{"gene":"WDR73","run_date":"2026-04-28T23:00:23","timeline":{"discoveries":[{"year":2014,"finding":"WDR73 protein localizes diffusely in the cytoplasm during interphase but relocalizes to spindle poles and astral microtubules during mitosis. Loss of WDR73 in fibroblasts and WDR73-depleted podocytes causes abnormal nuclear morphology, low cell viability, and alterations of the microtubule network.","method":"Immunofluorescence/subcellular fractionation in patient fibroblasts and siRNA-depleted podocytes with phenotypic readout","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiment with functional consequence; single lab, multiple cell-type validations","pmids":["25466283"],"is_preprint":false},{"year":2015,"finding":"WDR73 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. Truncating disease-associated WDR73 mutant proteins (p.Phe296Leufs*26 and p.Arg256Profs*18) are unstable and show increased interaction with α- and β-tubulin and HSP-70/HSP-90, suggesting dysregulated chaperone engagement.","method":"Co-immunoprecipitation/pull-down of endogenous WDR73 complexes; recombinant mutant protein interaction assays","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction assays with multiple binding partners; single lab but multiple orthogonal targets tested","pmids":["26070982"],"is_preprint":false},{"year":2015,"finding":"WDR73 is concentrated at mitotic microtubules and is required for cell cycle progression, proliferation, and survival; patient fibroblasts homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early.","method":"Primary fibroblast culture from patients with homozygous frameshift mutation; proliferation and senescence assays","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — clean loss-of-function (patient-derived cells) with defined cellular phenotype; single lab","pmids":["26070982"],"is_preprint":false},{"year":2015,"finding":"Knockdown of wdr73 in zebrafish causes significant brain growth and morphogenesis defects resulting in a poorly differentiated midbrain and cerebellum, establishing a developmental role for WDR73 in brain morphogenesis in vivo.","method":"Morpholino knockdown in zebrafish embryos with phenotypic readout of brain morphology","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with specific developmental phenotype; single lab","pmids":["25873735"],"is_preprint":false},{"year":2021,"finding":"WDR73 physically interacts with INTS9 and INTS11, components of the Integrator complex. WDR73 suppression disrupts Integrator-regulated processing of uridylate-rich small nuclear RNAs (UsnRNAs) and impairs the transcriptional response to EGF stimulation, and alters expression of cell cycle regulatory genes.","method":"Co-immunoprecipitation of WDR73 with INTS9/INTS11; snRNA processing assays and EGF-response transcriptomics in WDR73-depleted cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with functional pathway validation by multiple orthogonal assays; single lab","pmids":["33686175"],"is_preprint":false},{"year":2022,"finding":"WDR73 directly interacts with PIP4K2C (a phosphatidylinositol-5-phosphate 4-kinase) and regulates its protein stability through the autophagy-lysosomal pathway. WDR73 knockout reduces PIP4K2C levels, leading to decreased PIP2 and impaired focal adhesion formation. Podocyte-specific Wdr73 conditional knockout mice show albuminuria and podocyte foot process injury, with impaired focal adhesion formation in primary podocytes.","method":"Protein microarray, GST pulldown (WDR73–PIP4K2C interaction); WDR73 KO HEK293 cells and conditional knockout mice with focal adhesion, PIP2, and proteinuria readouts","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 1–2 — GST pulldown plus in vivo mouse KO with multiple orthogonal readouts; single lab","pmids":["36290302"],"is_preprint":false}],"current_model":"WDR73 is a WD40-repeat protein that localizes to astral microtubules and spindle poles during mitosis (cytoplasmic during interphase), interacts with tubulins, HSP70/90, the CAD complex, and the Integrator complex subunits INTS9/INTS11, and stabilizes PIP4K2C via the autophagy-lysosomal pathway to support focal adhesion formation, UsnRNA processing, EGF-responsive transcription, and cell cycle progression; loss of function causes mitotic defects, nuclear morphology abnormalities, senescence, and podocyte/neuronal degeneration underlying Galloway-Mowat syndrome."},"narrative":{"teleology":[{"year":2014,"claim":"Establishing that WDR73 is a mitotic spindle-associated protein whose loss causes nuclear morphology defects and reduced viability resolved the first mechanistic question: where does the protein act and what happens without it?","evidence":"Immunofluorescence and subcellular fractionation in patient fibroblasts and siRNA-depleted podocytes","pmids":["25466283"],"confidence":"Medium","gaps":["No direct binding partner identified at this stage","Mechanism linking spindle localization to nuclear morphology defects not defined","Single-lab observation without independent replication"]},{"year":2015,"claim":"Identification of WDR73's physical interactome — tubulins, HSP70/90, and the CAD complex — and demonstration that disease-causing truncations destabilize the protein and dysregulate chaperone engagement established the molecular basis of loss-of-function pathogenesis.","evidence":"Co-immunoprecipitation and pull-down assays with endogenous and recombinant wild-type and mutant WDR73 proteins; patient fibroblast proliferation and senescence assays","pmids":["26070982"],"confidence":"Medium","gaps":["Functional significance of the WDR73–CAD interaction is unexplored","No structural model to explain how WD40 repeats engage tubulins versus chaperones","Cell cycle arrest mechanism not molecularly defined"]},{"year":2015,"claim":"Demonstration that wdr73 knockdown in zebrafish causes midbrain and cerebellar morphogenesis defects established an in vivo developmental requirement and linked WDR73 to the neurological component of Galloway-Mowat syndrome.","evidence":"Morpholino knockdown in zebrafish embryos with brain morphology phenotyping","pmids":["25873735"],"confidence":"Medium","gaps":["Morpholino off-target effects not fully excluded (no genetic mutant confirmation)","Downstream signaling pathways mediating brain defects not identified","Kidney phenotype not assessed in the zebrafish model"]},{"year":2021,"claim":"Discovery that WDR73 interacts with Integrator subunits INTS9/INTS11 and is required for UsnRNA processing and EGF-responsive transcription revealed a nuclear RNA-processing function orthogonal to its mitotic role.","evidence":"Co-immunoprecipitation of WDR73 with INTS9/INTS11; snRNA processing assays and EGF-response transcriptomics in WDR73-depleted cells","pmids":["33686175"],"confidence":"Medium","gaps":["Whether WDR73 is a stable Integrator complex subunit or a transient accessory factor is unresolved","Relative contribution of snRNA processing versus transcription defects to disease phenotype unknown","Single-lab finding without independent replication"]},{"year":2022,"claim":"Identification of PIP4K2C as a direct WDR73 binding partner whose stability depends on WDR73-mediated protection from autophagy-lysosomal degradation provided a mechanism for podocyte injury: reduced PIP2 and impaired focal adhesion formation.","evidence":"Protein microarray screen, GST pulldown, WDR73 KO HEK293 cells, and podocyte-specific Wdr73 conditional knockout mice with focal adhesion, PIP2, and proteinuria readouts","pmids":["36290302"],"confidence":"Medium","gaps":["Structural basis of the WDR73–PIP4K2C interaction not determined","Whether PIP4K2C stabilization accounts for neurological phenotypes is untested","Relationship between the PIP4K2C and Integrator pathways not explored"]},{"year":null,"claim":"How WDR73's multiple functions — mitotic spindle association, Integrator-mediated RNA processing, and PIP4K2C stabilization — are coordinated, and which function(s) primarily drive the neuronal versus podocyte pathology in Galloway-Mowat syndrome, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of WDR73 or its complexes exists","Relative contribution of each pathway to neuronal versus renal disease is unknown","No neuron-specific conditional knockout model has been reported"]}],"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":[4,5]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,4]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[5]}],"complexes":["Integrator complex (via INTS9/INTS11)"],"partners":["TUBA1A","TUBB","TUBG1","HSPA1A","HSP90AA1","CAD","INTS9","INTS11"],"other_free_text":[]},"mechanistic_narrative":"WDR73 is a WD40-repeat protein that localizes diffusely in the cytoplasm during interphase and relocalizes to spindle poles and astral microtubules during mitosis, where it interacts with α-, β-, and γ-tubulin, HSP70/90, and the CAD multi-enzyme complex to support cell cycle progression and cell survival [PMID:25466283, PMID:26070982]. WDR73 also physically associates with Integrator complex subunits INTS9 and INTS11, and its depletion disrupts UsnRNA 3′-end processing and the transcriptional response to EGF stimulation [PMID:33686175]. WDR73 directly binds PIP4K2C and stabilizes it via the autophagy-lysosomal pathway, maintaining PIP2 levels required for focal adhesion formation in podocytes; podocyte-specific Wdr73 knockout in mice causes albuminuria and foot process effacement [PMID:36290302]. Loss-of-function mutations in WDR73 cause Galloway-Mowat syndrome, characterized by nephrotic syndrome and neurodevelopmental defects including impaired brain morphogenesis [PMID:25466283, PMID:25873735]."},"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":91,"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":17,"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":7155,"output_tokens":1584,"usd":0.022613},"stage2":{"model":"claude-opus-4-6","input_tokens":4843,"output_tokens":1931,"usd":0.108735},"total_usd":0.131348,"stage1_batch_id":"msgbatch_01BparvgRZ9S2LMidvaoo86K","stage2_batch_id":"msgbatch_01NkBfv9SVZWthhS7j6mU6G3","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. Loss of WDR73 in fibroblasts and WDR73-depleted podocytes causes abnormal nuclear morphology, low cell viability, and alterations of the microtubule network.\",\n      \"method\": \"Immunofluorescence/subcellular fractionation in patient fibroblasts and siRNA-depleted podocytes with phenotypic readout\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional consequence; single lab, multiple cell-type validations\",\n      \"pmids\": [\"25466283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WDR73 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. Truncating disease-associated WDR73 mutant proteins (p.Phe296Leufs*26 and p.Arg256Profs*18) are unstable and show increased interaction with α- and β-tubulin and HSP-70/HSP-90, suggesting dysregulated chaperone engagement.\",\n      \"method\": \"Co-immunoprecipitation/pull-down of endogenous WDR73 complexes; recombinant mutant protein interaction assays\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction assays with multiple binding partners; single lab but multiple orthogonal targets tested\",\n      \"pmids\": [\"26070982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WDR73 is concentrated at mitotic microtubules and is required for cell cycle progression, proliferation, and survival; patient fibroblasts homozygous for WDR73 p.Phe296Leufs*26 proliferate poorly in primary culture and senesce early.\",\n      \"method\": \"Primary fibroblast culture from patients with homozygous frameshift mutation; proliferation and senescence assays\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function (patient-derived cells) with defined cellular phenotype; single lab\",\n      \"pmids\": [\"26070982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Knockdown of wdr73 in zebrafish causes significant brain growth and morphogenesis defects resulting in a poorly differentiated midbrain and cerebellum, establishing a developmental role for WDR73 in brain morphogenesis in vivo.\",\n      \"method\": \"Morpholino knockdown in zebrafish embryos with phenotypic readout of brain morphology\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with specific developmental phenotype; single lab\",\n      \"pmids\": [\"25873735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR73 physically interacts with INTS9 and INTS11, components of the Integrator complex. WDR73 suppression disrupts Integrator-regulated processing of uridylate-rich small nuclear RNAs (UsnRNAs) and impairs the transcriptional response to EGF stimulation, and alters expression of cell cycle regulatory genes.\",\n      \"method\": \"Co-immunoprecipitation of WDR73 with INTS9/INTS11; snRNA processing assays and EGF-response transcriptomics in WDR73-depleted cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with functional pathway validation by multiple orthogonal assays; single lab\",\n      \"pmids\": [\"33686175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR73 directly interacts with PIP4K2C (a phosphatidylinositol-5-phosphate 4-kinase) and regulates its protein stability through the autophagy-lysosomal pathway. WDR73 knockout reduces PIP4K2C levels, leading to decreased PIP2 and impaired focal adhesion formation. Podocyte-specific Wdr73 conditional knockout mice show albuminuria and podocyte foot process injury, with impaired focal adhesion formation in primary podocytes.\",\n      \"method\": \"Protein microarray, GST pulldown (WDR73–PIP4K2C interaction); WDR73 KO HEK293 cells and conditional knockout mice with focal adhesion, PIP2, and proteinuria readouts\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — GST pulldown plus in vivo mouse KO with multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"36290302\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR73 is a WD40-repeat protein that localizes to astral microtubules and spindle poles during mitosis (cytoplasmic during interphase), interacts with tubulins, HSP70/90, the CAD complex, and the Integrator complex subunits INTS9/INTS11, and stabilizes PIP4K2C via the autophagy-lysosomal pathway to support focal adhesion formation, UsnRNA processing, EGF-responsive transcription, and cell cycle progression; loss of function causes mitotic defects, nuclear morphology abnormalities, senescence, and podocyte/neuronal degeneration underlying Galloway-Mowat syndrome.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"WDR73 is a WD40-repeat protein that localizes diffusely in the cytoplasm during interphase and relocalizes to spindle poles and astral microtubules during mitosis, where it interacts with α-, β-, and γ-tubulin, HSP70/90, and the CAD multi-enzyme complex to support cell cycle progression and cell survival [PMID:25466283, PMID:26070982]. WDR73 also physically associates with Integrator complex subunits INTS9 and INTS11, and its depletion disrupts UsnRNA 3′-end processing and the transcriptional response to EGF stimulation [PMID:33686175]. WDR73 directly binds PIP4K2C and stabilizes it via the autophagy-lysosomal pathway, maintaining PIP2 levels required for focal adhesion formation in podocytes; podocyte-specific Wdr73 knockout in mice causes albuminuria and foot process effacement [PMID:36290302]. Loss-of-function mutations in WDR73 cause Galloway-Mowat syndrome, characterized by nephrotic syndrome and neurodevelopmental defects including impaired brain morphogenesis [PMID:25466283, PMID:25873735].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that WDR73 is a mitotic spindle-associated protein whose loss causes nuclear morphology defects and reduced viability resolved the first mechanistic question: where does the protein act and what happens without it?\",\n      \"evidence\": \"Immunofluorescence and subcellular fractionation in patient fibroblasts and siRNA-depleted podocytes\",\n      \"pmids\": [\"25466283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct binding partner identified at this stage\",\n        \"Mechanism linking spindle localization to nuclear morphology defects not defined\",\n        \"Single-lab observation without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of WDR73's physical interactome — tubulins, HSP70/90, and the CAD complex — and demonstration that disease-causing truncations destabilize the protein and dysregulate chaperone engagement established the molecular basis of loss-of-function pathogenesis.\",\n      \"evidence\": \"Co-immunoprecipitation and pull-down assays with endogenous and recombinant wild-type and mutant WDR73 proteins; patient fibroblast proliferation and senescence assays\",\n      \"pmids\": [\"26070982\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of the WDR73–CAD interaction is unexplored\",\n        \"No structural model to explain how WD40 repeats engage tubulins versus chaperones\",\n        \"Cell cycle arrest mechanism not molecularly defined\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstration that wdr73 knockdown in zebrafish causes midbrain and cerebellar morphogenesis defects established an in vivo developmental requirement and linked WDR73 to the neurological component of Galloway-Mowat syndrome.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish embryos with brain morphology phenotyping\",\n      \"pmids\": [\"25873735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Morpholino off-target effects not fully excluded (no genetic mutant confirmation)\",\n        \"Downstream signaling pathways mediating brain defects not identified\",\n        \"Kidney phenotype not assessed in the zebrafish model\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that WDR73 interacts with Integrator subunits INTS9/INTS11 and is required for UsnRNA processing and EGF-responsive transcription revealed a nuclear RNA-processing function orthogonal to its mitotic role.\",\n      \"evidence\": \"Co-immunoprecipitation of WDR73 with INTS9/INTS11; snRNA processing assays and EGF-response transcriptomics in WDR73-depleted cells\",\n      \"pmids\": [\"33686175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether WDR73 is a stable Integrator complex subunit or a transient accessory factor is unresolved\",\n        \"Relative contribution of snRNA processing versus transcription defects to disease phenotype unknown\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of PIP4K2C as a direct WDR73 binding partner whose stability depends on WDR73-mediated protection from autophagy-lysosomal degradation provided a mechanism for podocyte injury: reduced PIP2 and impaired focal adhesion formation.\",\n      \"evidence\": \"Protein microarray screen, GST pulldown, WDR73 KO HEK293 cells, and podocyte-specific Wdr73 conditional knockout mice with focal adhesion, PIP2, and proteinuria readouts\",\n      \"pmids\": [\"36290302\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of the WDR73–PIP4K2C interaction not determined\",\n        \"Whether PIP4K2C stabilization accounts for neurological phenotypes is untested\",\n        \"Relationship between the PIP4K2C and Integrator pathways not explored\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR73's multiple functions — mitotic spindle association, Integrator-mediated RNA processing, and PIP4K2C stabilization — are coordinated, and which function(s) primarily drive the neuronal versus podocyte pathology in Galloway-Mowat syndrome, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of WDR73 or its complexes exists\",\n        \"Relative contribution of each pathway to neuronal versus renal disease is unknown\",\n        \"No neuron-specific conditional knockout model has been reported\"\n      ]\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, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\n      \"Integrator complex (via INTS9/INTS11)\"\n    ],\n    \"partners\": [\n      \"TUBA1A\",\n      \"TUBB\",\n      \"TUBG1\",\n      \"HSPA1A\",\n      \"HSP90AA1\",\n      \"CAD\",\n      \"INTS9\",\n      \"INTS11\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}