{"gene":"WDR11","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2010,"finding":"WDR11 protein interacts with EMX1, a homeodomain transcription factor involved in olfactory neuron development. Missense mutations in WD domains (A435T, R448Q, H690Q) reduce or abolish this interaction, implicating WDR11-EMX1 interaction in normal pubertal development.","method":"Co-immunoprecipitation / protein-protein interaction assay with missense mutant constructs","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction demonstrated with mutant constructs confirming functional relevance, single lab but multiple mutations tested","pmids":["20887964"],"is_preprint":false},{"year":2017,"finding":"WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. WDR11 shuttles from the cilium to the nucleus in response to Hh signalling, regulates proteolytic processing of GLI3, and cooperates with transcription factor EMX1 to induce downstream Hh pathway gene expression and GnRH production. Loss-of-function in mouse and zebrafish causes defective Hh signalling and ciliated tissue dysgenesis. CHH/KS-associated human mutations result in loss of WDR11 function.","method":"Wdr11 knockout mouse, zebrafish knockdown, immunofluorescence/live imaging of cilium-to-nucleus shuttling, GLI3 processing assay, luciferase reporter for Hh target gene expression, Hh agonist rescue experiment","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse, zebrafish KD, subcellular localization, GLI3 processing, transcriptional reporter, pharmacological rescue) across two model organisms in a single rigorous study","pmids":["29263200"],"is_preprint":false},{"year":2017,"finding":"A WDR11 missense mutation (I436V) causes loss of capacity to bind its functional partner EMX1 and loss of nuclear localization, as demonstrated by Western blotting, co-immunofluorescence, and leptomycin B nuclear export inhibition assays.","method":"Western blotting, co-immunofluorescence, leptomycin B treatment with immunofluorescence","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (co-IF, nuclear export assay) in single lab confirming binding and localization defect of specific mutant","pmids":["28453858"],"is_preprint":false},{"year":2018,"finding":"WDR11 forms a stable complex with FAM91A1 and C17orf75 (the WDR11 complex) that localises to the TGN region. The complex is recruited onto AP-1-derived vesicles (not AP-1 itself) and facilitates their tethering at the TGN via golgin-245 by recruiting TBC1D23. Knockout of WDR11 substantially reduces capture of vesicles by golgin-245 in a tethering assay.","method":"Stable complex purification, knockout cells, vesicle tethering assay, structured illumination microscopy, golgin relocation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution-level vesicle tethering assay combined with KO cells, super-resolution microscopy, and relocation assay providing multiple orthogonal lines of evidence in a single rigorous study","pmids":["29426865"],"is_preprint":false},{"year":2015,"finding":"WDR11 is a TGN-resident protein that interacts specifically with HSV virion components (including ICP0) at the trans-Golgi network. During HSV infection, WDR11 undergoes dramatic relocalization from defined perinuclear TGN structures to a dispersed cytoplasmic distribution, dependent on viral late gene expression (not ICP0). Knockdown of WDR11 produces a modest but consistent decrease in yields of both wild-type and ICP0-null viruses without affecting viral gene expression, suggesting a role in viral assembly and/or secondary envelopment.","method":"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, viral yield assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction demonstrated by Co-IP, localization by IF, functional role by KD with quantitative viral yield readout, single lab","pmids":["26178983"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of the human WDR11-FAM91A1 complex reveals that WDR11 directly and specifically recognizes a subset of acidic clusters termed super acidic clusters (SACs) on cargo proteins. WDR11 complex assembly and SAC-binding are indispensable for the trafficking of SAC-containing proteins from endosomes to the TGN and for proper neuronal development in zebrafish.","method":"Cryo-EM structure determination, in vitro binding assays, WDR11 complex knockout/rescue, zebrafish neuronal development assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structure combined with in vitro binding validation, KO rescue, and in vivo zebrafish functional assay in a single rigorous study","pmids":["39013469"],"is_preprint":false},{"year":2001,"finding":"WDR11 is a WD-repeat gene disrupted by a balanced t(10;19) reciprocal translocation in the A172 glioblastoma cell line. The translocation deletes exon 5, resulting in a chimeric transcript encoding a WDR11 polypeptide truncated after the second of six WD-repeats, fused to the 3' UTR of ZNF320. WDR11 is ubiquitously expressed and maps to chromosome 10q26, a region with frequent LOH in glial tumors.","method":"Positional cloning, RT-PCR, Northern blot, FISH","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — positional cloning with molecular characterization of translocation breakpoint and chimeric transcript in a single rigorous study","pmids":["11536051"],"is_preprint":false},{"year":2023,"finding":"WDR11 is required for primordial germ cell (PGC) development, regulating both canonical (PTCH1/BOC-cilia-dependent) and noncanonical (PTCH2/GAS1-cilia-independent) Hedgehog signalling in parallel. Loss of WDR11 disrupts PGC motility and proliferation. PTCH1/BOC or PTCH2/GAS1 receptor context dictates SMO localisation inside or outside cilia, respectively, and WDR11 loss affects SMO signalling in both contexts. WDR11 also promotes ciliogenesis potentially through interaction with IFT20, and GAS1 is induced by PTCH2-specific HH signalling in a WDR11-dependent manner.","method":"Wdr11-deficient mouse embryo analysis, co-immunoprecipitation (WDR11-IFT20), immunofluorescence of SMO localisation, PGC motility and proliferation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotypes and Co-IP interaction data, single lab, multiple pathway readouts","pmids":["37516749"],"is_preprint":false},{"year":2017,"finding":"WDR11 overexpression in Group 3 medulloblastoma (G3 MB) tumorspheres leads to extended survival in a mouse G3 MB model and downregulates genes in the WNT signalling pathway (including Ccnd1/2/3, Myc, Tcf7l1), consistent with tumor suppressive activity mediated through WNT pathway inhibition.","method":"Whole-exome sequencing, overexpression survival experiment, transcriptome analysis of G3 MB tumorspheres","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression survival assay and transcriptome correlation, single lab, no direct mechanistic dissection of WNT pathway modulation","pmids":["29029386"],"is_preprint":false}],"current_model":"WDR11 is a WD-repeat β-propeller protein that forms a stable complex with FAM91A1 (and C17orf75) at the trans-Golgi network, where it acts as a sequence-specific cargo receptor for super-acidic-cluster (SAC)-containing proteins downstream of the AP-1 clathrin coat to facilitate endosome-to-TGN vesicle tethering via golgin-245 and TBC1D23; in parallel, WDR11 shuttles between the primary cilium and nucleus in response to Hedgehog signalling, regulates GLI3 proteolytic processing, and cooperates with the transcription factor EMX1 to drive Hh target gene expression and GnRH neuron development, such that loss-of-function mutations in WDR11 impair both ciliary Hh signalling and TGN trafficking, causing hypogonadotropic hypogonadism/Kallmann syndrome and broader ciliopathy phenotypes."},"narrative":{"mechanistic_narrative":"WDR11 is a WD-repeat β-propeller protein that operates at the interface of trans-Golgi network (TGN) membrane trafficking and Hedgehog-dependent developmental signalling [PMID:29263200, PMID:29426865]. At the TGN, WDR11 assembles into a stable complex with FAM91A1 and C17orf75 that is recruited onto AP-1-derived vesicles and tethers them at the TGN via golgin-245 through recruitment of TBC1D23, with loss of WDR11 sharply reducing golgin-245-dependent vesicle capture [PMID:29426865]. A cryo-EM structure of the WDR11–FAM91A1 complex shows that WDR11 directly recognizes super-acidic clusters (SACs) on cargo proteins, acting as a sequence-specific cargo receptor required for endosome-to-TGN transport of SAC-containing cargo and for neuronal development [PMID:39013469]. In parallel, WDR11 shuttles between the primary cilium and the nucleus in response to Hedgehog signalling, where it regulates proteolytic processing of GLI3 and cooperates with the homeodomain transcription factor EMX1 to drive Hh target gene expression and GnRH neuron development; loss-of-function abolishes ciliogenesis and Hh signalling in mouse and zebrafish [PMID:20887964, PMID:29263200]. WDR11 governs both canonical and noncanonical (PTCH2/GAS1) Hedgehog branches and is required for primordial germ cell motility and proliferation, in part through interaction with the ciliary protein IFT20 [PMID:37516749]. Disease-associated missense mutations in the WD domains disrupt EMX1 binding and nuclear localization, linking WDR11 loss-of-function to congenital hypogonadotropic hypogonadism/Kallmann syndrome [PMID:20887964, PMID:28453858].","teleology":[{"year":2001,"claim":"Established WDR11 as a ubiquitously expressed WD-repeat gene at a tumor-associated locus, providing the first molecular handle before any function was known.","evidence":"Positional cloning and breakpoint characterization of a t(10;19) translocation in a glioblastoma cell line","pmids":["11536051"],"confidence":"Medium","gaps":["No functional role for the gene or chimeric transcript demonstrated","Causal link to glioma tumorigenesis not established"]},{"year":2010,"claim":"Identified the first functional partner of WDR11 and tied it to a developmental phenotype, showing WD-domain mutations disrupt the EMX1 interaction relevant to pubertal development.","evidence":"Co-immunoprecipitation with disease-associated missense mutant constructs","pmids":["20887964"],"confidence":"Medium","gaps":["Mechanism by which WDR11-EMX1 binding controls transcription not defined","Single-lab interaction data"]},{"year":2017,"claim":"Placed WDR11 within the Hedgehog pathway, defining a cilium-to-nucleus shuttling role that links GLI3 processing and EMX1-dependent transcription to ciliogenesis and GnRH biology.","evidence":"Wdr11 knockout mouse, zebrafish knockdown, cilium-to-nucleus imaging, GLI3 processing assay, Hh reporter and agonist rescue; plus a mutation abolishing EMX1 binding and nuclear localization shown by leptomycin B assay","pmids":["29263200","28453858"],"confidence":"High","gaps":["Molecular basis of nucleocytoplasmic shuttling not resolved","How WDR11 mechanistically alters GLI3 processing unclear","Relationship between ciliary and transcriptional functions unmapped"]},{"year":2018,"claim":"Defined a distinct membrane-trafficking role, showing WDR11 is a stable complex subunit that tethers AP-1-derived vesicles at the TGN, separating this activity from the ciliary signalling function.","evidence":"Stable complex purification, knockout cells, in vitro vesicle tethering assay, super-resolution microscopy, golgin relocation assay","pmids":["29426865"],"confidence":"High","gaps":["Cargo identity not yet defined","Whether trafficking and Hedgehog roles are mechanistically connected unknown"]},{"year":2023,"claim":"Extended WDR11's Hedgehog role to both canonical and noncanonical branches and to primordial germ cell development, implicating a direct ciliary interaction with IFT20.","evidence":"Wdr11-deficient mouse embryos, SMO localization imaging, PGC motility/proliferation assays, WDR11-IFT20 co-immunoprecipitation","pmids":["37516749"],"confidence":"Medium","gaps":["WDR11-IFT20 interaction shown by single Co-IP without reciprocal validation","Mechanism distinguishing canonical vs noncanonical branch regulation unresolved"]},{"year":2024,"claim":"Provided the structural and biochemical basis for cargo selection, identifying WDR11 as a sequence-specific receptor for super-acidic-cluster motifs.","evidence":"Cryo-EM of WDR11-FAM91A1, in vitro binding assays, knockout/rescue, zebrafish neuronal development assay","pmids":["39013469"],"confidence":"High","gaps":["Full repertoire of SAC-containing cargo not catalogued","Connection between cargo trafficking defects and Hedgehog/GnRH phenotypes not established"]},{"year":null,"claim":"How WDR11's TGN cargo-receptor activity and its ciliary/Hedgehog signalling functions are integrated into a single coherent mechanism remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Whether disease mutations act primarily through trafficking or signalling defects is unknown","No unified model linking SAC cargo transport to GLI3 processing and EMX1 transcription"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[3,5]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3,4]},{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,5,7]}],"complexes":["WDR11 complex (WDR11-FAM91A1-C17orf75)"],"partners":["FAM91A1","C17ORF75","EMX1","TBC1D23","GOLGIN-245","IFT20"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BZH6","full_name":"WD repeat-containing protein 11","aliases":["Bromodomain and WD repeat-containing protein 2","WD repeat-containing protein 15"],"length_aa":1224,"mass_kda":136.7,"function":"Involved in the Hedgehog (Hh) signaling pathway, is essential for normal ciliogenesis (PubMed:29263200). Regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotropin-releasing hormone production (PubMed:29263200). WDR11 complex facilitates the tethering of Adaptor protein-1 complex (AP-1)-derived vesicles. WDR11 complex acts together with TBC1D23 to facilitate the golgin-mediated capture of vesicles generated using AP-1 (PubMed:29426865)","subcellular_location":"Cytoplasm, cytoskeleton, cilium basal body; Cytoplasm; Nucleus; Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasmic vesicle; Golgi apparatus, trans-Golgi network","url":"https://www.uniprot.org/uniprotkb/Q9BZH6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR11","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"COPA","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"PTGES3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR11","total_profiled":1310},"omim":[{"mim_id":"620237","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 78; MRT78","url":"https://www.omim.org/entry/620237"},{"mim_id":"614858","title":"HYPOGONADOTROPIC HYPOGONADISM 14 WITH OR WITHOUT ANOSMIA; HH14","url":"https://www.omim.org/entry/614858"},{"mim_id":"606427","title":"ZINC FINGER PROTEIN 320; ZNF320","url":"https://www.omim.org/entry/606427"},{"mim_id":"606417","title":"WD REPEAT-CONTAINING PROTEIN 11; WDR11","url":"https://www.omim.org/entry/606417"},{"mim_id":"147950","title":"HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA; HH2","url":"https://www.omim.org/entry/147950"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Microtubules","reliability":"Supported"},{"location":"Primary cilium","reliability":"Supported"},{"location":"End piece","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Flagellar centriole","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR11"},"hgnc":{"alias_symbol":["KIAA1351","FLJ10506","WDR15","HH14","DR11","SRI1"],"prev_symbol":["BRWD2"]},"alphafold":{"accession":"Q9BZH6","domains":[{"cath_id":"-","chopping":"848-943_1136-1218","consensus_level":"medium","plddt":88.2463,"start":848,"end":1218},{"cath_id":"2.40.128","chopping":"290-321_337-388_401-439_447-460","consensus_level":"medium","plddt":86.5855,"start":290,"end":460}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZH6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZH6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZH6-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR11","jax_strain_url":"https://www.jax.org/strain/search?query=WDR11"},"sequence":{"accession":"Q9BZH6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BZH6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BZH6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZH6"}},"corpus_meta":[{"pmid":"10049951","id":"PMC_10049951","title":"Melanoma 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oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41357601","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23588,"output_tokens":2643,"usd":0.055204,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9810,"output_tokens":2726,"usd":0.0586,"stage2_stop_reason":"end_turn"},"total_usd":0.113804,"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\": 2010,\n      \"finding\": \"WDR11 protein interacts with EMX1, a homeodomain transcription factor involved in olfactory neuron development. Missense mutations in WD domains (A435T, R448Q, H690Q) reduce or abolish this interaction, implicating WDR11-EMX1 interaction in normal pubertal development.\",\n      \"method\": \"Co-immunoprecipitation / protein-protein interaction assay with missense mutant constructs\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction demonstrated with mutant constructs confirming functional relevance, single lab but multiple mutations tested\",\n      \"pmids\": [\"20887964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. WDR11 shuttles from the cilium to the nucleus in response to Hh signalling, regulates proteolytic processing of GLI3, and cooperates with transcription factor EMX1 to induce downstream Hh pathway gene expression and GnRH production. Loss-of-function in mouse and zebrafish causes defective Hh signalling and ciliated tissue dysgenesis. CHH/KS-associated human mutations result in loss of WDR11 function.\",\n      \"method\": \"Wdr11 knockout mouse, zebrafish knockdown, immunofluorescence/live imaging of cilium-to-nucleus shuttling, GLI3 processing assay, luciferase reporter for Hh target gene expression, Hh agonist rescue experiment\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mouse, zebrafish KD, subcellular localization, GLI3 processing, transcriptional reporter, pharmacological rescue) across two model organisms in a single rigorous study\",\n      \"pmids\": [\"29263200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A WDR11 missense mutation (I436V) causes loss of capacity to bind its functional partner EMX1 and loss of nuclear localization, as demonstrated by Western blotting, co-immunofluorescence, and leptomycin B nuclear export inhibition assays.\",\n      \"method\": \"Western blotting, co-immunofluorescence, leptomycin B treatment with immunofluorescence\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (co-IF, nuclear export assay) in single lab confirming binding and localization defect of specific mutant\",\n      \"pmids\": [\"28453858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WDR11 forms a stable complex with FAM91A1 and C17orf75 (the WDR11 complex) that localises to the TGN region. The complex is recruited onto AP-1-derived vesicles (not AP-1 itself) and facilitates their tethering at the TGN via golgin-245 by recruiting TBC1D23. Knockout of WDR11 substantially reduces capture of vesicles by golgin-245 in a tethering assay.\",\n      \"method\": \"Stable complex purification, knockout cells, vesicle tethering assay, structured illumination microscopy, golgin relocation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution-level vesicle tethering assay combined with KO cells, super-resolution microscopy, and relocation assay providing multiple orthogonal lines of evidence in a single rigorous study\",\n      \"pmids\": [\"29426865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"WDR11 is a TGN-resident protein that interacts specifically with HSV virion components (including ICP0) at the trans-Golgi network. During HSV infection, WDR11 undergoes dramatic relocalization from defined perinuclear TGN structures to a dispersed cytoplasmic distribution, dependent on viral late gene expression (not ICP0). Knockdown of WDR11 produces a modest but consistent decrease in yields of both wild-type and ICP0-null viruses without affecting viral gene expression, suggesting a role in viral assembly and/or secondary envelopment.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, viral yield assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction demonstrated by Co-IP, localization by IF, functional role by KD with quantitative viral yield readout, single lab\",\n      \"pmids\": [\"26178983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of the human WDR11-FAM91A1 complex reveals that WDR11 directly and specifically recognizes a subset of acidic clusters termed super acidic clusters (SACs) on cargo proteins. WDR11 complex assembly and SAC-binding are indispensable for the trafficking of SAC-containing proteins from endosomes to the TGN and for proper neuronal development in zebrafish.\",\n      \"method\": \"Cryo-EM structure determination, in vitro binding assays, WDR11 complex knockout/rescue, zebrafish neuronal development assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structure combined with in vitro binding validation, KO rescue, and in vivo zebrafish functional assay in a single rigorous study\",\n      \"pmids\": [\"39013469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"WDR11 is a WD-repeat gene disrupted by a balanced t(10;19) reciprocal translocation in the A172 glioblastoma cell line. The translocation deletes exon 5, resulting in a chimeric transcript encoding a WDR11 polypeptide truncated after the second of six WD-repeats, fused to the 3' UTR of ZNF320. WDR11 is ubiquitously expressed and maps to chromosome 10q26, a region with frequent LOH in glial tumors.\",\n      \"method\": \"Positional cloning, RT-PCR, Northern blot, FISH\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — positional cloning with molecular characterization of translocation breakpoint and chimeric transcript in a single rigorous study\",\n      \"pmids\": [\"11536051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WDR11 is required for primordial germ cell (PGC) development, regulating both canonical (PTCH1/BOC-cilia-dependent) and noncanonical (PTCH2/GAS1-cilia-independent) Hedgehog signalling in parallel. Loss of WDR11 disrupts PGC motility and proliferation. PTCH1/BOC or PTCH2/GAS1 receptor context dictates SMO localisation inside or outside cilia, respectively, and WDR11 loss affects SMO signalling in both contexts. WDR11 also promotes ciliogenesis potentially through interaction with IFT20, and GAS1 is induced by PTCH2-specific HH signalling in a WDR11-dependent manner.\",\n      \"method\": \"Wdr11-deficient mouse embryo analysis, co-immunoprecipitation (WDR11-IFT20), immunofluorescence of SMO localisation, PGC motility and proliferation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined cellular phenotypes and Co-IP interaction data, single lab, multiple pathway readouts\",\n      \"pmids\": [\"37516749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"WDR11 overexpression in Group 3 medulloblastoma (G3 MB) tumorspheres leads to extended survival in a mouse G3 MB model and downregulates genes in the WNT signalling pathway (including Ccnd1/2/3, Myc, Tcf7l1), consistent with tumor suppressive activity mediated through WNT pathway inhibition.\",\n      \"method\": \"Whole-exome sequencing, overexpression survival experiment, transcriptome analysis of G3 MB tumorspheres\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression survival assay and transcriptome correlation, single lab, no direct mechanistic dissection of WNT pathway modulation\",\n      \"pmids\": [\"29029386\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR11 is a WD-repeat β-propeller protein that forms a stable complex with FAM91A1 (and C17orf75) at the trans-Golgi network, where it acts as a sequence-specific cargo receptor for super-acidic-cluster (SAC)-containing proteins downstream of the AP-1 clathrin coat to facilitate endosome-to-TGN vesicle tethering via golgin-245 and TBC1D23; in parallel, WDR11 shuttles between the primary cilium and nucleus in response to Hedgehog signalling, regulates GLI3 proteolytic processing, and cooperates with the transcription factor EMX1 to drive Hh target gene expression and GnRH neuron development, such that loss-of-function mutations in WDR11 impair both ciliary Hh signalling and TGN trafficking, causing hypogonadotropic hypogonadism/Kallmann syndrome and broader ciliopathy phenotypes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR11 is a WD-repeat β-propeller protein that operates at the interface of trans-Golgi network (TGN) membrane trafficking and Hedgehog-dependent developmental signalling [#1, #3]. At the TGN, WDR11 assembles into a stable complex with FAM91A1 and C17orf75 that is recruited onto AP-1-derived vesicles and tethers them at the TGN via golgin-245 through recruitment of TBC1D23, with loss of WDR11 sharply reducing golgin-245-dependent vesicle capture [#3]. A cryo-EM structure of the WDR11–FAM91A1 complex shows that WDR11 directly recognizes super-acidic clusters (SACs) on cargo proteins, acting as a sequence-specific cargo receptor required for endosome-to-TGN transport of SAC-containing cargo and for neuronal development [#5]. In parallel, WDR11 shuttles between the primary cilium and the nucleus in response to Hedgehog signalling, where it regulates proteolytic processing of GLI3 and cooperates with the homeodomain transcription factor EMX1 to drive Hh target gene expression and GnRH neuron development; loss-of-function abolishes ciliogenesis and Hh signalling in mouse and zebrafish [#0, #1]. WDR11 governs both canonical and noncanonical (PTCH2/GAS1) Hedgehog branches and is required for primordial germ cell motility and proliferation, in part through interaction with the ciliary protein IFT20 [#7]. Disease-associated missense mutations in the WD domains disrupt EMX1 binding and nuclear localization, linking WDR11 loss-of-function to congenital hypogonadotropic hypogonadism/Kallmann syndrome [#0, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established WDR11 as a ubiquitously expressed WD-repeat gene at a tumor-associated locus, providing the first molecular handle before any function was known.\",\n      \"evidence\": \"Positional cloning and breakpoint characterization of a t(10;19) translocation in a glioblastoma cell line\",\n      \"pmids\": [\"11536051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional role for the gene or chimeric transcript demonstrated\", \"Causal link to glioma tumorigenesis not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the first functional partner of WDR11 and tied it to a developmental phenotype, showing WD-domain mutations disrupt the EMX1 interaction relevant to pubertal development.\",\n      \"evidence\": \"Co-immunoprecipitation with disease-associated missense mutant constructs\",\n      \"pmids\": [\"20887964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which WDR11-EMX1 binding controls transcription not defined\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Placed WDR11 within the Hedgehog pathway, defining a cilium-to-nucleus shuttling role that links GLI3 processing and EMX1-dependent transcription to ciliogenesis and GnRH biology.\",\n      \"evidence\": \"Wdr11 knockout mouse, zebrafish knockdown, cilium-to-nucleus imaging, GLI3 processing assay, Hh reporter and agonist rescue; plus a mutation abolishing EMX1 binding and nuclear localization shown by leptomycin B assay\",\n      \"pmids\": [\"29263200\", \"28453858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of nucleocytoplasmic shuttling not resolved\", \"How WDR11 mechanistically alters GLI3 processing unclear\", \"Relationship between ciliary and transcriptional functions unmapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a distinct membrane-trafficking role, showing WDR11 is a stable complex subunit that tethers AP-1-derived vesicles at the TGN, separating this activity from the ciliary signalling function.\",\n      \"evidence\": \"Stable complex purification, knockout cells, in vitro vesicle tethering assay, super-resolution microscopy, golgin relocation assay\",\n      \"pmids\": [\"29426865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo identity not yet defined\", \"Whether trafficking and Hedgehog roles are mechanistically connected unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended WDR11's Hedgehog role to both canonical and noncanonical branches and to primordial germ cell development, implicating a direct ciliary interaction with IFT20.\",\n      \"evidence\": \"Wdr11-deficient mouse embryos, SMO localization imaging, PGC motility/proliferation assays, WDR11-IFT20 co-immunoprecipitation\",\n      \"pmids\": [\"37516749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"WDR11-IFT20 interaction shown by single Co-IP without reciprocal validation\", \"Mechanism distinguishing canonical vs noncanonical branch regulation unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural and biochemical basis for cargo selection, identifying WDR11 as a sequence-specific receptor for super-acidic-cluster motifs.\",\n      \"evidence\": \"Cryo-EM of WDR11-FAM91A1, in vitro binding assays, knockout/rescue, zebrafish neuronal development assay\",\n      \"pmids\": [\"39013469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of SAC-containing cargo not catalogued\", \"Connection between cargo trafficking defects and Hedgehog/GnRH phenotypes not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR11's TGN cargo-receptor activity and its ciliary/Hedgehog signalling functions are integrated into a single coherent mechanism remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether disease mutations act primarily through trafficking or signalling defects is unknown\", \"No unified model linking SAC cargo transport to GLI3 processing and EMX1 transcription\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016192\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 5, 7]}\n    ],\n    \"complexes\": [\"WDR11 complex (WDR11-FAM91A1-C17orf75)\"],\n    \"partners\": [\"FAM91A1\", \"C17orf75\", \"EMX1\", \"TBC1D23\", \"golgin-245\", \"IFT20\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}