Affinage

CC2D2A

Coiled-coil and C2 domain-containing protein 2A · UniProt Q9P2K1

Length
1620 aa
Mass
186.2 kDa
Annotated
2026-06-09
25 papers in source corpus 9 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CC2D2A is a centriolar and ciliary transition-zone protein essential for ciliogenesis and cilia-based signaling (PMID:18513680, PMID:24947469). At the mother centriole it localizes to the subdistal appendages and is required for their assembly, with its loss eliminating the appendage marker ODF2 and reducing ninein, thereby blocking axoneme biogenesis and cilium formation (PMID:24947469); in photoreceptors it instead concentrates at the connecting cilium/transition zone (PMID:21816947). CC2D2A physically interacts with the ciliopathy protein CEP290 and with the centrosomal protein NINL, and it acts genetically with both in ciliary function (PMID:18950740, PMID:26485645). Through the NINL interaction it organizes a docking and fusion platform for cilia-directed cargo vesicles at the periciliary membrane, where loss of CC2D2A disorganizes the t-SNAREs SNAP25 and Syntaxin3 and the exocyst component Exoc4, placing its function at the final vesicle-fusion step of opsin carrier trafficking and rendering cytoplasmic Rab8 accumulation a downstream consequence (PMID:26485645, PMID:29281629). Because functional cilia are required for Sonic Hedgehog signaling, loss of CC2D2A disrupts Shh pathway activity and produces cell-type-specific cilia loss, retinal degeneration with phototransduction-protein mislocalization, and pleiotropic developmental defects (PMID:24947469, PMID:30133325).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2008 Medium

    Established CC2D2A as a basal-body protein operating in a shared ciliary pathway with a known ciliopathy gene, framing it as a candidate ciliary component rather than an orphan disease gene.

    Evidence Yeast two-hybrid and GST pull-down with CEP290 plus immunofluorescence, and zebrafish genetic epistasis showing synergistic pronephric cysts on cep290 knockdown in cc2d2a mutants

    PMID:18950740

    Open questions at the time
    • Binding interface and stoichiometry of the CC2D2A-CEP290 interaction undefined
    • Does not establish what molecular step in ciliary assembly the pair controls
  2. 2008 Medium

    Demonstrated that CC2D2A is required for cilium formation in human cells, directly linking loss-of-function to a ciliogenesis defect.

    Evidence Immunofluorescence of patient-derived fibroblasts homozygous for CC2D2A loss-of-function mutations

    PMID:18513680

    Open questions at the time
    • Single method (immunofluorescence)
    • Does not resolve the molecular step at which ciliogenesis fails
  3. 2011 Medium

    Connected CC2D2A to Rab8-dependent vesicle trafficking and localized it to the photoreceptor connecting cilium, beginning to define a trafficking role beyond bulk cilium assembly.

    Evidence Zebrafish cc2d2a mutant analysis with rab8 morpholino genetic interaction, immunofluorescence localization, and electroretinogram

    PMID:21816947

    Open questions at the time
    • Whether CC2D2A acts upstream of or in parallel with Rab8 unresolved at this stage
    • No direct biochemical link between CC2D2A and the trafficking machinery
  4. 2014 High

    Defined the structural basis of CC2D2A's ciliogenesis requirement by placing it at the mother-centriole subdistal appendages and showing these appendages fail to assemble without it.

    Evidence Immuno-EM localization and TEM/immunofluorescence in Cc2d2a knockout mouse MEFs showing loss of ODF2 and reduced ninein; Shh pathway analysis in knockout embryos

    PMID:24947469

    Open questions at the time
    • How CC2D2A recruits or stabilizes ODF2/ninein at appendages is unknown
    • Mechanistic link between appendage loss and Shh disruption not dissected
  5. 2015 High

    Identified NINL as a direct CC2D2A partner and built a model in which CC2D2A-NINL provides a docking point for cilia-directed cargo vesicles via the Rab8-associated docking factor MICAL3.

    Evidence Co-immunoprecipitation, co-localization, zebrafish ninl knockdown phenocopy and genetic interaction in cc2d2a mutants, and interactome mass spectrometry identifying MICAL3

    PMID:26485645

    Open questions at the time
    • Direct vesicle-docking activity of the CC2D2A-NINL complex not reconstituted
    • Whether MICAL3 link is direct or indirect not established
  6. 2017 High

    Pinpointed CC2D2A's trafficking role to the final vesicle-fusion step by showing it organizes the SNARE/exocyst machinery, reframing Rab8 mislocalization as a downstream consequence.

    Evidence CLEM, live imaging, and SNARE/exocyst marker immunofluorescence in cc2d2a mutant zebrafish photoreceptors

    PMID:29281629

    Open questions at the time
    • Direct physical interaction between CC2D2A and SNAP25/Syntaxin3/Exoc4 not demonstrated
    • Mechanism by which CC2D2A spatially organizes the fusion machinery unknown
  7. 2018 Medium

    Established that CC2D2A's ciliary requirement is tissue- and cell-type-specific, accounting for the distinct retinal and developmental manifestations of its loss.

    Evidence Conditional and congenital Mks6 (Cc2d2a) knockout mice with immunofluorescence and multi-tissue phenotyping

    PMID:30133325

    Open questions at the time
    • Molecular basis of cell-type selectivity not identified
    • Link between altered microtubule modifications and CC2D2A function unclear
  8. 2024 Low

    Attributed cilia assembly and signaling functions specifically to the CC2D2A C2 domain, beginning to map function onto protein domains.

    Evidence shRNA knockdown of the C2 domain in IMCD-3 cells with immunofluorescence and RNA-seq profiling of cilium/IFT/Hedgehog genes

    PMID:38231387

    Open questions at the time
    • No rescue or protein-level validation of C2 domain function
    • Transcriptomic readout cannot distinguish direct from indirect effects
  9. 2024 Low

    Linked an isoform-specific nonsense variant to isolated nephronophthisis, offering a transcript-level explanation for tissue-restricted disease.

    Evidence Tissue-specific transcript analysis, promoter assays, and patient cDNA expression in MDCK cells showing partial translation re-initiation

    PMID:38987663

    Open questions at the time
    • Single patient, single lab
    • Translation re-initiation as an escape mechanism not functionally confirmed at protein level

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CC2D2A physically couples its subdistal-appendage scaffolding role to organization of the periciliary SNARE/exocyst fusion machinery remains unresolved.
  • No direct biochemical interaction shown between CC2D2A and SNARE/exocyst components
  • Structural mechanism of appendage assembly by CC2D2A unknown
  • How domain-level functions partition across CC2D2A's roles is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 2
Localization
GO:0005815 microtubule organizing center 2 GO:0005929 cilium 2 GO:0005886 plasma membrane 1
Pathway
GO:0005929 cilium 2 R-HSA-162582 Signal Transduction 1 R-HSA-1852241 Organelle biogenesis and maintenance 1 R-HSA-5653656 Vesicle-mediated transport 1
Partners
CEP290NINL
Complex memberships
subdistal appendage

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 CC2D2A protein localizes to the basal body in ciliated cells and physically interacts with CEP290 (the product of another ciliopathy gene), as demonstrated by yeast two-hybrid and GST pull-down experiments. Yeast two-hybrid, GST pull-down, immunofluorescence localization American journal of human genetics Medium 18950740
2008 Knockdown of cep290 in cc2d2a (sentinel) mutant zebrafish results in a synergistic pronephric cyst phenotype, establishing a genetic interaction between CC2D2A and CEP290 in ciliary function. Zebrafish genetic epistasis / morpholino knockdown in mutant background American journal of human genetics Medium 18950740
2008 Patient fibroblasts homozygous for CC2D2A loss-of-function mutations lack primary cilia, demonstrating that CC2D2A is required for cilia formation. Immunofluorescence of patient-derived fibroblasts American journal of human genetics Medium 18513680
2011 In cc2d2a mutant zebrafish photoreceptors, Rab8 (a key regulator of opsin carrier vesicle trafficking) is mislocalized, and partial knockdown of rab8 enhances the cc2d2a retinal and kidney phenotypes, indicating CC2D2A functions upstream or in concert with Rab8-dependent vesicle trafficking. CC2D2A localizes to the connecting cilium/transition zone in photoreceptors. Zebrafish mutant analysis, morpholino knockdown genetic interaction, immunofluorescence localization, electroretinogram Human molecular genetics Medium 21816947
2014 CC2D2A localizes to subdistal appendages of the mother centriole (confirmed by immuno-EM), and Cc2d2a−/− mouse embryonic fibroblasts lack subdistal appendages (or have abnormal ones) with loss of the subdistal appendage marker ODF2 and reduction of ninein, demonstrating that CC2D2A is essential for subdistal appendage assembly, which in turn is required for axoneme biogenesis and ciliogenesis. Transmission electron microscopy, immuno-electron microscopy, immunofluorescence in Cc2d2a knockout mouse MEFs Nature communications High 24947469
2014 Loss of Cc2d2a in mouse embryos disrupts cilia-dependent Sonic Hedgehog (Shh) signaling, with cilia absent in the embryonic node and other somatic tissues, linking CC2D2A-dependent ciliogenesis to Shh pathway activity underlying exencephaly. Cc2d2a knockout mouse, analysis of Shh signaling pathway markers, phenotypic characterization Nature communications Medium 24947469
2015 CC2D2A physically interacts with the centrosomal protein NINL; NINL partially co-localizes with CC2D2A at the base of cilia; ninl knockdown in zebrafish phenocopies cc2d2a loss (photoreceptor outer segment loss, opsin mislocalization, vesicle accumulation); partial ninl knockdown in cc2d2a−/− embryos enhances the retinal phenotype, indicating a genetic interaction. The NINL interactome also contains MICAL3, a Rab8-interacting vesicle docking/fusion protein, supporting a model where CC2D2A–NINL provides a docking point for cilia-directed cargo vesicles. Co-immunoprecipitation/physical interaction assay, zebrafish morpholino knockdown, genetic interaction in cc2d2a mutant background, co-localization immunofluorescence, interactome mass spectrometry PLoS genetics High 26485645
2017 Loss of Cc2d2a in zebrafish photoreceptors disorganizes the vesicle fusion machinery at the periciliary membrane: the t-SNAREs SNAP25 and Syntaxin3 and the exocyst component Exoc4 are mislocalized or lost, leading to progressive accumulation of opsin-containing vesicles. Rab8 cytoplasmic accumulation is a secondary (downstream) consequence rather than the primary defect, placing CC2D2A's function at the final vesicle fusion step of opsin carrier vesicle trafficking. Correlative light and electron microscopy (CLEM), live imaging in zebrafish photoreceptors, immunofluorescence of SNARE/exocyst components in cc2d2a mutants PLoS genetics High 29281629
2018 Conditional Mks6 (Cc2d2a) knockout in mouse retina causes severe retinal degeneration with mislocalization of phototransduction cascade proteins, and congenital loss causes embryonic lethality with cell-type-specific cilia loss and altered cytoskeletal microtubule modifications, establishing tissue- and cell type-specific requirements for CC2D2A in cilia formation and sensory signaling. Conditional and congenital Mks6 knockout mouse, immunofluorescence, phenotypic analysis across multiple tissues FASEB journal Medium 30133325
2024 Knockdown of the C2 domain of Cc2d2a in IMCD-3 cells produces defective cilia morphology and downregulates genes involved in cilium assembly, intraflagellar transport (IFT), polarity patterning, and Hedgehog signaling, indicating that the C2 domain is specifically required for cilia assembly and cilia-mediated signaling. shRNA knockdown in IMCD-3 cells, immunofluorescence, RNA-seq gene expression profiling, bioinformatics Experimental brain research Low 38231387
2024 A homozygous nonsense variant in CC2D2A (p.Arg34*) that primarily affects a kidney-predominant transcript isoform causes isolated nephronophthisis; expression analysis in MDCK cells demonstrates partial translation re-initiation downstream of the stop codon as a possible escape mechanism, providing mechanistic insight into tissue-specific disease manifestation. Tissue-specific transcript/isoform analysis, promoter activity assay, patient cDNA expression in MDCK cells European journal of human genetics Low 38987663

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. American journal of human genetics 184 18950740
2008 Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. American journal of human genetics 116 18513680
2009 Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). Journal of medical genetics 111 19574260
2011 The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking. Human molecular genetics 100 21816947
2008 CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa. American journal of human genetics 80 18387594
2009 CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. Human mutation 78 19777577
2015 The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking. PLoS genetics 71 26485645
2014 Ciliopathy-associated gene Cc2d2a promotes assembly of subdistal appendages on the mother centriole during cilia biogenesis. Nature communications 71 24947469
2012 Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures. Journal of medical genetics 59 22241855
2019 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. PloS one 33 30970040
2017 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. PLoS genetics 26 29281629
2018 Mks6 mutations reveal tissue- and cell type-specific roles for the cilia transition zone. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 30133325
2021 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. Molecular genetics & genomic medicine 13 33486889
2014 First-trimester diagnosis of Meckel-Gruber syndrome by fetal ultrasound with molecular identification of CC2D2A mutations by next-generation sequencing. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology 12 24706459
2016 Novel CC2D2A compound heterozygous mutations cause Joubert syndrome. Molecular medicine reports 8 27959436
2011 Positive association of CC2D1A and CC2D2A gene haplotypes with mental retardation in a Han Chinese population. DNA and cell biology 8 22023432
2021 A girl with a mutation of the ciliary gene CC2D2A presenting with FSGS and nephronophthisis. CEN case reports 6 34435324
2023 Exome Analysis Reveals Novel Missense and Deletion Variants in the CC2D2A Gene as Causative of Joubert Syndrome. Genes 4 37107568
2020 Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family. The journal of gene medicine 3 32989887
2024 Expanding the phenotypic spectrum of CC2D2A-related ciliopathies: a rare homozygous nonsense variant in a patient with suspected nephronophthisis. European journal of human genetics : EJHG 2 38987663
2023 Biallelic CC2D2A variants, SNV and LINE-1 insertion simultaneously identified in siblings using long-read whole-genome sequencing and haplotype phasing. Journal of human genetics 2 36765129
2021 Establishment of three Joubert syndrome-derived induced pluripotent stem cell (iPSC) lines harbouring compound heterozygous mutations in CC2D2A gene. Stem cell research 2 34182252
2024 Joubert syndrome causing mutation in C2 domain of CC2D2A affects structural integrity of cilia and cellular signaling molecules. Experimental brain research 1 38231387
2015 [Clinical and genetic analysis for a Joubert syndrome family with CC2D2A gene mutations]. Zhonghua er ke za zhi = Chinese journal of pediatrics 1 26310553
2026 Compound heterozygous mutations in CC2D2A cause Meckel-Gruber syndrome: a case report and review of the literature. Journal of medical case reports 0 42083041

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