{"gene":"CC2D2A","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2008,"finding":"CC2D2A protein localizes to the basal body in ciliated cells and physically interacts with the ciliopathy-associated protein CEP290, as demonstrated by yeast two-hybrid and GST pull-down experiments.","method":"Yeast two-hybrid, GST pull-down, immunofluorescence localization","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — two orthogonal in vitro interaction assays (Y2H + GST pulldown) plus localization, replicated by genetic interaction in zebrafish","pmids":["18950740"],"is_preprint":false},{"year":2008,"finding":"Knockdown of cep290 in cc2d2a (sentinel) mutant zebrafish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and placing both in the same cilium/basal body functional pathway.","method":"Zebrafish genetic epistasis (morpholino knockdown in mutant background)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with clear quantitative phenotypic readout in vivo","pmids":["18950740"],"is_preprint":false},{"year":2008,"finding":"Loss of CC2D2A function causes absence of cilia in patient fibroblasts, establishing a critical role for CC2D2A in cilia formation.","method":"Immunofluorescence of patient-derived fibroblasts (loss-of-function)","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 — single method (immunofluorescence) in patient cells, replicated in other models","pmids":["18513680"],"is_preprint":false},{"year":2011,"finding":"Cc2d2a localizes to the connecting cilium in photoreceptors and to the transition zone in other ciliated cell types; loss of cc2d2a in zebrafish causes trafficking defects of transmembrane outer segment proteins (opsins), vesicle accumulation, and mislocalization of Rab8, identifying a role for Cc2d2a in Rab8-dependent vesicle trafficking and fusion rather than primary ciliogenesis.","method":"Zebrafish cc2d2a mutant analysis, electroretinogram, immunofluorescence, partial rab8 knockdown enhancement","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, functional assay, genetic interaction), independent of earlier basal body work","pmids":["21816947"],"is_preprint":false},{"year":2014,"finding":"CC2D2A is essential for the assembly of subdistal appendages on the mother centriole; in Cc2d2a-/- mouse embryonic fibroblasts, subdistal appendages are absent or abnormal, ODF2 is undetectable and ninein is reduced, while mother centrioles and pericentriolar proteins are present. CC2D2A localizes to subdistal appendages by immuno-electron microscopy in wild-type cells.","method":"Cc2d2a knockout mouse, transmission electron microscopy, immuno-EM, immunofluorescence of MEFs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — immuno-EM localization combined with KO phenotypic analysis using TEM and immunofluorescence, multiple orthogonal methods","pmids":["24947469"],"is_preprint":false},{"year":2014,"finding":"Loss of Cc2d2a in mouse disrupts cilia-dependent Shh signaling, as indicated by exencephaly and absence of cilia in the embryonic node, implicating CC2D2A in Hedgehog pathway transduction via cilia.","method":"Cc2d2a knockout mouse, analysis of Shh pathway phenotypes (exencephaly, node cilia)","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined phenotypic readout but Shh pathway disruption is inferred from cilia loss rather than direct pathway assay","pmids":["24947469"],"is_preprint":false},{"year":2015,"finding":"CC2D2A physically associates with the centrosomal protein NINL; NINL partially co-localizes with CC2D2A at the base of cilia; partial ninl knockdown in cc2d2a-/- zebrafish enhances the retinal phenotype, indicating a genetic interaction. The NINL interactome further identifies MICAL3, a Rab8-interacting protein involved in vesicle docking and fusion, supporting a model where CC2D2A-NINL provides a docking platform for cilia-directed cargo vesicles.","method":"Co-immunoprecipitation, zebrafish genetic interaction (morpholino + mutant), mass spectrometry interactome","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus genetic epistasis in vivo plus MS interactome, multiple orthogonal methods","pmids":["26485645"],"is_preprint":false},{"year":2017,"finding":"CC2D2A loss in zebrafish photoreceptors disorganizes the vesicle fusion machinery at the periciliary membrane, with mislocalization and loss of t-SNAREs SNAP25 and Syntaxin3 and the exocyst component Exoc4, causing progressive accumulation of opsin-containing vesicles; Rab8 cytoplasmic accumulation is a secondary defect. Live imaging and correlative light-electron microscopy demonstrate Rab8 co-trafficking with opsins in vesicular structures in wild-type photoreceptors.","method":"Correlative light and electron microscopy, live imaging, immunofluorescence in cc2d2a zebrafish mutants","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1-2 — correlative EM + live imaging + loss-of-function with specific molecular markers, multiple orthogonal approaches","pmids":["29281629"],"is_preprint":false},{"year":2018,"finding":"Conditional and congenital Mks6 (CC2D2A) mutant mice display cilia loss and altered cytoskeletal microtubule modifications in a cell-type-specific manner; conditional retinal mutants show severe retinal degeneration with mislocalization of phototransduction cascade proteins, demonstrating tissue-specific roles for CC2D2A at the transition zone.","method":"Conditional and congenital mouse knockouts, immunofluorescence, electron microscopy","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined cellular phenotype, multiple tissues examined","pmids":["30133325"],"is_preprint":false},{"year":2024,"finding":"Knockdown of the C2 domain of Cc2d2a in IMCD-3 cells causes defective cilia morphology and downregulation of genes involved in cilium assembly, IFT, protein trafficking to the cilium, and Hedgehog signaling, demonstrating that the C2 domain is specifically required for cilia assembly and cilia-mediated cellular signaling.","method":"shRNA knockdown in IMCD-3 cells, immunofluorescence, RNA-seq/bioinformatics","journal":"Experimental brain research","confidence":"Medium","confidence_rationale":"Tier 2-3 — domain-specific KD with transcriptomic phenotyping, single lab with two methods","pmids":["38231387"],"is_preprint":false},{"year":2024,"finding":"A homozygous nonsense variant in CC2D2A (p.Arg34*) primarily affects a kidney-predominant transcript isoform but not isoforms predominant in other tissues; expression analysis in MDCK cells demonstrates partial translation re-initiation downstream of the stop codon as a possible escape from nonsense-mediated decay, providing mechanistic insight into tissue-specific disease manifestation.","method":"Promoter activity analysis, cDNA expression in MDCK cells, tissue-specific transcript analysis","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — cell-based functional assay combined with transcript analysis, single lab","pmids":["38987663"],"is_preprint":false}],"current_model":"CC2D2A encodes a coiled-coil and C2 domain-containing protein that localizes to the subdistal appendages of the mother centriole and to the transition zone at the ciliary base, where it is required for subdistal appendage assembly, ciliogenesis, and the organization of the periciliary vesicle fusion machinery (including t-SNAREs SNAP25/Syntaxin3 and exocyst component Exoc4); it physically interacts with CEP290 and NINL to facilitate Rab8-dependent trafficking of ciliary cargo vesicles, and its C2 domain supports cilia-mediated Hedgehog and other signaling pathways, with loss-of-function causing Meckel and Joubert syndromes."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing that CC2D2A is a basal body protein that physically and genetically interacts with the ciliopathy protein CEP290 placed it within the cilium/basal body functional module and explained its link to ciliopathies.","evidence":"Yeast two-hybrid, GST pull-down, immunofluorescence localization, and zebrafish morpholino epistasis in cc2d2a mutants","pmids":["18950740","18513680"],"confidence":"High","gaps":["Precise substructure within the basal body where CC2D2A resides was not resolved","Mechanism by which CC2D2A promotes cilia formation was unknown","Nature of functional cooperation with CEP290 was undefined"]},{"year":2011,"claim":"Showing that CC2D2A localizes to the transition zone/connecting cilium and that its loss causes Rab8 mislocalization and vesicle accumulation distinguished a vesicle trafficking role from a simple structural ciliogenesis role.","evidence":"Zebrafish cc2d2a mutant photoreceptor analysis with electroretinography, immunofluorescence, and rab8 genetic interaction","pmids":["21816947"],"confidence":"High","gaps":["Whether CC2D2A directly binds Rab8 or acts indirectly was unknown","The role at subdistal appendages vs. transition zone was not separated","Applicability to mammalian ciliogenesis remained untested"]},{"year":2014,"claim":"Immuno-EM localization to subdistal appendages and demonstration that Cc2d2a knockout abolishes these structures in mouse cells resolved the sub-centriolar site of action and identified CC2D2A as required for subdistal appendage assembly and cilia-dependent Shh signaling.","evidence":"Cc2d2a knockout mouse, immuno-EM, transmission EM, immunofluorescence of MEFs, Shh pathway phenotyping","pmids":["24947469"],"confidence":"High","gaps":["Direct versus indirect role in ODF2/ninein recruitment was unresolved","Shh disruption was inferred from cilia loss rather than direct pathway assay","Whether subdistal appendage and transition zone roles are mechanistically separable was unclear"]},{"year":2015,"claim":"Identification of NINL as a physical and genetic interacting partner of CC2D2A, linked via MICAL3 to Rab8-mediated vesicle docking, defined a molecular docking platform model for cilia-directed cargo delivery.","evidence":"Reciprocal co-immunoprecipitation, zebrafish morpholino-mutant epistasis, mass spectrometry interactome of NINL","pmids":["26485645"],"confidence":"High","gaps":["Whether CC2D2A-NINL interaction is direct or bridged was not fully resolved","Stoichiometry and structure of the docking platform were unknown","Whether MICAL3 is recruited directly by CC2D2A was not tested"]},{"year":2017,"claim":"Demonstrating that CC2D2A loss disorganizes the periciliary SNARE/exocyst machinery (SNAP25, Syntaxin3, Exoc4) and that Rab8 mislocalization is secondary established CC2D2A as an upstream organizer of the vesicle fusion step rather than a direct Rab8 effector.","evidence":"Correlative light-electron microscopy, live imaging of Rab8-opsin co-trafficking, immunofluorescence in cc2d2a zebrafish mutants","pmids":["29281629"],"confidence":"High","gaps":["Direct biochemical interaction between CC2D2A and SNARE/exocyst components was not shown","Whether SNARE disorganization is a cause or consequence of subdistal appendage loss was unresolved","Mammalian validation of the periciliary fusion model was lacking"]},{"year":2018,"claim":"Conditional knockout studies revealed cell-type-specific requirements for CC2D2A in cilia maintenance and cytoskeletal modification, demonstrating that its transition zone role varies across tissues and is not limited to initial ciliogenesis.","evidence":"Conditional and congenital Mks6/Cc2d2a mouse knockouts with immunofluorescence and electron microscopy across multiple tissues","pmids":["30133325"],"confidence":"High","gaps":["Molecular basis of tissue specificity was not identified","Whether altered microtubule modifications are a direct or indirect effect of CC2D2A loss was unclear"]},{"year":2024,"claim":"Pinpointing the C2 domain as specifically required for cilia assembly and Hedgehog-related gene expression, and revealing that tissue-specific isoform usage underlies variable disease severity, refined the domain-function map and explained genotype-phenotype variability.","evidence":"shRNA knockdown of C2 domain in IMCD-3 cells with RNA-seq; promoter/isoform analysis and cDNA expression in MDCK cells for a nonsense variant","pmids":["38231387","38987663"],"confidence":"Medium","gaps":["Structural basis of C2 domain function (lipid binding, protein interaction) is unknown","Isoform-specific rescue experiments have not been performed in vivo","Extent of translational re-initiation as a disease modifier needs independent confirmation"]},{"year":null,"claim":"The direct biochemical mechanism by which CC2D2A organizes the SNARE/exocyst fusion machinery and subdistal appendage components, and the structural basis of its C2 domain function, remain to be determined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of CC2D2A or its domain interactions exists","Direct binding to SNARE/exocyst components has not been demonstrated","Reconstitution of CC2D2A-dependent vesicle fusion has not been achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,7]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,3,4,8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,4,8,9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9]}],"complexes":[],"partners":["CEP290","NINL","SNAP25","STX3","EXOC4"],"other_free_text":[]},"mechanistic_narrative":"CC2D2A is a coiled-coil and C2 domain-containing protein essential for ciliogenesis, ciliary trafficking, and cilia-dependent signaling. It localizes to the subdistal appendages of the mother centriole and the transition zone of cilia, where it is required for subdistal appendage assembly (recruiting ODF2 and ninein) and for organizing the periciliary vesicle fusion machinery, including t-SNAREs SNAP25 and Syntaxin3 and the exocyst component Exoc4 [PMID:24947469, PMID:29281629]. CC2D2A physically interacts with CEP290 and NINL to facilitate Rab8-dependent trafficking of ciliary cargo vesicles, and its C2 domain is specifically required for cilia assembly and Hedgehog signaling [PMID:18950740, PMID:26485645, PMID:38231387]. Loss-of-function mutations in CC2D2A cause Meckel and Joubert syndromes, with tissue-specific manifestations linked in part to differential transcript isoform usage [PMID:18513680, PMID:38987663]."},"prefetch_data":{"uniprot":{"accession":"Q9P2K1","full_name":"Coiled-coil and C2 domain-containing protein 2A","aliases":[],"length_aa":1620,"mass_kda":186.2,"function":"Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Required for ciliogenesis and sonic hedgehog/SHH signaling (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q9P2K1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CC2D2A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CC2D2A","total_profiled":1310},"omim":[{"mim_id":"620248","title":"TRANSMEMBRANE PROTEIN 80; TMEM80","url":"https://www.omim.org/entry/620248"},{"mim_id":"619845","title":"RETINITIS PIGMENTOSA 93; RP93","url":"https://www.omim.org/entry/619845"},{"mim_id":"619113","title":"COACH SYNDROME 3; COACH3","url":"https://www.omim.org/entry/619113"},{"mim_id":"619111","title":"COACH SYNDROME 2; COACH2","url":"https://www.omim.org/entry/619111"},{"mim_id":"618884","title":"PROTEINURIA, CHRONIC BENIGN; PROCHOB","url":"https://www.omim.org/entry/618884"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Connecting piece","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"retina","ntpm":78.4}],"url":"https://www.proteinatlas.org/search/CC2D2A"},"hgnc":{"alias_symbol":["KIAA1345","MKS6","JBTS9"],"prev_symbol":[]},"alphafold":{"accession":"Q9P2K1","domains":[{"cath_id":"2.60.40.150","chopping":"409-421_657-808","consensus_level":"medium","plddt":86.0261,"start":409,"end":808},{"cath_id":"2.60.40.150","chopping":"1029-1057_1098-1166_1174-1214_1235-1253","consensus_level":"medium","plddt":79.7452,"start":1029,"end":1253},{"cath_id":"3.10.620.30","chopping":"1255-1465","consensus_level":"high","plddt":84.7628,"start":1255,"end":1465}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2K1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2K1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9P2K1-F1-predicted_aligned_error_v6.png","plddt_mean":69.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CC2D2A","jax_strain_url":"https://www.jax.org/strain/search?query=CC2D2A"},"sequence":{"accession":"Q9P2K1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9P2K1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9P2K1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9P2K1"}},"corpus_meta":[{"pmid":"18950740","id":"PMC_18950740","title":"CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18950740","citation_count":184,"is_preprint":false},{"pmid":"18513680","id":"PMC_18513680","title":"Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18513680","citation_count":116,"is_preprint":false},{"pmid":"19574260","id":"PMC_19574260","title":"Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis).","date":"2009","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19574260","citation_count":111,"is_preprint":false},{"pmid":"21816947","id":"PMC_21816947","title":"The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21816947","citation_count":100,"is_preprint":false},{"pmid":"18387594","id":"PMC_18387594","title":"CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18387594","citation_count":80,"is_preprint":false},{"pmid":"19777577","id":"PMC_19777577","title":"CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation.","date":"2009","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/19777577","citation_count":78,"is_preprint":false},{"pmid":"26485645","id":"PMC_26485645","title":"The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26485645","citation_count":70,"is_preprint":false},{"pmid":"24947469","id":"PMC_24947469","title":"Ciliopathy-associated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24947469","citation_count":69,"is_preprint":false},{"pmid":"22241855","id":"PMC_22241855","title":"Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures.","date":"2012","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22241855","citation_count":59,"is_preprint":false},{"pmid":"30970040","id":"PMC_30970040","title":"Ciliary genes arl13b, ahi1 and cc2d2a differentially modify expression of visual acuity phenotypes but do not enhance retinal degeneration due to mutation of cep290 in zebrafish.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30970040","citation_count":32,"is_preprint":false},{"pmid":"29281629","id":"PMC_29281629","title":"Loss-of-function of the ciliopathy protein Cc2d2a disorganizes the vesicle fusion machinery at the periciliary membrane and indirectly affects Rab8-trafficking in zebrafish photoreceptors.","date":"2017","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29281629","citation_count":26,"is_preprint":false},{"pmid":"30133325","id":"PMC_30133325","title":"Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30133325","citation_count":19,"is_preprint":false},{"pmid":"24706459","id":"PMC_24706459","title":"First-trimester diagnosis of Meckel-Gruber syndrome by fetal ultrasound with molecular identification of CC2D2A mutations by next-generation sequencing.","date":"2014","source":"Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/24706459","citation_count":12,"is_preprint":false},{"pmid":"33486889","id":"PMC_33486889","title":"Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies.","date":"2021","source":"Molecular genetics & genomic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33486889","citation_count":12,"is_preprint":false},{"pmid":"22023432","id":"PMC_22023432","title":"Positive association of CC2D1A and CC2D2A gene haplotypes with mental retardation in a Han Chinese population.","date":"2011","source":"DNA and cell 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novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family.","date":"2020","source":"The journal of gene medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32989887","citation_count":3,"is_preprint":false},{"pmid":"36765129","id":"PMC_36765129","title":"Biallelic CC2D2A variants, SNV and LINE-1 insertion simultaneously identified in siblings using long-read whole-genome sequencing and haplotype phasing.","date":"2023","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36765129","citation_count":2,"is_preprint":false},{"pmid":"34182252","id":"PMC_34182252","title":"Establishment of three Joubert syndrome-derived induced pluripotent stem cell (iPSC) lines harbouring compound heterozygous mutations in CC2D2A gene.","date":"2021","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/34182252","citation_count":2,"is_preprint":false},{"pmid":"38987663","id":"PMC_38987663","title":"Expanding the phenotypic spectrum of CC2D2A-related ciliopathies: a rare homozygous nonsense variant in a patient with suspected nephronophthisis.","date":"2024","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/38987663","citation_count":2,"is_preprint":false},{"pmid":"38231387","id":"PMC_38231387","title":"Joubert syndrome causing mutation in C2 domain of CC2D2A affects structural integrity of cilia and cellular signaling molecules.","date":"2024","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/38231387","citation_count":1,"is_preprint":false},{"pmid":"26310553","id":"PMC_26310553","title":"[Clinical and genetic analysis for a Joubert syndrome family with CC2D2A gene mutations].","date":"2015","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/26310553","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.26.690869","title":"A single  <i>Musashi</i>  gene allele is 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   \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — two orthogonal in vitro interaction assays (Y2H + GST pulldown) plus localization, replicated by genetic interaction in zebrafish\",\n      \"pmids\": [\"18950740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Knockdown of cep290 in cc2d2a (sentinel) mutant zebrafish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and placing both in the same cilium/basal body functional pathway.\",\n      \"method\": \"Zebrafish genetic epistasis (morpholino knockdown in mutant background)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with clear quantitative phenotypic readout in vivo\",\n      \"pmids\": [\"18950740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Loss of CC2D2A function causes absence of cilia in patient fibroblasts, establishing a critical role for CC2D2A in cilia formation.\",\n      \"method\": \"Immunofluorescence of patient-derived fibroblasts (loss-of-function)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single method (immunofluorescence) in patient cells, replicated in other models\",\n      \"pmids\": [\"18513680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cc2d2a localizes to the connecting cilium in photoreceptors and to the transition zone in other ciliated cell types; loss of cc2d2a in zebrafish causes trafficking defects of transmembrane outer segment proteins (opsins), vesicle accumulation, and mislocalization of Rab8, identifying a role for Cc2d2a in Rab8-dependent vesicle trafficking and fusion rather than primary ciliogenesis.\",\n      \"method\": \"Zebrafish cc2d2a mutant analysis, electroretinogram, immunofluorescence, partial rab8 knockdown enhancement\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, functional assay, genetic interaction), independent of earlier basal body work\",\n      \"pmids\": [\"21816947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CC2D2A is essential for the assembly of subdistal appendages on the mother centriole; in Cc2d2a-/- mouse embryonic fibroblasts, subdistal appendages are absent or abnormal, ODF2 is undetectable and ninein is reduced, while mother centrioles and pericentriolar proteins are present. CC2D2A localizes to subdistal appendages by immuno-electron microscopy in wild-type cells.\",\n      \"method\": \"Cc2d2a knockout mouse, transmission electron microscopy, immuno-EM, immunofluorescence of MEFs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — immuno-EM localization combined with KO phenotypic analysis using TEM and immunofluorescence, multiple orthogonal methods\",\n      \"pmids\": [\"24947469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of Cc2d2a in mouse disrupts cilia-dependent Shh signaling, as indicated by exencephaly and absence of cilia in the embryonic node, implicating CC2D2A in Hedgehog pathway transduction via cilia.\",\n      \"method\": \"Cc2d2a knockout mouse, analysis of Shh pathway phenotypes (exencephaly, node cilia)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotypic readout but Shh pathway disruption is inferred from cilia loss rather than direct pathway assay\",\n      \"pmids\": [\"24947469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CC2D2A physically associates with the centrosomal protein NINL; NINL partially co-localizes with CC2D2A at the base of cilia; partial ninl knockdown in cc2d2a-/- zebrafish enhances the retinal phenotype, indicating a genetic interaction. The NINL interactome further identifies MICAL3, a Rab8-interacting protein involved in vesicle docking and fusion, supporting a model where CC2D2A-NINL provides a docking platform for cilia-directed cargo vesicles.\",\n      \"method\": \"Co-immunoprecipitation, zebrafish genetic interaction (morpholino + mutant), mass spectrometry interactome\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus genetic epistasis in vivo plus MS interactome, multiple orthogonal methods\",\n      \"pmids\": [\"26485645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CC2D2A loss in zebrafish photoreceptors disorganizes the vesicle fusion machinery at the periciliary membrane, with mislocalization and loss of t-SNAREs SNAP25 and Syntaxin3 and the exocyst component Exoc4, causing progressive accumulation of opsin-containing vesicles; Rab8 cytoplasmic accumulation is a secondary defect. Live imaging and correlative light-electron microscopy demonstrate Rab8 co-trafficking with opsins in vesicular structures in wild-type photoreceptors.\",\n      \"method\": \"Correlative light and electron microscopy, live imaging, immunofluorescence in cc2d2a zebrafish mutants\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — correlative EM + live imaging + loss-of-function with specific molecular markers, multiple orthogonal approaches\",\n      \"pmids\": [\"29281629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional and congenital Mks6 (CC2D2A) mutant mice display cilia loss and altered cytoskeletal microtubule modifications in a cell-type-specific manner; conditional retinal mutants show severe retinal degeneration with mislocalization of phototransduction cascade proteins, demonstrating tissue-specific roles for CC2D2A at the transition zone.\",\n      \"method\": \"Conditional and congenital mouse knockouts, immunofluorescence, electron microscopy\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined cellular phenotype, multiple tissues examined\",\n      \"pmids\": [\"30133325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Knockdown of the C2 domain of Cc2d2a in IMCD-3 cells causes defective cilia morphology and downregulation of genes involved in cilium assembly, IFT, protein trafficking to the cilium, and Hedgehog signaling, demonstrating that the C2 domain is specifically required for cilia assembly and cilia-mediated cellular signaling.\",\n      \"method\": \"shRNA knockdown in IMCD-3 cells, immunofluorescence, RNA-seq/bioinformatics\",\n      \"journal\": \"Experimental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — domain-specific KD with transcriptomic phenotyping, single lab with two methods\",\n      \"pmids\": [\"38231387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A homozygous nonsense variant in CC2D2A (p.Arg34*) primarily affects a kidney-predominant transcript isoform but not isoforms predominant in other tissues; expression analysis in MDCK cells demonstrates partial translation re-initiation downstream of the stop codon as a possible escape from nonsense-mediated decay, providing mechanistic insight into tissue-specific disease manifestation.\",\n      \"method\": \"Promoter activity analysis, cDNA expression in MDCK cells, tissue-specific transcript analysis\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — cell-based functional assay combined with transcript analysis, single lab\",\n      \"pmids\": [\"38987663\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CC2D2A encodes a coiled-coil and C2 domain-containing protein that localizes to the subdistal appendages of the mother centriole and to the transition zone at the ciliary base, where it is required for subdistal appendage assembly, ciliogenesis, and the organization of the periciliary vesicle fusion machinery (including t-SNAREs SNAP25/Syntaxin3 and exocyst component Exoc4); it physically interacts with CEP290 and NINL to facilitate Rab8-dependent trafficking of ciliary cargo vesicles, and its C2 domain supports cilia-mediated Hedgehog and other signaling pathways, with loss-of-function causing Meckel and Joubert syndromes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CC2D2A is a coiled-coil and C2 domain-containing protein essential for ciliogenesis, ciliary trafficking, and cilia-dependent signaling. It localizes to the subdistal appendages of the mother centriole and the transition zone of cilia, where it is required for subdistal appendage assembly (recruiting ODF2 and ninein) and for organizing the periciliary vesicle fusion machinery, including t-SNAREs SNAP25 and Syntaxin3 and the exocyst component Exoc4 [PMID:24947469, PMID:29281629]. CC2D2A physically interacts with CEP290 and NINL to facilitate Rab8-dependent trafficking of ciliary cargo vesicles, and its C2 domain is specifically required for cilia assembly and Hedgehog signaling [PMID:18950740, PMID:26485645, PMID:38231387]. Loss-of-function mutations in CC2D2A cause Meckel and Joubert syndromes, with tissue-specific manifestations linked in part to differential transcript isoform usage [PMID:18513680, PMID:38987663].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing that CC2D2A is a basal body protein that physically and genetically interacts with the ciliopathy protein CEP290 placed it within the cilium/basal body functional module and explained its link to ciliopathies.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, immunofluorescence localization, and zebrafish morpholino epistasis in cc2d2a mutants\",\n      \"pmids\": [\"18950740\", \"18513680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise substructure within the basal body where CC2D2A resides was not resolved\",\n        \"Mechanism by which CC2D2A promotes cilia formation was unknown\",\n        \"Nature of functional cooperation with CEP290 was undefined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showing that CC2D2A localizes to the transition zone/connecting cilium and that its loss causes Rab8 mislocalization and vesicle accumulation distinguished a vesicle trafficking role from a simple structural ciliogenesis role.\",\n      \"evidence\": \"Zebrafish cc2d2a mutant photoreceptor analysis with electroretinography, immunofluorescence, and rab8 genetic interaction\",\n      \"pmids\": [\"21816947\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CC2D2A directly binds Rab8 or acts indirectly was unknown\",\n        \"The role at subdistal appendages vs. transition zone was not separated\",\n        \"Applicability to mammalian ciliogenesis remained untested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Immuno-EM localization to subdistal appendages and demonstration that Cc2d2a knockout abolishes these structures in mouse cells resolved the sub-centriolar site of action and identified CC2D2A as required for subdistal appendage assembly and cilia-dependent Shh signaling.\",\n      \"evidence\": \"Cc2d2a knockout mouse, immuno-EM, transmission EM, immunofluorescence of MEFs, Shh pathway phenotyping\",\n      \"pmids\": [\"24947469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct versus indirect role in ODF2/ninein recruitment was unresolved\",\n        \"Shh disruption was inferred from cilia loss rather than direct pathway assay\",\n        \"Whether subdistal appendage and transition zone roles are mechanistically separable was unclear\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of NINL as a physical and genetic interacting partner of CC2D2A, linked via MICAL3 to Rab8-mediated vesicle docking, defined a molecular docking platform model for cilia-directed cargo delivery.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, zebrafish morpholino-mutant epistasis, mass spectrometry interactome of NINL\",\n      \"pmids\": [\"26485645\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CC2D2A-NINL interaction is direct or bridged was not fully resolved\",\n        \"Stoichiometry and structure of the docking platform were unknown\",\n        \"Whether MICAL3 is recruited directly by CC2D2A was not tested\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that CC2D2A loss disorganizes the periciliary SNARE/exocyst machinery (SNAP25, Syntaxin3, Exoc4) and that Rab8 mislocalization is secondary established CC2D2A as an upstream organizer of the vesicle fusion step rather than a direct Rab8 effector.\",\n      \"evidence\": \"Correlative light-electron microscopy, live imaging of Rab8-opsin co-trafficking, immunofluorescence in cc2d2a zebrafish mutants\",\n      \"pmids\": [\"29281629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical interaction between CC2D2A and SNARE/exocyst components was not shown\",\n        \"Whether SNARE disorganization is a cause or consequence of subdistal appendage loss was unresolved\",\n        \"Mammalian validation of the periciliary fusion model was lacking\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional knockout studies revealed cell-type-specific requirements for CC2D2A in cilia maintenance and cytoskeletal modification, demonstrating that its transition zone role varies across tissues and is not limited to initial ciliogenesis.\",\n      \"evidence\": \"Conditional and congenital Mks6/Cc2d2a mouse knockouts with immunofluorescence and electron microscopy across multiple tissues\",\n      \"pmids\": [\"30133325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis of tissue specificity was not identified\",\n        \"Whether altered microtubule modifications are a direct or indirect effect of CC2D2A loss was unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Pinpointing the C2 domain as specifically required for cilia assembly and Hedgehog-related gene expression, and revealing that tissue-specific isoform usage underlies variable disease severity, refined the domain-function map and explained genotype-phenotype variability.\",\n      \"evidence\": \"shRNA knockdown of C2 domain in IMCD-3 cells with RNA-seq; promoter/isoform analysis and cDNA expression in MDCK cells for a nonsense variant\",\n      \"pmids\": [\"38231387\", \"38987663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of C2 domain function (lipid binding, protein interaction) is unknown\",\n        \"Isoform-specific rescue experiments have not been performed in vivo\",\n        \"Extent of translational re-initiation as a disease modifier needs independent confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct biochemical mechanism by which CC2D2A organizes the SNARE/exocyst fusion machinery and subdistal appendage components, and the structural basis of its C2 domain function, remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of CC2D2A or its domain interactions exists\",\n        \"Direct binding to SNARE/exocyst components has not been demonstrated\",\n        \"Reconstitution of CC2D2A-dependent vesicle fusion has not been achieved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 3, 4, 8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 4, 8, 9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CEP290\",\n      \"NINL\",\n      \"SNAP25\",\n      \"STX3\",\n      \"EXOC4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}