{"gene":"WDR37","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2019,"finding":"Drosophila null allele of the WDR37 ortholog (CG12333/wdr37) causes bang sensitivity (seizure phenotype), climbing defects, and grip strength defects; these phenotypes are rescued by human reference WDR37 cDNA but not by two disease-associated variants, demonstrating that these variants severely impair WDR37 protein function in vivo.","method":"Drosophila null allele generation (GAL4 replacement), UAS-cDNA rescue experiments with human wild-type and mutant WDR37","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — in vivo functional rescue with human WT vs. mutant cDNA, two orthogonal phenotypic readouts, replicated across multiple alleles in one rigorous study","pmids":["31327508"],"is_preprint":false},{"year":2019,"finding":"Wild-type WDR37 protein is localized predominantly in the cytoplasm; disease-associated missense mutant proteins show similar subcellular localization and similar protein levels compared to wild-type.","method":"Immunocytochemistry and western blot in human cells expressing WT and mutant WDR37","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (ICC + western blot) in a single lab","pmids":["31327510"],"is_preprint":false},{"year":2019,"finding":"Zebrafish heterozygous for missense variants (including p.Ser129Cys, replicating a human variant) show poor growth and larval lethality, whereas heterozygous frameshift alleles survive to adulthood, indicating a dominant-negative mechanism for the missense variants. RNA-seq of embryos with a missense variant detected significant upregulation of cholesterol biosynthesis pathways.","method":"CRISPR-Cas9 genome editing in zebrafish generating missense and frameshift alleles; RNA-seq transcriptomic analysis","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic allelic series with functional comparison, RNA-seq pathway analysis, single lab","pmids":["31327510"],"is_preprint":false},{"year":2021,"finding":"Pacs1 and Wdr37 form a complex that is required for normal ER calcium handling in lymphocytes. Deletion of Pacs1 or Wdr37 causes peripheral lymphopenia linked to blunted Ca2+ release from the ER after antigen receptor stimulation, and Pacs1-deficient cells show diminished inositol triphosphate receptor expression together with increased ER and oxidative stress.","method":"Forward genetic screening in mice; genetic deletion of Pacs1 or Wdr37; Ca2+ flux measurements; protein expression analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — forward genetic screen, independent Pacs1 and Wdr37 knockouts, functional Ca2+ assays, multiple phenotypic readouts across labs","pmids":["33630350"],"is_preprint":false},{"year":2021,"finding":"WDR37 forms homodimers and strongly binds PACS1 and PACS2; these interactions were confirmed by co-immunoprecipitation, yeast two-hybrid assays, and immunocytochemical colocalization in human cells. A novel disease-associated variant p.(Asp220Gly), located within the second WD40 motif, loses the ability to bind PACS1 and PACS2, while retaining the ability to dimerize with wild-type WDR37.","method":"Co-immunoprecipitation, yeast two-hybrid assay, immunocytochemistry; functional variant analysis","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — three orthogonal methods (Co-IP, Y2H, ICC) for interaction, plus structure-function analysis of multiple variants in single study","pmids":["34642815"],"is_preprint":false},{"year":2021,"finding":"Novel WDR37 disease-associated variants in the C-terminal region (p.Asp220Gly, p.Asp260Asn, p.Pro257His) show normal cellular localization but reduced protein expression levels compared to wild-type WDR37.","method":"Immunocytochemistry and western blot in human cells expressing mutant WDR37","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (ICC + western blot), single lab","pmids":["34642815"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structure of the Pacs1-Wdr37 complex reveals that Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR). This interaction stabilizes Wdr37 and is critical for the expression of both proteins. The pathogenic Pacs1-R203W mutation (which causes neurodevelopmental syndrome) lies on a solvent-exposed surface of the FBR and does not disrupt complex formation; Pacs1-R203W remains dependent on Wdr37 for stability. Structural homology of the FBR to synaptotagmin C2 domains reveals a potential ability of Pacs1 to bind negatively charged phospholipids through a positively charged cleft.","method":"Cryo-electron microscopy structure determination; biochemical stability assays; targeted proteolytic degradation of Wdr37 to reduce Pacs1-R203W levels","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with functional validation and mutagenesis analysis, preprint, single lab but multiple orthogonal methods","pmids":["41279321"],"is_preprint":true}],"current_model":"WDR37 is a WD40 repeat-containing protein that forms a stable complex with PACS1 and PACS2 (and homodimerizes), binding PACS1 through its furin-binding region as revealed by cryo-EM; this complex is required for ER calcium homeostasis and lymphocyte quiescence, with disease-associated variants disrupting PACS binding, reducing protein stability, or impairing function as demonstrated by Drosophila and zebrafish in vivo rescue experiments."},"narrative":{"mechanistic_narrative":"WDR37 is a cytoplasmic WD40 repeat protein that functions as a stable binding partner of the PACS proteins PACS1 and PACS2, governing ER calcium homeostasis and lymphocyte quiescence [PMID:33630350, PMID:34642815]. It homodimerizes and binds PACS1 and PACS2 strongly, with the interaction mediated by a conserved interface within the PACS1 furin-binding region that stabilizes both proteins and is required for their reciprocal expression [PMID:34642815, PMID:41279321]. The PACS1–WDR37 complex is required for normal ER Ca2+ handling: loss of either protein produces peripheral lymphopenia with blunted antigen-receptor-triggered Ca2+ release from the ER, diminished IP3 receptor expression, and elevated ER and oxidative stress [PMID:33630350]. Disease-associated WDR37 variants act through distinct molecular failures — abolishing PACS binding while sparing dimerization, reducing protein stability, or impairing function in vivo — and in vivo rescue in Drosophila and dominant-negative behavior of missense alleles in zebrafish establish their pathogenicity [PMID:31327508, PMID:31327510, PMID:34642815].","teleology":[{"year":2019,"claim":"Established that WDR37 has an essential, conserved organismal function and that human disease variants disrupt it, moving WDR37 from a candidate gene to a functionally validated one.","evidence":"Drosophila null allele with human WT vs. mutant cDNA rescue across seizure, climbing, and grip-strength readouts","pmids":["31327508"],"confidence":"High","gaps":["Molecular activity underlying the phenotypes not defined","No biochemical partners identified at this stage"]},{"year":2019,"claim":"Defined WDR37 as a predominantly cytoplasmic protein and showed missense variants do not grossly alter localization or steady-state levels, indicating pathogenicity arises from a functional rather than trafficking/stability defect for these alleles.","evidence":"Immunocytochemistry and western blot of WT and mutant WDR37 in human cells; zebrafish CRISPR allelic series with RNA-seq","pmids":["31327510"],"confidence":"Medium","gaps":["Dominant-negative mechanism inferred genetically, not biochemically resolved","Cholesterol biosynthesis upregulation not mechanistically linked to WDR37 activity"]},{"year":2021,"claim":"Identified the physiological role of the PACS1–WDR37 complex in ER calcium signaling and lymphocyte biology, linking WDR37 to IP3R-dependent Ca2+ release and cellular stress control.","evidence":"Forward genetic screen in mice with independent Pacs1 and Wdr37 knockouts, Ca2+ flux assays, and protein expression analysis","pmids":["33630350"],"confidence":"High","gaps":["Direct molecular link between the complex and IP3R regulation unresolved","Whether WDR37 acts catalytically or as a scaffold not determined"]},{"year":2021,"claim":"Mapped the protein-interaction logic of WDR37, showing it homodimerizes and binds both PACS1 and PACS2, and that variant pathogenicity can be explained by selective loss of PACS binding or reduced stability.","evidence":"Co-IP, yeast two-hybrid, and immunocytochemistry with structure-function analysis of C-terminal WD40 variants in human cells","pmids":["34642815"],"confidence":"High","gaps":["Functional consequence of PACS-binding loss vs. reduced stability not separated downstream","No structural detail of the interaction interface at this stage"]},{"year":2025,"claim":"Resolved the structural basis of PACS1–WDR37 assembly, showing PACS1's furin-binding region forms the binding interface and that the complex is mutually stabilizing, reframing how the PACS1-R203W syndrome variant relates to WDR37 dependence.","evidence":"Cryo-EM structure determination with stability assays and targeted WDR37 degradation (preprint)","pmids":["41279321"],"confidence":"High","gaps":["Phospholipid-binding capacity of the FBR cleft inferred from C2-domain homology, not functionally tested","How complex assembly couples to ER Ca2+ regulation not structurally addressed"]},{"year":null,"claim":"The molecular activity of WDR37 itself — how the PACS1–WDR37 complex mechanistically controls IP3R expression and ER Ca2+ release — remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No catalytic or direct effector activity established for WDR37","Connection between the structural interface and the calcium phenotype not bridged"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]}],"pathway":[],"complexes":["PACS1-WDR37 complex"],"partners":["PACS1","PACS2","WDR37"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2I8","full_name":"WD repeat-containing protein 37","aliases":[],"length_aa":494,"mass_kda":54.7,"function":"Required for normal ER Ca2+ handling in lymphocytes. Together with PACS1, it plays an essential role in stabilizing peripheral lymphocyte populations","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9Y2I8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR37","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SNRPC","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR37","total_profiled":1310},"omim":[{"mim_id":"618652","title":"NEUROOCULOCARDIOGENITOURINARY SYNDROME; NOCGUS","url":"https://www.omim.org/entry/618652"},{"mim_id":"618586","title":"WD REPEAT-CONTAINING PROTEIN 37; WDR37","url":"https://www.omim.org/entry/618586"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Intermediate filaments","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR37"},"hgnc":{"alias_symbol":["KIAA0982"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2I8","domains":[{"cath_id":"2.130.10.10","chopping":"146-230_262-487","consensus_level":"medium","plddt":94.3536,"start":146,"end":487}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2I8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2I8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2I8-F1-predicted_aligned_error_v6.png","plddt_mean":78.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR37","jax_strain_url":"https://www.jax.org/strain/search?query=WDR37"},"sequence":{"accession":"Q9Y2I8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2I8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2I8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2I8"}},"corpus_meta":[{"pmid":"31327508","id":"PMC_31327508","title":"De Novo Variants in WDR37 Are Associated with Epilepsy, Colobomas, Dysmorphism, Developmental Delay, Intellectual Disability, and Cerebellar Hypoplasia.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31327508","citation_count":38,"is_preprint":false},{"pmid":"31327510","id":"PMC_31327510","title":"De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31327510","citation_count":30,"is_preprint":false},{"pmid":"33630350","id":"PMC_33630350","title":"Calcium flux control by Pacs1-Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases.","date":"2021","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/33630350","citation_count":26,"is_preprint":false},{"pmid":"34642815","id":"PMC_34642815","title":"WDR37 syndrome: identification of a distinct new cluster of disease-associated variants and functional analyses of mutant proteins.","date":"2021","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34642815","citation_count":12,"is_preprint":false},{"pmid":"33369122","id":"PMC_33369122","title":"Coloboma may be a shared feature in a spectrum of disorders caused by mutations in the WDR37-PACS1-PACS2 axis.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/33369122","citation_count":11,"is_preprint":false},{"pmid":"32530092","id":"PMC_32530092","title":"Expanding the phenotypic spectrum consequent upon de novo WDR37 missense variants.","date":"2020","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32530092","citation_count":9,"is_preprint":false},{"pmid":"37064331","id":"PMC_37064331","title":"First Report of Mexican Patients with PACS1-Related Neurodevelopmental Disorder and Review of the PACS1-, PACS2-, and WDR37-Related Ophthalmological Manifestations.","date":"2022","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/37064331","citation_count":2,"is_preprint":false},{"pmid":"38044197","id":"PMC_38044197","title":"Splicing variant of WDR37 in a case of Neurooculocardiogenitourinary syndrome.","date":"2023","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/38044197","citation_count":2,"is_preprint":false},{"pmid":"40869285","id":"PMC_40869285","title":"AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40869285","citation_count":1,"is_preprint":false},{"pmid":"41279321","id":"PMC_41279321","title":"The Structural Basis for Pacs1-Wdr37 Complex Assembly and Stability.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41279321","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7277,"output_tokens":1809,"usd":0.024483,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8648,"output_tokens":2022,"usd":0.046895,"stage2_stop_reason":"end_turn"},"total_usd":0.071378,"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\": 2019,\n      \"finding\": \"Drosophila null allele of the WDR37 ortholog (CG12333/wdr37) causes bang sensitivity (seizure phenotype), climbing defects, and grip strength defects; these phenotypes are rescued by human reference WDR37 cDNA but not by two disease-associated variants, demonstrating that these variants severely impair WDR37 protein function in vivo.\",\n      \"method\": \"Drosophila null allele generation (GAL4 replacement), UAS-cDNA rescue experiments with human wild-type and mutant WDR37\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — in vivo functional rescue with human WT vs. mutant cDNA, two orthogonal phenotypic readouts, replicated across multiple alleles in one rigorous study\",\n      \"pmids\": [\"31327508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Wild-type WDR37 protein is localized predominantly in the cytoplasm; disease-associated missense mutant proteins show similar subcellular localization and similar protein levels compared to wild-type.\",\n      \"method\": \"Immunocytochemistry and western blot in human cells expressing WT and mutant WDR37\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (ICC + western blot) in a single lab\",\n      \"pmids\": [\"31327510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Zebrafish heterozygous for missense variants (including p.Ser129Cys, replicating a human variant) show poor growth and larval lethality, whereas heterozygous frameshift alleles survive to adulthood, indicating a dominant-negative mechanism for the missense variants. RNA-seq of embryos with a missense variant detected significant upregulation of cholesterol biosynthesis pathways.\",\n      \"method\": \"CRISPR-Cas9 genome editing in zebrafish generating missense and frameshift alleles; RNA-seq transcriptomic analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic allelic series with functional comparison, RNA-seq pathway analysis, single lab\",\n      \"pmids\": [\"31327510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pacs1 and Wdr37 form a complex that is required for normal ER calcium handling in lymphocytes. Deletion of Pacs1 or Wdr37 causes peripheral lymphopenia linked to blunted Ca2+ release from the ER after antigen receptor stimulation, and Pacs1-deficient cells show diminished inositol triphosphate receptor expression together with increased ER and oxidative stress.\",\n      \"method\": \"Forward genetic screening in mice; genetic deletion of Pacs1 or Wdr37; Ca2+ flux measurements; protein expression analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — forward genetic screen, independent Pacs1 and Wdr37 knockouts, functional Ca2+ assays, multiple phenotypic readouts across labs\",\n      \"pmids\": [\"33630350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WDR37 forms homodimers and strongly binds PACS1 and PACS2; these interactions were confirmed by co-immunoprecipitation, yeast two-hybrid assays, and immunocytochemical colocalization in human cells. A novel disease-associated variant p.(Asp220Gly), located within the second WD40 motif, loses the ability to bind PACS1 and PACS2, while retaining the ability to dimerize with wild-type WDR37.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid assay, immunocytochemistry; functional variant analysis\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three orthogonal methods (Co-IP, Y2H, ICC) for interaction, plus structure-function analysis of multiple variants in single study\",\n      \"pmids\": [\"34642815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Novel WDR37 disease-associated variants in the C-terminal region (p.Asp220Gly, p.Asp260Asn, p.Pro257His) show normal cellular localization but reduced protein expression levels compared to wild-type WDR37.\",\n      \"method\": \"Immunocytochemistry and western blot in human cells expressing mutant WDR37\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (ICC + western blot), single lab\",\n      \"pmids\": [\"34642815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structure of the Pacs1-Wdr37 complex reveals that Pacs1 binds Wdr37 through a conserved interface within its furin-binding region (FBR). This interaction stabilizes Wdr37 and is critical for the expression of both proteins. The pathogenic Pacs1-R203W mutation (which causes neurodevelopmental syndrome) lies on a solvent-exposed surface of the FBR and does not disrupt complex formation; Pacs1-R203W remains dependent on Wdr37 for stability. Structural homology of the FBR to synaptotagmin C2 domains reveals a potential ability of Pacs1 to bind negatively charged phospholipids through a positively charged cleft.\",\n      \"method\": \"Cryo-electron microscopy structure determination; biochemical stability assays; targeted proteolytic degradation of Wdr37 to reduce Pacs1-R203W levels\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with functional validation and mutagenesis analysis, preprint, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"41279321\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"WDR37 is a WD40 repeat-containing protein that forms a stable complex with PACS1 and PACS2 (and homodimerizes), binding PACS1 through its furin-binding region as revealed by cryo-EM; this complex is required for ER calcium homeostasis and lymphocyte quiescence, with disease-associated variants disrupting PACS binding, reducing protein stability, or impairing function as demonstrated by Drosophila and zebrafish in vivo rescue experiments.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR37 is a cytoplasmic WD40 repeat protein that functions as a stable binding partner of the PACS proteins PACS1 and PACS2, governing ER calcium homeostasis and lymphocyte quiescence [#3, #4]. It homodimerizes and binds PACS1 and PACS2 strongly, with the interaction mediated by a conserved interface within the PACS1 furin-binding region that stabilizes both proteins and is required for their reciprocal expression [#4, #6]. The PACS1–WDR37 complex is required for normal ER Ca2+ handling: loss of either protein produces peripheral lymphopenia with blunted antigen-receptor-triggered Ca2+ release from the ER, diminished IP3 receptor expression, and elevated ER and oxidative stress [#3]. Disease-associated WDR37 variants act through distinct molecular failures — abolishing PACS binding while sparing dimerization, reducing protein stability, or impairing function in vivo — and in vivo rescue in Drosophila and dominant-negative behavior of missense alleles in zebrafish establish their pathogenicity [#0, #2, #4, #5].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that WDR37 has an essential, conserved organismal function and that human disease variants disrupt it, moving WDR37 from a candidate gene to a functionally validated one.\",\n      \"evidence\": \"Drosophila null allele with human WT vs. mutant cDNA rescue across seizure, climbing, and grip-strength readouts\",\n      \"pmids\": [\"31327508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular activity underlying the phenotypes not defined\", \"No biochemical partners identified at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined WDR37 as a predominantly cytoplasmic protein and showed missense variants do not grossly alter localization or steady-state levels, indicating pathogenicity arises from a functional rather than trafficking/stability defect for these alleles.\",\n      \"evidence\": \"Immunocytochemistry and western blot of WT and mutant WDR37 in human cells; zebrafish CRISPR allelic series with RNA-seq\",\n      \"pmids\": [\"31327510\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dominant-negative mechanism inferred genetically, not biochemically resolved\", \"Cholesterol biosynthesis upregulation not mechanistically linked to WDR37 activity\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified the physiological role of the PACS1–WDR37 complex in ER calcium signaling and lymphocyte biology, linking WDR37 to IP3R-dependent Ca2+ release and cellular stress control.\",\n      \"evidence\": \"Forward genetic screen in mice with independent Pacs1 and Wdr37 knockouts, Ca2+ flux assays, and protein expression analysis\",\n      \"pmids\": [\"33630350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between the complex and IP3R regulation unresolved\", \"Whether WDR37 acts catalytically or as a scaffold not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped the protein-interaction logic of WDR37, showing it homodimerizes and binds both PACS1 and PACS2, and that variant pathogenicity can be explained by selective loss of PACS binding or reduced stability.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, and immunocytochemistry with structure-function analysis of C-terminal WD40 variants in human cells\",\n      \"pmids\": [\"34642815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of PACS-binding loss vs. reduced stability not separated downstream\", \"No structural detail of the interaction interface at this stage\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved the structural basis of PACS1–WDR37 assembly, showing PACS1's furin-binding region forms the binding interface and that the complex is mutually stabilizing, reframing how the PACS1-R203W syndrome variant relates to WDR37 dependence.\",\n      \"evidence\": \"Cryo-EM structure determination with stability assays and targeted WDR37 degradation (preprint)\",\n      \"pmids\": [\"41279321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phospholipid-binding capacity of the FBR cleft inferred from C2-domain homology, not functionally tested\", \"How complex assembly couples to ER Ca2+ regulation not structurally addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular activity of WDR37 itself — how the PACS1–WDR37 complex mechanistically controls IP3R expression and ER Ca2+ release — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic or direct effector activity established for WDR37\", \"Connection between the structural interface and the calcium phenotype not bridged\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0008953897\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"PACS1-WDR37 complex\"],\n    \"partners\": [\"PACS1\", \"PACS2\", \"WDR37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}