{"gene":"WDR36","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2008,"finding":"WDR36 (Wdr36) is the functional homolog of yeast Utp21 and localizes to the nucleolus, where it is required for processing of 18S rRNA (ribosome biogenesis). Loss of Wdr36 function in zebrafish causes defects in 18S rRNA processing and abnormal nucleolar morphology.","method":"Sequence alignment, subcellular localization (nucleolus), loss-of-function in zebrafish with rRNA processing assay and nucleolar morphology readout","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, rRNA processing assay, morphology), replicated in mammalian cells (PMID:21051332) and yeast (PMID:18469340)","pmids":["18469340"],"is_preprint":false},{"year":2008,"finding":"Loss of Wdr36 function activates the p53 stress-response pathway, suggesting that co-inheritance of defects in p53 pathway genes may influence the impact of WDR36 variants.","method":"Loss-of-function in zebrafish with p53 pathway readout","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined pathway readout in a single lab, corroborated by mammalian cell data in PMID:21051332","pmids":["18469340","21051332"],"is_preprint":false},{"year":2010,"finding":"WDR36 is essential for mammalian preimplantation development: homozygous Wdr36 knockout causes embryonic lethality before the blastocyst stage in mice, and siRNA-mediated depletion replicates this lethality.","method":"Targeted gene deletion in mice (knockout); siRNA knockdown in mouse embryos","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined lethal phenotype, replicated with independent siRNA approach in the same study","pmids":["21051332"],"is_preprint":false},{"year":2010,"finding":"WDR36 localizes to the nucleolus in human trabecular meshwork (HTM-N) cells, co-localizing with nucleolar proteins nucleophosmin and PWP2; both endogenous and recombinant/epitope-tagged WDR36 show this nucleolar localization.","method":"Immunocytochemistry and recombinant/epitope-tagged protein localization in human cells","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization by immunocytochemistry with co-localization controls, confirmed with tagged recombinant protein","pmids":["21051332"],"is_preprint":false},{"year":2010,"finding":"Knockdown of WDR36 in human trabecular meshwork (HTM-N) cells delays maturation of 18S rRNA: northern blot shows decreased 21S rRNA (precursor of 18S rRNA), and metabolic-labeling experiments show delayed 18S rRNA maturation. WDR36 depletion also induces apoptotic cell death with upregulation of BAX, TP53, and CDKN1A mRNAs.","method":"siRNA knockdown in human cells; northern blot; metabolic labeling; RT-PCR/mRNA quantification","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro rRNA processing assay (northern blot + metabolic labeling) combined with functional cell death readout, multiple orthogonal methods in one study","pmids":["21051332"],"is_preprint":false},{"year":2008,"finding":"In the yeast UtpB subcomplex of the SSU processome, the HAT (half-a-tetratricopeptide repeat) domain of Utp6 directly binds a specific peptide in Utp21 (the yeast ortholog of WDR36) with a Kd of ~10 µM; an intact HAT domain is essential for efficient pre-rRNA processing and cell growth.","method":"Comprehensive interaction mapping within UtpB subcomplex; point and deletion mutagenesis of Utp6; biophysical binding assay (Kd measurement); pre-rRNA processing assay; growth assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of protein-protein interaction, biophysical Kd measurement, mutagenesis, and functional rRNA processing assay combined in one study","pmids":["18725399"],"is_preprint":false},{"year":2009,"finding":"POAG-associated WDR36 sequence variants introduced into yeast UTP21 do not produce defects alone, but in combination with disruption of STI1 (a synthetic interactor of UTP21), 5 of 11 tested variants show altered cell viability corresponding to reduced or elevated pre-rRNA levels, demonstrating that WDR36 variants can alter rRNA processing in a specific genetic background.","method":"Yeast model system with site-directed mutagenesis of UTP21; genetic epistasis (double mutant with STI1 deletion); rRNA processing assay; growth/viability assay","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in yeast with rRNA processing readout; single lab","pmids":["19150991"],"is_preprint":false},{"year":2011,"finding":"WDR36 acts as a scaffold protein: it directly interacts with the C-terminus and first intracellular loop of the thromboxane A2 receptor β (TPβ) (confirmed by yeast two-hybrid and GST pulldown), co-immunoprecipitates with Gαq and PLCβ in cells, promotes TPβ–Gαq interaction, increases Gαq–PLCβ interaction, prevents sequestration of activated Gαq by GRK2, and augments the presence of TPβ in PLCβ immunoprecipitates. WDR36 overexpression enhances and siRNA knockdown inhibits TPβ-induced Gαq signalling. The complex translocates from plasma membrane to intracellular vesicles upon receptor stimulation.","method":"Yeast two-hybrid; GST pulldown; co-immunoprecipitation; confocal microscopy; siRNA knockdown; overexpression functional assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, direct pulldown, yeast two-hybrid, localization, and functional signalling assays with KD/OE all in one study; multiple orthogonal methods","pmids":["21940795"],"is_preprint":false},{"year":2011,"finding":"Disease-associated WDR36 variants affect WDR36's ability to modulate Gαq-mediated signalling by TPβ, linking glaucoma-associated variants to the scaffold/signalling function.","method":"Overexpression of disease-variant WDR36 constructs with Gαq signalling readout in cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, functional assay with variant constructs but no structural/mechanistic detail of how variants alter binding","pmids":["21940795"],"is_preprint":false},{"year":2010,"finding":"Transgenic mice overexpressing mutant mouse Wdr36 Del605-607 (equivalent to human D658G region) develop progressive peripheral retinal degeneration with normal IOP; RGCs and amacrine cell synapses are affected, and axon outgrowth of cultured RGCs from these mice is significantly reduced. Molecular modeling shows the deletion removes a hydrogen bond stabilizing the 6th β-propeller of the second domain.","method":"Transgenic mouse overexpression; retinal histology; RGC axon outgrowth assay; molecular modeling","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — transgenic mouse with defined retinal phenotype and direct RGC axon assay; molecular modeling is computational; single lab","pmids":["20631153"],"is_preprint":false},{"year":2014,"finding":"Utp21 (yeast WDR36 ortholog) interacts with Hsp90 and co-chaperones; steady-state levels of Utp21 are reduced upon Hsp90 mutation or inhibition. The utp21-S602F mutation shows severe/lethal growth defects when combined with Hsp90 or co-chaperone mutations. Three Utp21 mutants analogous to glaucoma-associated WDR36 mutations show reduced levels in yeast expressing Hsp90 or co-chaperone mutations, indicating Hsp90 buffers the effects of these mutations.","method":"Genetic interaction analysis (double mutant growth assays); Hsp90 inhibition; protein level measurement in yeast","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and protein stability assays; single lab; yeast model","pmids":["24647762"],"is_preprint":false},{"year":2011,"finding":"STI1 variant K434R combined with specific UTP21 (WDR36 yeast ortholog) variants causes significantly altered culture growth at 37°C, but does not significantly alter 18S rRNA levels, supporting a conserved molecular pathway involving STI1 and WDR36 affecting cell proliferation rather than direct rRNA processing.","method":"Yeast model system; double-mutant growth assays; 18S rRNA quantification; gene sequencing in POAG patients","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in yeast with functional readout; corroborated by patient variant discovery; single lab","pmids":["21850170"],"is_preprint":false},{"year":2020,"finding":"WDR36 overexpression delays SphK1 (sphingosine kinase-1) translocation to the plasma membrane induced by Gq-coupled M3, B2, and H1 receptors, while augmenting TPβ receptor-induced calcium signalling. WDR36 increases inositol phosphate production by TPβ but attenuates it by M3 and B2 receptors, consistent with WDR36 scavenging Gαq and PLCβ to orchestrate Gq signalling complexes.","method":"Overexpression in HEK-293 cells and C2C12 myoblasts; live-cell imaging of SphK1 translocation; inositol phosphate assay; calcium imaging","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays in two cell lines; single lab; builds on prior study (PMID:21940795)","pmids":["32244061"],"is_preprint":false},{"year":2022,"finding":"WDR36 knockdown in human extended pluripotent stem (EPS) cells disrupts self-renewal and promotes mesodermal differentiation; p53 inhibition reverses these effects, placing WDR36 upstream of p53 in the self-renewal regulatory pathway.","method":"Inducible knockdown and overexpression in human EPS cells; differentiation assays; p53 inhibitor rescue experiment","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotype and genetic epistasis (p53 rescue); single lab","pmids":["35937980"],"is_preprint":false},{"year":2024,"finding":"WDR36 interacts with glycolytic metabolic protein LDHA (lactate dehydrogenase A) and positively regulates glycolysis during the late stage of human blastoid formation. WDR36 interference blocks trophectoderm lineage commitment and downregulates glucose metabolism, linking WDR36 to glycolytic regulation of cell fate.","method":"Co-immunoprecipitation (WDR36-LDHA interaction); siRNA knockdown in blastoids; transcriptomics; targeted metabolomics","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifies binding partner, knockdown with metabolomics and transcriptomics readout; single lab; blastoid model","pmids":["39656902"],"is_preprint":false},{"year":2025,"finding":"WDR36 overexpression inhibits migration, chemotaxis, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs), while WDR36 depletion promotes these processes and also promotes senescence.","method":"Scratch-wound migration assay; transwell chemotaxis assay; ALP activity, Alizarin red staining, calcium content; RT-qPCR; SA-β-galactosidase staining; overexpression and knockdown","journal":"World journal of stem cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional overexpression/knockdown assays with phenotypic readouts; no molecular mechanism identified; single lab","pmids":["40061266"],"is_preprint":false},{"year":2026,"finding":"ELAVL1 binds WDR36 mRNA and promotes its protein translation (post-transcriptional regulation). WDR36 overexpression reduces OGD/R-induced cell death, calcium overload, and p53 pathway activation in retinal precursor cells; WDR36 knockdown abolishes ELAVL1's protective effects, placing WDR36 downstream of ELAVL1 in the p53 inhibition pathway under acute pressure-ischemia stress.","method":"RNA-binding protein interaction assay (ELAVL1-WDR36 mRNA); siRNA knockdown; plasmid overexpression; AAV in vivo delivery; cell death assay; calcium measurement; p53 pathway markers","journal":"Open life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (in vitro + in vivo), genetic epistasis (WDR36 KD reverses ELAVL1 OE protection); single lab","pmids":["42046554"],"is_preprint":false}],"current_model":"WDR36 is a WD40-repeat nucleolar scaffold protein that functions as an essential component of the small subunit (SSU) processome for 18S rRNA maturation and ribosome biogenesis (ortholog of yeast Utp21/UTP21), activates the p53 stress-response pathway when depleted, and additionally serves as a plasma-membrane scaffold that tethers Gαq, PLCβ, and G-protein-coupled receptors (notably TPβ) to orchestrate Gq-mediated signalling; disease-associated variants impair both its rRNA processing function (in specific genetic backgrounds) and its ability to modulate Gαq signalling."},"narrative":{"mechanistic_narrative":"WDR36 is a WD40-repeat nucleolar protein that functions in 18S rRNA maturation and ribosome biogenesis as the functional homolog of yeast Utp21, a component of the SSU processome [PMID:18469340]. In human cells it localizes to the nucleolus alongside nucleophosmin and PWP2, and its depletion delays processing of the 21S precursor and maturation of 18S rRNA [PMID:21051332]. Within the yeast UtpB subcomplex, the WDR36 ortholog Utp21 is engaged through a direct HAT-domain contact from Utp6 that is required for efficient pre-rRNA processing [PMID:18725399]. WDR36 is essential for early development: homozygous knockout causes mouse preimplantation lethality, and its loss activates a p53 stress response—inducing BAX, TP53, and CDKN1A and triggering apoptosis—that is reversible by p53 inhibition and governs stem-cell self-renewal [PMID:18469340, PMID:21051332, PMID:35937980]. Beyond the nucleolus, WDR36 acts as a plasma-membrane scaffold that binds the thromboxane A2 receptor β (TPβ) and assembles Gαq–PLCβ–receptor complexes, promoting receptor–Gαq coupling, protecting activated Gαq from GRK2 sequestration, and thereby selectively shaping Gq-mediated signalling and calcium responses [PMID:21940795, PMID:32244061]. Glaucoma-associated WDR36 variants impair rRNA processing only in sensitizing genetic backgrounds and also alter WDR36's modulation of Gαq signalling, and a deletion variant modeled in transgenic mice produces progressive retinal degeneration with reduced retinal ganglion cell axon outgrowth [PMID:19150991, PMID:21940795, PMID:20631153].","teleology":[{"year":2008,"claim":"Established WDR36's core molecular identity by showing it is the functional ortholog of yeast Utp21 and a nucleolar factor required for 18S rRNA processing, placing it in ribosome biogenesis.","evidence":"Sequence alignment, nucleolar localization, and loss-of-function with rRNA processing and nucleolar morphology readouts in zebrafish","pmids":["18469340"],"confidence":"High","gaps":["Did not define the human SSU processome subcomplex composition","No direct biochemical assay of WDR36 enzymatic or binding activity in vertebrates"]},{"year":2008,"claim":"Connected WDR36 loss to the p53 stress-response axis, framing how variant impact could depend on co-inherited p53-pathway status.","evidence":"Zebrafish loss-of-function with p53 pathway readout","pmids":["18469340","21051332"],"confidence":"Medium","gaps":["Did not establish whether p53 activation is a direct sensor of disrupted ribosome biogenesis","No mechanism linking WDR36 depletion to specific p53 effectors"]},{"year":2008,"claim":"Resolved a direct intermolecular contact in the SSU processome by mapping a HAT-domain interaction between Utp6 and the WDR36 ortholog Utp21 and showing it is functionally required.","evidence":"Interaction mapping, mutagenesis, biophysical Kd measurement, and pre-rRNA processing/growth assays in yeast UtpB subcomplex","pmids":["18725399"],"confidence":"High","gaps":["Interaction demonstrated in yeast, not human WDR36","Structural basis of the peptide contact not solved"]},{"year":2010,"claim":"Demonstrated WDR36 is essential for mammalian development and confirmed its conserved nucleolar rRNA-processing role in human cells, linking depletion to p53-dependent apoptosis.","evidence":"Mouse knockout and siRNA embryo lethality; human HTM-N cell localization, northern blot/metabolic labeling rRNA assays, and apoptosis/mRNA readouts","pmids":["21051332"],"confidence":"High","gaps":["Did not separate the developmental requirement from the general ribosome-biogenesis defect","Tissue-specific roles in trabecular meshwork beyond rRNA processing not defined"]},{"year":2009,"claim":"Showed that POAG-associated WDR36 variants are not intrinsically defective but become functionally consequential for rRNA processing only in a sensitizing genetic background.","evidence":"Yeast UTP21 site-directed mutants with STI1 deletion epistasis and rRNA processing/viability assays","pmids":["19150991"],"confidence":"Medium","gaps":["Relevance of STI1 modifier to human trabecular meshwork unestablished","Did not identify the human equivalent genetic modifier"]},{"year":2010,"claim":"Provided an in vivo disease-relevant phenotype by showing a WDR36 deletion variant drives retinal degeneration and impaired RGC axon outgrowth independent of intraocular pressure.","evidence":"Transgenic mouse overexpression with retinal histology, RGC axon outgrowth assay, and molecular modeling","pmids":["20631153"],"confidence":"Medium","gaps":["Molecular modeling of the destabilized β-propeller is computational","Mechanism linking the structural change to neuronal phenotype not biochemically resolved"]},{"year":2011,"claim":"Revealed a second, non-nucleolar function: WDR36 acts as a plasma-membrane scaffold organizing TPβ–Gαq–PLCβ complexes to potentiate Gq signalling.","evidence":"Yeast two-hybrid, GST pulldown, reciprocal Co-IP, confocal microscopy, and KD/OE signalling assays in cells","pmids":["21940795"],"confidence":"High","gaps":["Structural basis of the WDR40-repeat scaffold engaging Gαq/PLCβ unknown","Relationship between the nucleolar and membrane pools of WDR36 not defined"]},{"year":2011,"claim":"Linked glaucoma-associated WDR36 variants to the scaffold/signalling activity, broadening the disease mechanism beyond rRNA processing.","evidence":"Overexpression of disease-variant constructs with Gαq signalling readout in cells","pmids":["21940795"],"confidence":"Medium","gaps":["No structural/biochemical mechanism for how variants alter binding","Effect sizes not connected to clinical variant penetrance"]},{"year":2011,"claim":"Reinforced a conserved STI1–WDR36 modifier axis affecting proliferation rather than direct rRNA levels, refining how modifiers act.","evidence":"Yeast double-mutant growth assays, 18S rRNA quantification, and POAG patient variant sequencing","pmids":["21850170"],"confidence":"Medium","gaps":["Decouples growth from rRNA without identifying the proliferation effector","Human STI1/STIP1 modifier role not tested directly"]},{"year":2014,"claim":"Identified Hsp90/co-chaperone buffering as a mechanism that masks the effects of WDR36 disease-analogous mutations on protein stability.","evidence":"Yeast genetic interaction and protein-level assays under Hsp90 inhibition/mutation","pmids":["24647762"],"confidence":"Medium","gaps":["Chaperone buffering shown in yeast, not human WDR36","Whether Hsp90 directly binds WDR36 in mammalian cells untested"]},{"year":2020,"claim":"Refined the scaffold model by showing WDR36 differentially tunes Gq output across receptors, consistent with scavenging Gαq and PLCβ into specific signalling complexes.","evidence":"Overexpression in HEK-293 and C2C12 cells with SphK1 translocation imaging, inositol phosphate assays, and calcium imaging","pmids":["32244061"],"confidence":"Medium","gaps":["Receptor-selectivity mechanism not structurally defined","Endogenous physiological consequences of differential Gq tuning untested"]},{"year":2022,"claim":"Positioned WDR36 upstream of p53 in controlling stem-cell self-renewal versus differentiation, extending the depletion-p53 link to a developmental decision.","evidence":"Inducible knockdown/overexpression in human EPS cells with differentiation assays and p53 inhibitor rescue","pmids":["35937980"],"confidence":"Medium","gaps":["Did not establish whether the p53 effect is secondary to ribosome-biogenesis stress","Direct molecular link from WDR36 to p53 activation not defined"]},{"year":2024,"claim":"Uncovered a metabolic role by showing WDR36 binds LDHA and promotes glycolysis to drive trophectoderm lineage commitment.","evidence":"Co-IP, siRNA knockdown in blastoids, transcriptomics, and targeted metabolomics","pmids":["39656902"],"confidence":"Medium","gaps":["Single Co-IP for the WDR36-LDHA interaction without reciprocal/structural validation","Mechanism by which WDR36 regulates LDHA activity unknown"]},{"year":2026,"claim":"Embedded WDR36 in a post-transcriptional protective circuit, showing ELAVL1 promotes WDR36 translation and WDR36 mediates ELAVL1's suppression of p53-driven ischemic retinal cell death.","evidence":"RNA-binding protein assay, siRNA knockdown, overexpression, AAV in vivo delivery, cell death/calcium assays, and p53 markers in retinal precursor cells","pmids":["42046554"],"confidence":"Medium","gaps":["Whether protection depends on WDR36's ribosome-biogenesis or scaffold function not separated","Direct molecular step from WDR36 to p53 inhibition unresolved"]},{"year":null,"claim":"How WDR36's nucleolar rRNA-processing role, its plasma-membrane Gq scaffold role, and its metabolic/LDHA interaction are integrated within a single cell—and which function underlies its glaucoma association—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of human WDR36 in either the SSU processome or the Gq complex","Mechanism partitioning WDR36 between nucleolar and membrane pools unknown","Causal function for glaucoma pathology not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[7,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[7,12]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,4,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,13]}],"complexes":["SSU processome (UtpB subcomplex)"],"partners":["TBXA2R","GNAQ","PLCB","GRK2","LDHA","ELAVL1","UTP6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NI36","full_name":"WD repeat-containing protein 36","aliases":["T-cell activation WD repeat-containing protein","TA-WDRP"],"length_aa":895,"mass_kda":99.4,"function":"Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Involved in the nucleolar processing of SSU 18S rRNA (PubMed:21051332, PubMed:34516797). Involved in T-cell activation and highly coregulated with IL2 (PubMed:15177553)","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/Q8NI36/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR36","classification":"Common Essential","n_dependent_lines":383,"n_total_lines":383,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/WDR36","total_profiled":1310},"omim":[{"mim_id":"620948","title":"UTP6 SMALL SUBUNIT PROCESSOME COMPONENT; UTP6","url":"https://www.omim.org/entry/620948"},{"mim_id":"613412","title":"ESOPHAGITIS, EOSINOPHILIC, 2; EOE2","url":"https://www.omim.org/entry/613412"},{"mim_id":"611274","title":"GLAUCOMA 1, OPEN ANGLE, N; GLC1N","url":"https://www.omim.org/entry/611274"},{"mim_id":"610535","title":"GLAUCOMA 1, OPEN ANGLE, M; GLC1M","url":"https://www.omim.org/entry/610535"},{"mim_id":"609887","title":"GLAUCOMA 1, OPEN ANGLE, G; GLC1G","url":"https://www.omim.org/entry/609887"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoli","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR36"},"hgnc":{"alias_symbol":["TA-WDRP","UTP21"],"prev_symbol":["GLC1G"]},"alphafold":{"accession":"Q8NI36","domains":[{"cath_id":"2.130.10.10","chopping":"66-76_581-725","consensus_level":"medium","plddt":90.9725,"start":66,"end":725},{"cath_id":"2.130.10.10","chopping":"380-579","consensus_level":"medium","plddt":89.376,"start":380,"end":579},{"cath_id":"1.20.1310","chopping":"826-951","consensus_level":"medium","plddt":89.9299,"start":826,"end":951}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NI36","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NI36-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NI36-F1-predicted_aligned_error_v6.png","plddt_mean":87.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR36","jax_strain_url":"https://www.jax.org/strain/search?query=WDR36"},"sequence":{"accession":"Q8NI36","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NI36.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NI36/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NI36"}},"corpus_meta":[{"pmid":"16723468","id":"PMC_16723468","title":"Distribution of WDR36 DNA sequence variants in patients with primary open-angle glaucoma.","date":"2006","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/16723468","citation_count":95,"is_preprint":false},{"pmid":"18469340","id":"PMC_18469340","title":"The primary open-angle glaucoma gene WDR36 functions in ribosomal RNA processing and interacts with the p53 stress-response pathway.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18469340","citation_count":90,"is_preprint":false},{"pmid":"16876519","id":"PMC_16876519","title":"A Glaucoma Case-control Study of the WDR36 Gene D658G sequence variant.","date":"2006","source":"American journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/16876519","citation_count":54,"is_preprint":false},{"pmid":"18172102","id":"PMC_18172102","title":"Profiling of WDR36 missense variants in German patients with glaucoma.","date":"2008","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/18172102","citation_count":50,"is_preprint":false},{"pmid":"21051332","id":"PMC_21051332","title":"Lack of WDR36 leads to preimplantation embryonic lethality in mice and delays the formation of small subunit ribosomal RNA in human cells in vitro.","date":"2010","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21051332","citation_count":47,"is_preprint":false},{"pmid":"18725399","id":"PMC_18725399","title":"A direct interaction between the Utp6 half-a-tetratricopeptide repeat domain and a specific peptide in Utp21 is essential for efficient pre-rRNA processing.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18725399","citation_count":42,"is_preprint":false},{"pmid":"29540704","id":"PMC_29540704","title":"Detection of mutations in MYOC, OPTN, NTF4, WDR36 and CYP1B1 in Chinese juvenile onset open-angle glaucoma using exome sequencing.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29540704","citation_count":42,"is_preprint":false},{"pmid":"19150991","id":"PMC_19150991","title":"Glaucoma-associated WDR36 variants encode functional defects in a yeast model system.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19150991","citation_count":41,"is_preprint":false},{"pmid":"17960130","id":"PMC_17960130","title":"Association between primary open-angle glaucoma and WDR36 DNA sequence variants in Japanese.","date":"2007","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/17960130","citation_count":39,"is_preprint":false},{"pmid":"20631153","id":"PMC_20631153","title":"Mutant WDR36 directly affects axon growth of retinal ganglion cells leading to progressive retinal degeneration in mice.","date":"2010","source":"Human molecular 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science","url":"https://pubmed.ncbi.nlm.nih.gov/21931130","citation_count":28,"is_preprint":false},{"pmid":"19347049","id":"PMC_19347049","title":"Different WDR36 mutation pattern in Chinese patients with primary open-angle glaucoma.","date":"2009","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/19347049","citation_count":28,"is_preprint":false},{"pmid":"21940795","id":"PMC_21940795","title":"WDR36 acts as a scaffold protein tethering a G-protein-coupled receptor, Gαq and phospholipase Cβ in a signalling complex.","date":"2011","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/21940795","citation_count":22,"is_preprint":false},{"pmid":"20813748","id":"PMC_20813748","title":"Association between primary open-angle glaucoma (POAG) and WDR36 sequence variance in Italian families affected by POAG.","date":"2010","source":"The British journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/20813748","citation_count":17,"is_preprint":false},{"pmid":"25261604","id":"PMC_25261604","title":"Heterozygote Wdr36-deficient mice do not develop glaucoma.","date":"2014","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/25261604","citation_count":14,"is_preprint":false},{"pmid":"22025897","id":"PMC_22025897","title":"WDR36 variants in East Indian primary open-angle glaucoma patients.","date":"2011","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/22025897","citation_count":14,"is_preprint":false},{"pmid":"28658128","id":"PMC_28658128","title":"Association of WDR36 polymorphisms with primary open angle glaucoma: A systematic review and meta-analysis.","date":"2017","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28658128","citation_count":13,"is_preprint":false},{"pmid":"24647762","id":"PMC_24647762","title":"The ribosomal biogenesis protein Utp21 interacts with Hsp90 and has 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Loss of Wdr36 function in zebrafish causes defects in 18S rRNA processing and abnormal nucleolar morphology.\",\n      \"method\": \"Sequence alignment, subcellular localization (nucleolus), loss-of-function in zebrafish with rRNA processing assay and nucleolar morphology readout\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, rRNA processing assay, morphology), replicated in mammalian cells (PMID:21051332) and yeast (PMID:18469340)\",\n      \"pmids\": [\"18469340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of Wdr36 function activates the p53 stress-response pathway, suggesting that co-inheritance of defects in p53 pathway genes may influence the impact of WDR36 variants.\",\n      \"method\": \"Loss-of-function in zebrafish with p53 pathway readout\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined pathway readout in a single lab, corroborated by mammalian cell data in PMID:21051332\",\n      \"pmids\": [\"18469340\", \"21051332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WDR36 is essential for mammalian preimplantation development: homozygous Wdr36 knockout causes embryonic lethality before the blastocyst stage in mice, and siRNA-mediated depletion replicates this lethality.\",\n      \"method\": \"Targeted gene deletion in mice (knockout); siRNA knockdown in mouse embryos\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined lethal phenotype, replicated with independent siRNA approach in the same study\",\n      \"pmids\": [\"21051332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"WDR36 localizes to the nucleolus in human trabecular meshwork (HTM-N) cells, co-localizing with nucleolar proteins nucleophosmin and PWP2; both endogenous and recombinant/epitope-tagged WDR36 show this nucleolar localization.\",\n      \"method\": \"Immunocytochemistry and recombinant/epitope-tagged protein localization in human cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization by immunocytochemistry with co-localization controls, confirmed with tagged recombinant protein\",\n      \"pmids\": [\"21051332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Knockdown of WDR36 in human trabecular meshwork (HTM-N) cells delays maturation of 18S rRNA: northern blot shows decreased 21S rRNA (precursor of 18S rRNA), and metabolic-labeling experiments show delayed 18S rRNA maturation. WDR36 depletion also induces apoptotic cell death with upregulation of BAX, TP53, and CDKN1A mRNAs.\",\n      \"method\": \"siRNA knockdown in human cells; northern blot; metabolic labeling; RT-PCR/mRNA quantification\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro rRNA processing assay (northern blot + metabolic labeling) combined with functional cell death readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21051332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In the yeast UtpB subcomplex of the SSU processome, the HAT (half-a-tetratricopeptide repeat) domain of Utp6 directly binds a specific peptide in Utp21 (the yeast ortholog of WDR36) with a Kd of ~10 µM; an intact HAT domain is essential for efficient pre-rRNA processing and cell growth.\",\n      \"method\": \"Comprehensive interaction mapping within UtpB subcomplex; point and deletion mutagenesis of Utp6; biophysical binding assay (Kd measurement); pre-rRNA processing assay; growth assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of protein-protein interaction, biophysical Kd measurement, mutagenesis, and functional rRNA processing assay combined in one study\",\n      \"pmids\": [\"18725399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"POAG-associated WDR36 sequence variants introduced into yeast UTP21 do not produce defects alone, but in combination with disruption of STI1 (a synthetic interactor of UTP21), 5 of 11 tested variants show altered cell viability corresponding to reduced or elevated pre-rRNA levels, demonstrating that WDR36 variants can alter rRNA processing in a specific genetic background.\",\n      \"method\": \"Yeast model system with site-directed mutagenesis of UTP21; genetic epistasis (double mutant with STI1 deletion); rRNA processing assay; growth/viability assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in yeast with rRNA processing readout; single lab\",\n      \"pmids\": [\"19150991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"WDR36 acts as a scaffold protein: it directly interacts with the C-terminus and first intracellular loop of the thromboxane A2 receptor β (TPβ) (confirmed by yeast two-hybrid and GST pulldown), co-immunoprecipitates with Gαq and PLCβ in cells, promotes TPβ–Gαq interaction, increases Gαq–PLCβ interaction, prevents sequestration of activated Gαq by GRK2, and augments the presence of TPβ in PLCβ immunoprecipitates. WDR36 overexpression enhances and siRNA knockdown inhibits TPβ-induced Gαq signalling. The complex translocates from plasma membrane to intracellular vesicles upon receptor stimulation.\",\n      \"method\": \"Yeast two-hybrid; GST pulldown; co-immunoprecipitation; confocal microscopy; siRNA knockdown; overexpression functional assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, direct pulldown, yeast two-hybrid, localization, and functional signalling assays with KD/OE all in one study; multiple orthogonal methods\",\n      \"pmids\": [\"21940795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Disease-associated WDR36 variants affect WDR36's ability to modulate Gαq-mediated signalling by TPβ, linking glaucoma-associated variants to the scaffold/signalling function.\",\n      \"method\": \"Overexpression of disease-variant WDR36 constructs with Gαq signalling readout in cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, functional assay with variant constructs but no structural/mechanistic detail of how variants alter binding\",\n      \"pmids\": [\"21940795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Transgenic mice overexpressing mutant mouse Wdr36 Del605-607 (equivalent to human D658G region) develop progressive peripheral retinal degeneration with normal IOP; RGCs and amacrine cell synapses are affected, and axon outgrowth of cultured RGCs from these mice is significantly reduced. Molecular modeling shows the deletion removes a hydrogen bond stabilizing the 6th β-propeller of the second domain.\",\n      \"method\": \"Transgenic mouse overexpression; retinal histology; RGC axon outgrowth assay; molecular modeling\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — transgenic mouse with defined retinal phenotype and direct RGC axon assay; molecular modeling is computational; single lab\",\n      \"pmids\": [\"20631153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Utp21 (yeast WDR36 ortholog) interacts with Hsp90 and co-chaperones; steady-state levels of Utp21 are reduced upon Hsp90 mutation or inhibition. The utp21-S602F mutation shows severe/lethal growth defects when combined with Hsp90 or co-chaperone mutations. Three Utp21 mutants analogous to glaucoma-associated WDR36 mutations show reduced levels in yeast expressing Hsp90 or co-chaperone mutations, indicating Hsp90 buffers the effects of these mutations.\",\n      \"method\": \"Genetic interaction analysis (double mutant growth assays); Hsp90 inhibition; protein level measurement in yeast\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and protein stability assays; single lab; yeast model\",\n      \"pmids\": [\"24647762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STI1 variant K434R combined with specific UTP21 (WDR36 yeast ortholog) variants causes significantly altered culture growth at 37°C, but does not significantly alter 18S rRNA levels, supporting a conserved molecular pathway involving STI1 and WDR36 affecting cell proliferation rather than direct rRNA processing.\",\n      \"method\": \"Yeast model system; double-mutant growth assays; 18S rRNA quantification; gene sequencing in POAG patients\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in yeast with functional readout; corroborated by patient variant discovery; single lab\",\n      \"pmids\": [\"21850170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDR36 overexpression delays SphK1 (sphingosine kinase-1) translocation to the plasma membrane induced by Gq-coupled M3, B2, and H1 receptors, while augmenting TPβ receptor-induced calcium signalling. WDR36 increases inositol phosphate production by TPβ but attenuates it by M3 and B2 receptors, consistent with WDR36 scavenging Gαq and PLCβ to orchestrate Gq signalling complexes.\",\n      \"method\": \"Overexpression in HEK-293 cells and C2C12 myoblasts; live-cell imaging of SphK1 translocation; inositol phosphate assay; calcium imaging\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays in two cell lines; single lab; builds on prior study (PMID:21940795)\",\n      \"pmids\": [\"32244061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"WDR36 knockdown in human extended pluripotent stem (EPS) cells disrupts self-renewal and promotes mesodermal differentiation; p53 inhibition reverses these effects, placing WDR36 upstream of p53 in the self-renewal regulatory pathway.\",\n      \"method\": \"Inducible knockdown and overexpression in human EPS cells; differentiation assays; p53 inhibitor rescue experiment\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotype and genetic epistasis (p53 rescue); single lab\",\n      \"pmids\": [\"35937980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"WDR36 interacts with glycolytic metabolic protein LDHA (lactate dehydrogenase A) and positively regulates glycolysis during the late stage of human blastoid formation. WDR36 interference blocks trophectoderm lineage commitment and downregulates glucose metabolism, linking WDR36 to glycolytic regulation of cell fate.\",\n      \"method\": \"Co-immunoprecipitation (WDR36-LDHA interaction); siRNA knockdown in blastoids; transcriptomics; targeted metabolomics\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifies binding partner, knockdown with metabolomics and transcriptomics readout; single lab; blastoid model\",\n      \"pmids\": [\"39656902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WDR36 overexpression inhibits migration, chemotaxis, and osteogenic differentiation of periodontal ligament stem cells (PDLSCs), while WDR36 depletion promotes these processes and also promotes senescence.\",\n      \"method\": \"Scratch-wound migration assay; transwell chemotaxis assay; ALP activity, Alizarin red staining, calcium content; RT-qPCR; SA-β-galactosidase staining; overexpression and knockdown\",\n      \"journal\": \"World journal of stem cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional overexpression/knockdown assays with phenotypic readouts; no molecular mechanism identified; single lab\",\n      \"pmids\": [\"40061266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELAVL1 binds WDR36 mRNA and promotes its protein translation (post-transcriptional regulation). WDR36 overexpression reduces OGD/R-induced cell death, calcium overload, and p53 pathway activation in retinal precursor cells; WDR36 knockdown abolishes ELAVL1's protective effects, placing WDR36 downstream of ELAVL1 in the p53 inhibition pathway under acute pressure-ischemia stress.\",\n      \"method\": \"RNA-binding protein interaction assay (ELAVL1-WDR36 mRNA); siRNA knockdown; plasmid overexpression; AAV in vivo delivery; cell death assay; calcium measurement; p53 pathway markers\",\n      \"journal\": \"Open life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (in vitro + in vivo), genetic epistasis (WDR36 KD reverses ELAVL1 OE protection); single lab\",\n      \"pmids\": [\"42046554\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR36 is a WD40-repeat nucleolar scaffold protein that functions as an essential component of the small subunit (SSU) processome for 18S rRNA maturation and ribosome biogenesis (ortholog of yeast Utp21/UTP21), activates the p53 stress-response pathway when depleted, and additionally serves as a plasma-membrane scaffold that tethers Gαq, PLCβ, and G-protein-coupled receptors (notably TPβ) to orchestrate Gq-mediated signalling; disease-associated variants impair both its rRNA processing function (in specific genetic backgrounds) and its ability to modulate Gαq signalling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR36 is a WD40-repeat nucleolar protein that functions in 18S rRNA maturation and ribosome biogenesis as the functional homolog of yeast Utp21, a component of the SSU processome [#0]. In human cells it localizes to the nucleolus alongside nucleophosmin and PWP2, and its depletion delays processing of the 21S precursor and maturation of 18S rRNA [#3, #4]. Within the yeast UtpB subcomplex, the WDR36 ortholog Utp21 is engaged through a direct HAT-domain contact from Utp6 that is required for efficient pre-rRNA processing [#5]. WDR36 is essential for early development: homozygous knockout causes mouse preimplantation lethality, and its loss activates a p53 stress response—inducing BAX, TP53, and CDKN1A and triggering apoptosis—that is reversible by p53 inhibition and governs stem-cell self-renewal [#1, #2, #4, #13]. Beyond the nucleolus, WDR36 acts as a plasma-membrane scaffold that binds the thromboxane A2 receptor \\u03b2 (TP\\u03b2) and assembles G\\u03b1q\\u2013PLC\\u03b2\\u2013receptor complexes, promoting receptor\\u2013G\\u03b1q coupling, protecting activated G\\u03b1q from GRK2 sequestration, and thereby selectively shaping Gq-mediated signalling and calcium responses [#7, #12]. Glaucoma-associated WDR36 variants impair rRNA processing only in sensitizing genetic backgrounds and also alter WDR36's modulation of G\\u03b1q signalling, and a deletion variant modeled in transgenic mice produces progressive retinal degeneration with reduced retinal ganglion cell axon outgrowth [#6, #8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established WDR36's core molecular identity by showing it is the functional ortholog of yeast Utp21 and a nucleolar factor required for 18S rRNA processing, placing it in ribosome biogenesis.\",\n      \"evidence\": \"Sequence alignment, nucleolar localization, and loss-of-function with rRNA processing and nucleolar morphology readouts in zebrafish\",\n      \"pmids\": [\"18469340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the human SSU processome subcomplex composition\", \"No direct biochemical assay of WDR36 enzymatic or binding activity in vertebrates\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected WDR36 loss to the p53 stress-response axis, framing how variant impact could depend on co-inherited p53-pathway status.\",\n      \"evidence\": \"Zebrafish loss-of-function with p53 pathway readout\",\n      \"pmids\": [\"18469340\", \"21051332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether p53 activation is a direct sensor of disrupted ribosome biogenesis\", \"No mechanism linking WDR36 depletion to specific p53 effectors\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved a direct intermolecular contact in the SSU processome by mapping a HAT-domain interaction between Utp6 and the WDR36 ortholog Utp21 and showing it is functionally required.\",\n      \"evidence\": \"Interaction mapping, mutagenesis, biophysical Kd measurement, and pre-rRNA processing/growth assays in yeast UtpB subcomplex\",\n      \"pmids\": [\"18725399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction demonstrated in yeast, not human WDR36\", \"Structural basis of the peptide contact not solved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated WDR36 is essential for mammalian development and confirmed its conserved nucleolar rRNA-processing role in human cells, linking depletion to p53-dependent apoptosis.\",\n      \"evidence\": \"Mouse knockout and siRNA embryo lethality; human HTM-N cell localization, northern blot/metabolic labeling rRNA assays, and apoptosis/mRNA readouts\",\n      \"pmids\": [\"21051332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate the developmental requirement from the general ribosome-biogenesis defect\", \"Tissue-specific roles in trabecular meshwork beyond rRNA processing not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that POAG-associated WDR36 variants are not intrinsically defective but become functionally consequential for rRNA processing only in a sensitizing genetic background.\",\n      \"evidence\": \"Yeast UTP21 site-directed mutants with STI1 deletion epistasis and rRNA processing/viability assays\",\n      \"pmids\": [\"19150991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance of STI1 modifier to human trabecular meshwork unestablished\", \"Did not identify the human equivalent genetic modifier\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided an in vivo disease-relevant phenotype by showing a WDR36 deletion variant drives retinal degeneration and impaired RGC axon outgrowth independent of intraocular pressure.\",\n      \"evidence\": \"Transgenic mouse overexpression with retinal histology, RGC axon outgrowth assay, and molecular modeling\",\n      \"pmids\": [\"20631153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular modeling of the destabilized \\u03b2-propeller is computational\", \"Mechanism linking the structural change to neuronal phenotype not biochemically resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a second, non-nucleolar function: WDR36 acts as a plasma-membrane scaffold organizing TP\\u03b2\\u2013G\\u03b1q\\u2013PLC\\u03b2 complexes to potentiate Gq signalling.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, reciprocal Co-IP, confocal microscopy, and KD/OE signalling assays in cells\",\n      \"pmids\": [\"21940795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the WDR40-repeat scaffold engaging G\\u03b1q/PLC\\u03b2 unknown\", \"Relationship between the nucleolar and membrane pools of WDR36 not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked glaucoma-associated WDR36 variants to the scaffold/signalling activity, broadening the disease mechanism beyond rRNA processing.\",\n      \"evidence\": \"Overexpression of disease-variant constructs with G\\u03b1q signalling readout in cells\",\n      \"pmids\": [\"21940795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural/biochemical mechanism for how variants alter binding\", \"Effect sizes not connected to clinical variant penetrance\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Reinforced a conserved STI1\\u2013WDR36 modifier axis affecting proliferation rather than direct rRNA levels, refining how modifiers act.\",\n      \"evidence\": \"Yeast double-mutant growth assays, 18S rRNA quantification, and POAG patient variant sequencing\",\n      \"pmids\": [\"21850170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Decouples growth from rRNA without identifying the proliferation effector\", \"Human STI1/STIP1 modifier role not tested directly\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Hsp90/co-chaperone buffering as a mechanism that masks the effects of WDR36 disease-analogous mutations on protein stability.\",\n      \"evidence\": \"Yeast genetic interaction and protein-level assays under Hsp90 inhibition/mutation\",\n      \"pmids\": [\"24647762\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chaperone buffering shown in yeast, not human WDR36\", \"Whether Hsp90 directly binds WDR36 in mammalian cells untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Refined the scaffold model by showing WDR36 differentially tunes Gq output across receptors, consistent with scavenging G\\u03b1q and PLC\\u03b2 into specific signalling complexes.\",\n      \"evidence\": \"Overexpression in HEK-293 and C2C12 cells with SphK1 translocation imaging, inositol phosphate assays, and calcium imaging\",\n      \"pmids\": [\"32244061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor-selectivity mechanism not structurally defined\", \"Endogenous physiological consequences of differential Gq tuning untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned WDR36 upstream of p53 in controlling stem-cell self-renewal versus differentiation, extending the depletion-p53 link to a developmental decision.\",\n      \"evidence\": \"Inducible knockdown/overexpression in human EPS cells with differentiation assays and p53 inhibitor rescue\",\n      \"pmids\": [\"35937980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether the p53 effect is secondary to ribosome-biogenesis stress\", \"Direct molecular link from WDR36 to p53 activation not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a metabolic role by showing WDR36 binds LDHA and promotes glycolysis to drive trophectoderm lineage commitment.\",\n      \"evidence\": \"Co-IP, siRNA knockdown in blastoids, transcriptomics, and targeted metabolomics\",\n      \"pmids\": [\"39656902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP for the WDR36-LDHA interaction without reciprocal/structural validation\", \"Mechanism by which WDR36 regulates LDHA activity unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Embedded WDR36 in a post-transcriptional protective circuit, showing ELAVL1 promotes WDR36 translation and WDR36 mediates ELAVL1's suppression of p53-driven ischemic retinal cell death.\",\n      \"evidence\": \"RNA-binding protein assay, siRNA knockdown, overexpression, AAV in vivo delivery, cell death/calcium assays, and p53 markers in retinal precursor cells\",\n      \"pmids\": [\"42046554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether protection depends on WDR36's ribosome-biogenesis or scaffold function not separated\", \"Direct molecular step from WDR36 to p53 inhibition unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How WDR36's nucleolar rRNA-processing role, its plasma-membrane Gq scaffold role, and its metabolic/LDHA interaction are integrated within a single cell—and which function underlies its glaucoma association—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of human WDR36 in either the SSU processome or the Gq complex\", \"Mechanism partitioning WDR36 between nucleolar and membrane pools unknown\", \"Causal function for glaucoma pathology not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [7, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 13]}\n    ],\n    \"complexes\": [\"SSU processome (UtpB subcomplex)\"],\n    \"partners\": [\"TBXA2R\", \"GNAQ\", \"PLCB\", \"GRK2\", \"LDHA\", \"ELAVL1\", \"UTP6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}