{"gene":"CCDC22","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2013,"finding":"All COMMD family proteins bind directly to CCDC22; an XLID-associated CCDC22 mutation decreases CCDC22 protein expression and impairs its binding to COMMD proteins. CCDC22, together with COMMD8, directs the ubiquitination and degradation of IκB proteins, thereby promoting NF-κB activation. Patient-derived cells show impaired NF-κB activation due to decreased IκB ubiquitination and degradation.","method":"Co-immunoprecipitation of COMMD proteins with CCDC22; patient-derived lymphoblastoid cell lines assayed for IκB ubiquitination, degradation, and NF-κB activation; CCDC22 mutant protein expression analysis by western blot","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, patient-derived cell functional assays, and multiple orthogonal methods (ubiquitination, degradation, NF-κB reporter) in a single focused study","pmids":["23563313"],"is_preprint":false},{"year":2019,"finding":"The CCC complex (CCDC22/CCDC93/COMMD proteins) controls endosomal PI(3)P levels by regulating the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. CCC depletion elevates endosomal PI(3)P, leading to enhanced WASH complex recruitment and activation, excess endosomal F-actin, and trapping of internalized receptors. CCC and retriever share the common subunit VPS35L, but CCC integrity (not retriever) is specifically required for normal PI(3)P homeostasis.","method":"CCC complex depletion (siRNA/KO) with PI(3)P measurement, F-actin quantification, receptor recycling assays, phosphorylation and endosomal recruitment of MTMR2 assessed by fractionation and imaging, epistasis with retriever subunits","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (lipid measurement, live imaging, fractionation, genetic epistasis) in a single rigorous study with clean loss-of-function and defined molecular mechanism","pmids":["31537807"],"is_preprint":false},{"year":2014,"finding":"A missense variant in CCDC22 (p.Tyr557Cys) causes decreased CCDC22 protein expression and increased WASH1 expression in patient-derived lymphoblastoid cell lines, linking CCDC22 to regulation of the WASH complex in the context of endosomal recycling.","method":"Western blot of patient-derived immortalized lymphoblastoid cell lines showing altered CCDC22 and WASH1 protein levels; whole-exome sequencing and Sanger validation","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — western blot in patient cells with consistent genetic segregation, single lab, limited mechanistic follow-up","pmids":["24916641"],"is_preprint":false},{"year":2025,"finding":"CCDC22 missense mutations p.E208K and p.P172R impair CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding, demonstrating that the CCDC22-COMMD4 interaction is essential for CCC complex integrity.","method":"Biochemical analysis of CCC complex assembly in cells expressing CCDC22 mutants; Co-IP to assess CCDC22-COMMD4 binding; clinical correlation with attenuated 3C syndrome phenotype","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/complex assembly assay with defined interaction surface, single lab, supported by two independent mutations with parallel phenotype","pmids":["40448120"],"is_preprint":false}],"current_model":"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that functions in endosomal protein recycling: it binds all COMMD family proteins (with CCDC22-COMMD4 interaction critical for complex assembly), controls endosomal PI(3)P homeostasis by regulating phosphorylation and recruitment of the phosphatase MTMR2, and together with COMMD8 directs IκB ubiquitination and degradation to enable NF-κB activation; loss-of-function mutations reduce IκB turnover, blunt NF-κB signaling, elevate endosomal PI(3)P, dysregulate the WASH actin-nucleation complex, and cause X-linked intellectual disability / Ritscher-Schinzel syndrome."},"narrative":{"mechanistic_narrative":"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that governs endosomal protein recycling and inflammatory signaling [PMID:23563313, PMID:31537807]. It binds directly to all COMMD family proteins, and the CCDC22-COMMD4 interaction at a conserved interaction surface is essential for assembly of the CCC complex [PMID:23563313, PMID:40448120]. Within endosomal recycling, the CCC complex controls PI(3)P homeostasis by regulating the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2; loss of CCC integrity elevates endosomal PI(3)P, drives excess WASH complex recruitment and F-actin, and traps internalized receptors [PMID:31537807]. CCC integrity, rather than the related retriever complex with which it shares the VPS35L subunit, is specifically required for this PI(3)P regulation [PMID:31537807]. In parallel, CCDC22 acts together with COMMD8 to direct ubiquitination and degradation of IκB proteins, thereby promoting NF-κB activation [PMID:23563313]. Loss-of-function CCDC22 mutations decrease CCDC22 protein levels, impair COMMD binding and CCC assembly, blunt IκB turnover and NF-κB signaling, and dysregulate WASH expression, and cause X-linked intellectual disability / Ritscher-Schinzel (3C) syndrome [PMID:23563313, PMID:24916641, PMID:40448120].","teleology":[{"year":2013,"claim":"Established CCDC22 as a COMMD-binding protein with a direct role in inflammatory signaling, answering how a disease gene of unknown function connects to a defined molecular pathway.","evidence":"Co-IP of COMMD proteins with CCDC22 and patient-derived lymphoblastoid assays of IκB ubiquitination, degradation, and NF-κB activation","pmids":["23563313"],"confidence":"High","gaps":["Does not define how CCDC22-COMMD complexes select IκB for ubiquitination","Structural basis of CCDC22-COMMD binding not resolved"]},{"year":2014,"claim":"Linked a CCDC22 missense variant to altered WASH complex protein levels, extending CCDC22 function from NF-κB signaling toward endosomal recycling machinery.","evidence":"Western blot of patient-derived lymphoblastoid lines showing decreased CCDC22 and increased WASH1, with exome sequencing validation","pmids":["24916641"],"confidence":"Medium","gaps":["Single lab, limited mechanistic follow-up","Causal mechanism linking CCDC22 loss to WASH1 elevation not established"]},{"year":2019,"claim":"Defined the molecular mechanism by which the CCC complex regulates endosomal recycling, showing it controls PI(3)P levels via MTMR2 and thereby tunes WASH-driven actin and receptor trafficking.","evidence":"CCC depletion with PI(3)P measurement, F-actin quantification, receptor recycling assays, MTMR2 fractionation/imaging, and genetic epistasis with retriever subunits","pmids":["31537807"],"confidence":"High","gaps":["How CCC regulates MTMR2 phosphorylation mechanistically is unresolved","Direct enzymatic or catalytic role of CCDC22 itself not defined"]},{"year":2025,"claim":"Identified the CCDC22-COMMD4 interaction surface as essential for CCC assembly, explaining how specific patient missense mutations disrupt complex integrity.","evidence":"Complex assembly assays and Co-IP in cells expressing CCDC22 p.E208K and p.P172R mutants, with clinical correlation to attenuated 3C syndrome","pmids":["40448120"],"confidence":"Medium","gaps":["No high-resolution structure of the interaction surface","Single lab; functional consequences for PI(3)P/NF-κB not tested for these specific mutants"]},{"year":null,"claim":"How CCDC22's two reported activities — endosomal PI(3)P/recycling control and IκB ubiquitination for NF-κB — are coordinated within or between distinct CCDC22-containing assemblies remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating CCC assembly with substrate selection","Mechanism connecting endosomal function to NF-κB signaling not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":["CCC complex (COMMD/CCDC22/CCDC93)"],"partners":["COMMD4","COMMD8","CCDC93","VPS35L","MTMR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60826","full_name":"Coiled-coil domain-containing protein 22","aliases":[],"length_aa":627,"mass_kda":70.8,"function":"Component of the commander complex that is essential for endosomal recycling of transmembrane cargos; the Commander complex is composed of composed of the CCC subcomplex and the retriever subcomplex (PubMed:37172566, PubMed:38459129). Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels (PubMed:37172566, PubMed:38459129). Involved in regulation of NF-kappa-B signaling (PubMed:23563313). Promotes ubiquitination of I-kappa-B-kinase subunit IKBKB and its subsequent proteasomal degradation leading to NF-kappa-B activation; the function may involve association with COMMD8 and a CUL1-dependent E3 ubiquitin ligase complex (PubMed:23563313). May down-regulate NF-kappa-B activity via association with COMMD1 and involving a CUL2-dependent E3 ubiquitin ligase complex. Regulates the cellular localization of COMM domain-containing proteins, such as COMMD1 and COMMD10 (PubMed:23563313). Component of the CCC complex, which is involved in the regulation of endosomal recycling of surface proteins, including integrins, signaling receptor and channels. The CCC complex associates with SNX17, retriever and WASH complexes to prevent lysosomal degradation and promote cell surface recycling of numerous cargos such as integrins ITGA5:ITGB1 (PubMed:25355947, PubMed:28892079). Plays a role in copper ion homeostasis (PubMed:25355947). Involved in copper-dependent ATP7A trafficking between the trans-Golgi network and vesicles in the cell periphery; the function is proposed to depend on its association within the CCC complex and cooperation with the WASH complex on early endosomes (PubMed:25355947) (Microbial infection) The CCC complex, in collaboration with the heterotrimeric retriever complex, mediates the exit of human papillomavirus to the cell surface","subcellular_location":"Endosome; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/O60826/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC22","classification":"Not Classified","n_dependent_lines":175,"n_total_lines":1208,"dependency_fraction":0.14486754966887416},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000101997","cell_line_id":"CID000262","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"C16ORF62","stoichiometry":10.0},{"gene":"CCDC93","stoichiometry":10.0},{"gene":"COMMD6","stoichiometry":10.0},{"gene":"COMMD1","stoichiometry":10.0},{"gene":"FAM45A;FAM45B","stoichiometry":10.0},{"gene":"COMMD2","stoichiometry":10.0},{"gene":"COMMD9","stoichiometry":10.0},{"gene":"VPS29","stoichiometry":10.0},{"gene":"COMMD8","stoichiometry":10.0},{"gene":"COMMD3-BMI1;COMMD3;BMI1","stoichiometry":10.0}],"url":"https://opencell.sf.czbiohub.org/target/CID000262","total_profiled":1310},"omim":[{"mim_id":"620553","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 93; CCDC93","url":"https://www.omim.org/entry/620553"},{"mim_id":"619135","title":"RITSCHER-SCHINZEL SYNDROME 3; RTSC3","url":"https://www.omim.org/entry/619135"},{"mim_id":"618981","title":"VPS35 ENDOSOMAL PROTEIN-SORTING FACTOR-LIKE; VPS35L","url":"https://www.omim.org/entry/618981"},{"mim_id":"616704","title":"COMM DOMAIN-CONTAINING PROTEIN 10; COMMD10","url":"https://www.omim.org/entry/616704"},{"mim_id":"616656","title":"COMM DOMAIN-CONTAINING PROTEIN 8; COMMD8","url":"https://www.omim.org/entry/616656"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC22"},"hgnc":{"alias_symbol":["JM1"],"prev_symbol":["CXorf37"]},"alphafold":{"accession":"O60826","domains":[{"cath_id":"-","chopping":"121-162","consensus_level":"medium","plddt":74.4002,"start":121,"end":162},{"cath_id":"1.10.418","chopping":"2-111","consensus_level":"high","plddt":81.1306,"start":2,"end":111},{"cath_id":"1.20.1480","chopping":"507-597","consensus_level":"medium","plddt":92.7571,"start":507,"end":597}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60826","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60826-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60826-F1-predicted_aligned_error_v6.png","plddt_mean":78.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC22","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC22"},"sequence":{"accession":"O60826","fasta_url":"https://rest.uniprot.org/uniprotkb/O60826.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60826/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60826"}},"corpus_meta":[{"pmid":"31537807","id":"PMC_31537807","title":"Endosomal PI(3)P regulation by the COMMD/CCDC22/CCDC93 (CCC) complex controls membrane protein recycling.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31537807","citation_count":97,"is_preprint":false},{"pmid":"23563313","id":"PMC_23563313","title":"CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23563313","citation_count":91,"is_preprint":false},{"pmid":"18248983","id":"PMC_18248983","title":"Biological hydrogen production by immobilized cells of Clostridium tyrobutyricum JM1 isolated from a food waste treatment process.","date":"2008","source":"Bioresource technology","url":"https://pubmed.ncbi.nlm.nih.gov/18248983","citation_count":47,"is_preprint":false},{"pmid":"24916641","id":"PMC_24916641","title":"Missense variant in CCDC22 causes X-linked recessive intellectual disability with features of Ritscher-Schinzel/3C syndrome.","date":"2014","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/24916641","citation_count":46,"is_preprint":false},{"pmid":"11770015","id":"PMC_11770015","title":"Sanguinarine induces bimodal cell death in K562 but not in high Bcl-2-expressing JM1 cells.","date":"2001","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/11770015","citation_count":26,"is_preprint":false},{"pmid":"32600763","id":"PMC_32600763","title":"Lactobacillus gasseri JM1 with potential probiotic characteristics alleviates inflammatory response by activating the PI3K/Akt signaling pathway in vitro.","date":"2020","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/32600763","citation_count":26,"is_preprint":false},{"pmid":"36615796","id":"PMC_36615796","title":"Lactobacillus gasseri JM1 Isolated from Infant Feces Alleviates Colitis in Mice via Protecting the Intestinal Barrier.","date":"2022","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36615796","citation_count":24,"is_preprint":false},{"pmid":"37923200","id":"PMC_37923200","title":"The probiotic fermented milk of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 alleviates constipation via improving gastrointestinal motility and gut microbiota.","date":"2023","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/37923200","citation_count":20,"is_preprint":false},{"pmid":"36839197","id":"PMC_36839197","title":"The Probiotic Combination of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 Alleviates Gastrointestinal Motility Disorder via Improving Gut Microbiota.","date":"2023","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/36839197","citation_count":20,"is_preprint":false},{"pmid":"34020006","id":"PMC_34020006","title":"Expansion of the CCDC22 associated Ritscher-Schinzel/3C syndrome and review of the literature: Should the minimal diagnostic criteria be revised?","date":"2021","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34020006","citation_count":17,"is_preprint":false},{"pmid":"23468088","id":"PMC_23468088","title":"Indirubin-3'-monoxime promotes autophagic and apoptotic death in JM1 human acute lymphoblastic leukemia cells and K562 human chronic myelogenous leukemia cells.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23468088","citation_count":15,"is_preprint":false},{"pmid":"39426154","id":"PMC_39426154","title":"CCDC22 variants caused X-linked focal epilepsy and focal cortical dysplasia.","date":"2024","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/39426154","citation_count":12,"is_preprint":false},{"pmid":"27888057","id":"PMC_27888057","title":"Association between rs2294020 in X-linked CCDC22 and susceptibility to autoimmune diseases with focus on systemic lupus erythematosus.","date":"2016","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/27888057","citation_count":11,"is_preprint":false},{"pmid":"36130690","id":"PMC_36130690","title":"Expanding the pre- and postnatal phenotype of WASHC5 and CCDC22 -related Ritscher-Schinzel syndromes.","date":"2022","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36130690","citation_count":9,"is_preprint":false},{"pmid":"30706328","id":"PMC_30706328","title":"Identification of a novel CCDC22 mutation in a patient with severe Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis and aggressive natural killer cell leukemia.","date":"2019","source":"International journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/30706328","citation_count":7,"is_preprint":false},{"pmid":"33278894","id":"PMC_33278894","title":"Characterization of novel neutralizing mouse monoclonal antibody JM1-24-3 developed against MUC18 in metastatic melanoma.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33278894","citation_count":6,"is_preprint":false},{"pmid":"28470452","id":"PMC_28470452","title":"CCDC22 gene polymorphism is associated with advanced stages of endometriosis in a sample of Brazilian women.","date":"2017","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28470452","citation_count":2,"is_preprint":false},{"pmid":"40448120","id":"PMC_40448120","title":"CCDC22 mutations that impair COMMD binding cause attenuated 3C/Ritscher-Schinzel syndrome.","date":"2025","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40448120","citation_count":1,"is_preprint":false},{"pmid":"28935728","id":"PMC_28935728","title":"Draft Genome Sequence of Pantoea agglomerans JM1, a Strain Isolated from Soil Polluted by Industrial Production of Beta-Lactam Antibiotics That Exhibits Valacyclovir-Like Hydrolase Activity.","date":"2017","source":"Genome announcements","url":"https://pubmed.ncbi.nlm.nih.gov/28935728","citation_count":1,"is_preprint":false},{"pmid":"33059814","id":"PMC_33059814","title":"[Ritscher-Schinzel syndrome caused by CCDC22 gene mutation: a case report].","date":"2020","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/33059814","citation_count":0,"is_preprint":false},{"pmid":"41643309","id":"PMC_41643309","title":"Integrated proteomics and metabolomics revealed the influence of ultrasonic cavitation effects on the physicochemical properties and metabolic components during Lactobacillus gasseri JM1 fermentation in soymilk.","date":"2026","source":"Ultrasonics sonochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41643309","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12291,"output_tokens":1316,"usd":0.028306,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7982,"output_tokens":1934,"usd":0.04413,"stage2_stop_reason":"end_turn"},"total_usd":0.072436,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"All COMMD family proteins bind directly to CCDC22; an XLID-associated CCDC22 mutation decreases CCDC22 protein expression and impairs its binding to COMMD proteins. CCDC22, together with COMMD8, directs the ubiquitination and degradation of IκB proteins, thereby promoting NF-κB activation. Patient-derived cells show impaired NF-κB activation due to decreased IκB ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation of COMMD proteins with CCDC22; patient-derived lymphoblastoid cell lines assayed for IκB ubiquitination, degradation, and NF-κB activation; CCDC22 mutant protein expression analysis by western blot\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, patient-derived cell functional assays, and multiple orthogonal methods (ubiquitination, degradation, NF-κB reporter) in a single focused study\",\n      \"pmids\": [\"23563313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The CCC complex (CCDC22/CCDC93/COMMD proteins) controls endosomal PI(3)P levels by regulating the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2. CCC depletion elevates endosomal PI(3)P, leading to enhanced WASH complex recruitment and activation, excess endosomal F-actin, and trapping of internalized receptors. CCC and retriever share the common subunit VPS35L, but CCC integrity (not retriever) is specifically required for normal PI(3)P homeostasis.\",\n      \"method\": \"CCC complex depletion (siRNA/KO) with PI(3)P measurement, F-actin quantification, receptor recycling assays, phosphorylation and endosomal recruitment of MTMR2 assessed by fractionation and imaging, epistasis with retriever subunits\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (lipid measurement, live imaging, fractionation, genetic epistasis) in a single rigorous study with clean loss-of-function and defined molecular mechanism\",\n      \"pmids\": [\"31537807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A missense variant in CCDC22 (p.Tyr557Cys) causes decreased CCDC22 protein expression and increased WASH1 expression in patient-derived lymphoblastoid cell lines, linking CCDC22 to regulation of the WASH complex in the context of endosomal recycling.\",\n      \"method\": \"Western blot of patient-derived immortalized lymphoblastoid cell lines showing altered CCDC22 and WASH1 protein levels; whole-exome sequencing and Sanger validation\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — western blot in patient cells with consistent genetic segregation, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"24916641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CCDC22 missense mutations p.E208K and p.P172R impair CCC complex assembly by disrupting a conserved interaction surface required for CCDC22-COMMD4 binding, demonstrating that the CCDC22-COMMD4 interaction is essential for CCC complex integrity.\",\n      \"method\": \"Biochemical analysis of CCC complex assembly in cells expressing CCDC22 mutants; Co-IP to assess CCDC22-COMMD4 binding; clinical correlation with attenuated 3C syndrome phenotype\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/complex assembly assay with defined interaction surface, single lab, supported by two independent mutations with parallel phenotype\",\n      \"pmids\": [\"40448120\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that functions in endosomal protein recycling: it binds all COMMD family proteins (with CCDC22-COMMD4 interaction critical for complex assembly), controls endosomal PI(3)P homeostasis by regulating phosphorylation and recruitment of the phosphatase MTMR2, and together with COMMD8 directs IκB ubiquitination and degradation to enable NF-κB activation; loss-of-function mutations reduce IκB turnover, blunt NF-κB signaling, elevate endosomal PI(3)P, dysregulate the WASH actin-nucleation complex, and cause X-linked intellectual disability / Ritscher-Schinzel syndrome.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCDC22 is a core subunit of the CCC (COMMD/CCDC22/CCDC93) complex that governs endosomal protein recycling and inflammatory signaling [#0, #1]. It binds directly to all COMMD family proteins, and the CCDC22-COMMD4 interaction at a conserved interaction surface is essential for assembly of the CCC complex [#0, #3]. Within endosomal recycling, the CCC complex controls PI(3)P homeostasis by regulating the phosphorylation and endosomal recruitment of the PI(3)P phosphatase MTMR2; loss of CCC integrity elevates endosomal PI(3)P, drives excess WASH complex recruitment and F-actin, and traps internalized receptors [#1]. CCC integrity, rather than the related retriever complex with which it shares the VPS35L subunit, is specifically required for this PI(3)P regulation [#1]. In parallel, CCDC22 acts together with COMMD8 to direct ubiquitination and degradation of IκB proteins, thereby promoting NF-κB activation [#0]. Loss-of-function CCDC22 mutations decrease CCDC22 protein levels, impair COMMD binding and CCC assembly, blunt IκB turnover and NF-κB signaling, and dysregulate WASH expression, and cause X-linked intellectual disability / Ritscher-Schinzel (3C) syndrome [#0, #2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established CCDC22 as a COMMD-binding protein with a direct role in inflammatory signaling, answering how a disease gene of unknown function connects to a defined molecular pathway.\",\n      \"evidence\": \"Co-IP of COMMD proteins with CCDC22 and patient-derived lymphoblastoid assays of IκB ubiquitination, degradation, and NF-κB activation\",\n      \"pmids\": [\"23563313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how CCDC22-COMMD complexes select IκB for ubiquitination\", \"Structural basis of CCDC22-COMMD binding not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked a CCDC22 missense variant to altered WASH complex protein levels, extending CCDC22 function from NF-κB signaling toward endosomal recycling machinery.\",\n      \"evidence\": \"Western blot of patient-derived lymphoblastoid lines showing decreased CCDC22 and increased WASH1, with exome sequencing validation\",\n      \"pmids\": [\"24916641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, limited mechanistic follow-up\", \"Causal mechanism linking CCDC22 loss to WASH1 elevation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the molecular mechanism by which the CCC complex regulates endosomal recycling, showing it controls PI(3)P levels via MTMR2 and thereby tunes WASH-driven actin and receptor trafficking.\",\n      \"evidence\": \"CCC depletion with PI(3)P measurement, F-actin quantification, receptor recycling assays, MTMR2 fractionation/imaging, and genetic epistasis with retriever subunits\",\n      \"pmids\": [\"31537807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CCC regulates MTMR2 phosphorylation mechanistically is unresolved\", \"Direct enzymatic or catalytic role of CCDC22 itself not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified the CCDC22-COMMD4 interaction surface as essential for CCC assembly, explaining how specific patient missense mutations disrupt complex integrity.\",\n      \"evidence\": \"Complex assembly assays and Co-IP in cells expressing CCDC22 p.E208K and p.P172R mutants, with clinical correlation to attenuated 3C syndrome\",\n      \"pmids\": [\"40448120\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of the interaction surface\", \"Single lab; functional consequences for PI(3)P/NF-κB not tested for these specific mutants\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCDC22's two reported activities — endosomal PI(3)P/recycling control and IκB ubiquitination for NF-κB — are coordinated within or between distinct CCDC22-containing assemblies remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating CCC assembly with substrate selection\", \"Mechanism connecting endosomal function to NF-κB signaling not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"CCC complex (COMMD/CCDC22/CCDC93)\"],\n    \"partners\": [\"COMMD4\", \"COMMD8\", \"CCDC93\", \"VPS35L\", \"MTMR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}