain/search?query=WDR73"},"sequence":{"accession":"Q6P4I2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P4I2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P4I2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P4I2"}},"corpus_meta":[{"pmid":"25466283","id":"PMC_25466283","title":"Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25466283","citation_count":93,"is_preprint":false},{"pmid":"26070982","id":"PMC_26070982","title":"Recessive nephrocerebellar syndrome on the Galloway-Mowat syndrome spectrum is caused by homozygous protein-truncating mutations of WDR73.","date":"2015","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26070982","citation_count":51,"is_preprint":false},{"pmid":"25873735","id":"PMC_25873735","title":"Nonsense mutation in the WDR73 gene is associated with Galloway-Mowat syndrome.","date":"2015","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25873735","citation_count":33,"is_preprint":false},{"pmid":"27001912","id":"PMC_27001912","title":"Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene.","date":"2016","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/27001912","citation_count":31,"is_preprint":false},{"pmid":"33686175","id":"PMC_33686175","title":"Disruption of pathways regulated by Integrator complex in Galloway-Mowat syndrome due to WDR73 mutations.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33686175","citation_count":23,"is_preprint":false},{"pmid":"27983999","id":"PMC_27983999","title":"WDR73 missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in a consanguineous family.","date":"2016","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27983999","citation_count":18,"is_preprint":false},{"pmid":"30315938","id":"PMC_30315938","title":"WDR73-related galloway mowat syndrome with collapsing glomerulopathy.","date":"2018","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30315938","citation_count":11,"is_preprint":false},{"pmid":"36290302","id":"PMC_36290302","title":"WDR73 Depletion Destabilizes PIP4K2C Activity and Impairs Focal Adhesion Formation in Galloway-Mowat Syndrome.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36290302","citation_count":5,"is_preprint":false},{"pmid":"39572926","id":"PMC_39572926","title":"Galloway-Mowat syndrome with retinal involvement associated with a novel WDR73 variant: case report and review of the literature.","date":"2024","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39572926","citation_count":1,"is_preprint":false},{"pmid":"39532686","id":"PMC_39532686","title":"A Novel Compound Heterozygous Genotype of the WDR73 Gene Associated With a Psychomotor Retardation Syndrome Without Cerebellar Atrophy and Other CNS Structural Abnormalities.","date":"2024","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39532686","citation_count":1,"is_preprint":false},{"pmid":"40688758","id":"PMC_40688758","title":"Refining the Phenotypic and Genotypic Spectrum of WDR73-Related Galloway-Mowat Syndrome: A Case Series and Systematic Review.","date":"2025","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40688758","citation_count":0,"is_preprint":false},{"pmid":"41782252","id":"PMC_41782252","title":"A novel homozygous frameshift mutation in the WDR73 gene causes Galloway-Mowat syndrome in a Chinese consanguineous family.","date":"2026","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41782252","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7919,"output_tokens":1502,"usd":0.023144,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8234,"output_tokens":2316,"usd":0.049535,"stage2_stop_reason":"end_turn"},"total_usd":0.072679,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"WDR73 protein localizes diffusely in the cytoplasm during interphase but relocalizes to spindle poles and astral microtubules during mitosis, and its depletion in podocytes causes abnormal nuclear morphology, low cell viability, and alterations of the microtubule network.\",\n      \"method\": \"Immunofluorescence localization in cells, fibroblast analysis from affected patient, WDR73-depleted podocyte experiments\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence (nuclear morphology, cell viability, microtubule network alterations), single lab, two orthogonal approaches (patient fibroblasts + knockdown podocytes)\",\n      \"pmids\": [\"25466283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WDR73 protein physically interacts with α-, β-, and γ-tubulin, HSP-70, HSP-90, and the carbamoyl phosphate synthetase 2/aspartate transcarbamylase/dihydroorotase (CAD) multi-enzyme complex at mitotic microtubules. Truncated/loss-of-function mutant WDR73 proteins (p.Phe296Leufs*26 and p.Arg256Profs*18) are unstable and show increased interaction with α- and β-tubulin and HSP-70/HSP-90.\",\n      \"method\": \"Co-immunoprecipitation/interaction assays with recombinant truncated proteins; fibroblast proliferation assays\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — identified multiple binding partners by interaction assay with recombinant proteins including mutant forms, single lab, multiple partners tested\",\n      \"pmids\": [\"26070982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of WDR73 function in zebrafish (wdr73 morpholino knockdown) causes significant brain growth and morphogenesis defects, resulting in a poorly differentiated midbrain and cerebellum, establishing a direct role for WDR73 in brain development.\",\n      \"method\": \"Morpholino knockdown in zebrafish with morphological phenotypic readout\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean loss-of-function in a vertebrate model with defined cellular phenotype, single lab, single method\",\n      \"pmids\": [\"25873735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR73 physically interacts with the INTS9 and INTS11 subunits of the Integrator complex, and WDR73 suppression disrupts two Integrator-regulated pathways: processing of uridylate-rich small nuclear RNAs (UsnRNA) and the transcriptional response to EGF stimulation. WDR73 loss also leads to altered expression of genes encoding cell cycle regulatory proteins.\",\n      \"method\": \"Co-immunoprecipitation (interaction with INTS9 and INTS11), snRNA processing assays, transcriptional response assays, transcriptomic analysis of WDR73-suppressed cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal/direct interaction with Integrator subunits combined with functional pathway assays (snRNA processing, EGF transcriptional response), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33686175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR73 physically interacts with PIP4K2C (a phospholipid kinase) as validated by protein microarray and GST pulldown. WDR73 regulates PIP4K2C protein stability through the autophagy-lysosomal pathway. WDR73 knockout reduces PIP4K2C levels, leading to decreased PIP2 and impaired focal adhesion (FA) formation. Podocyte-specific Wdr73 conditional knockout mice show albuminuria and podocyte foot process injury with impaired FA formation in primary podocytes.\",\n      \"method\": \"Protein microarray, GST pulldown, WDR73 KO HEK293 cells, conditional knockout mouse model with ADR-induced nephropathy, primary podocyte culture, FA assays\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — GST pulldown plus in vivo KO mouse model with defined molecular mechanism (autophagy-lysosomal pathway degradation of PIP4K2C, PIP2 reduction, FA impairment) and functional renal phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36290302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR73 is a WD40-repeat protein that localizes to the cytoplasm during interphase and relocalizes to spindle poles and astral microtubules during mitosis, where it interacts with α/β/γ-tubulin, HSP-70/90, and the CAD multi-enzyme complex; it also associates with the Integrator complex subunits INTS9/INTS11 to regulate UsnRNA processing and EGF-stimulated transcription, and stabilizes the phospholipid kinase PIP4K2C via the autophagy-lysosomal pathway to sustain focal adhesion formation—collectively maintaining cell architecture, cell cycle progression, and survival in neurons and podocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR73 is a WD40-repeat protein required for the maintenance of cell architecture, cell cycle progression, and survival in neurons and podocytes [#0, #2]. It localizes diffusely in the cytoplasm during interphase and relocalizes to spindle poles and astral microtubules in mitosis, where it physically associates with α-, β-, and γ-tubulin, HSP-70/HSP-90, and the CAD multi-enzyme complex; its depletion disrupts the microtubule network, distorts nuclear morphology, and reduces cell viability [#0, #1]. Disease-associated truncating mutants are unstable and bind tubulin and the chaperones more avidly, indicating loss of normal WDR73 stability and microtubule association [#1]. Beyond the mitotic cytoskeleton, WDR73 interacts with the Integrator complex subunits INTS9 and INTS11 and is required for Integrator-dependent UsnRNA processing and the EGF-stimulated transcriptional response, with its loss perturbing cell-cycle regulatory gene expression [#3]. WDR73 also binds the phospholipid kinase PIP4K2C and stabilizes it against autophagy-lysosomal degradation, sustaining PIP2 levels and focal adhesion formation; podocyte-specific Wdr73 knockout mice develop albuminuria and foot-process injury [#4]. Loss of WDR73 in zebrafish causes brain growth and morphogenesis defects, establishing a developmental requirement consistent with its podocyte and neuronal roles [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established that WDR73 is a cell-cycle-regulated cytoskeletal protein whose loss compromises cell integrity, framing it as more than a static structural component.\",\n      \"evidence\": \"Immunofluorescence localization across cell cycle, patient fibroblast analysis, and WDR73-depleted podocyte assays\",\n      \"pmids\": [\"25466283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partners at the spindle not yet identified\", \"Mechanism linking microtubule association to nuclear morphology unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the molecular interactome of WDR73 at mitotic microtubules and showed disease mutants are unstable, connecting protein destabilization to aberrant tubulin/chaperone binding.\",\n      \"evidence\": \"Co-immunoprecipitation/interaction assays with recombinant wild-type and truncated proteins; fibroblast proliferation assays\",\n      \"pmids\": [\"26070982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CAD complex association not established\", \"Whether tubulin binding is direct or chaperone-mediated unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated an organismal requirement for WDR73 in vertebrate brain development, linking molecular dysfunction to the neurological phenotype.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish with morphological readout of midbrain/cerebellum\",\n      \"pmids\": [\"25873735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type and molecular basis of brain defect not dissected\", \"Morpholino specificity not cross-validated by mutant\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a nuclear/transcriptional axis for WDR73 through the Integrator complex, expanding its role beyond the cytoskeleton to RNA processing and signal-responsive transcription.\",\n      \"evidence\": \"Co-immunoprecipitation with INTS9/INTS11, snRNA processing assays, EGF transcriptional assays, and transcriptomics of suppressed cells\",\n      \"pmids\": [\"33686175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How WDR73 mechanistically contributes to Integrator activity unknown\", \"Relationship between cytoplasmic and Integrator-associated pools unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified a substrate-stabilization mechanism whereby WDR73 protects PIP4K2C from autophagy-lysosomal degradation to maintain PIP2 and focal adhesions, providing a molecular route to the podocyte phenotype in vivo.\",\n      \"evidence\": \"Protein microarray and GST pulldown, WDR73 KO HEK293 cells, conditional knockout mice with ADR nephropathy, and primary podocyte focal adhesion assays\",\n      \"pmids\": [\"36290302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WDR73 shields PIP4K2C from autophagic turnover at the molecular level unknown\", \"Integration of the PIP4K2C/FA axis with the mitotic and Integrator functions not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how WDR73's distinct activities — mitotic microtubule association, Integrator-dependent RNA/transcription regulation, and PIP4K2C stabilization — are coordinated into a single unifying biochemical function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of WDR73 or its complexes\", \"No defined catalytic or scaffolding mechanism unifying the three pathways\", \"Causal hierarchy among the phenotypes not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TUBA1A\", \"TUBB\", \"TUBG1\", \"HSPA8\", \"HSP90AA1\", \"INTS9\", \"INTS11\", \"PIP4K2C\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}