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Showing CFAP410 — C21ORF2 is a alias.

CFAP410

Cilia- and flagella-associated protein 410 · UniProt O43822

Length
256 aa
Mass
28.3 kDa
Annotated
2026-06-09
27 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CFAP410 (C21ORF2) is a basal body and connecting cilium protein that couples primary ciliogenesis to NEK1-dependent genome maintenance, and its loss of function disrupts both processes in neurons and photoreceptors (PMID:26294103, PMID:37188479, PMID:39703094). It is built from two modules: an N-terminal leucine-rich repeat domain that engages binding partners and a C-terminal domain that assembles into a tetrameric helical bundle required for correct basal body localization, disruption of which (e.g. the L224P variant) disassembles the tetramer and mislocalizes the protein (PMID:39255848, PMID:40018707). Through its leucine-rich repeat surface CFAP410 forms a tight complex with the kinase NEK1 via a dedicated C-terminal interaction domain on NEK1, and acts in the same pathway as NEK1 to promote homologous-recombination repair of DNA damage and to support ciliogenesis (PMID:26290490, PMID:37188479). CFAP410 abundance is controlled by the ubiquitin–proteasome system: the SCF substrate receptor FBXO3 binds and ubiquitylates it for degradation, while NEK1-mediated phosphorylation attenuates the FBXO3 interaction and stabilizes the protein (PMID:32891887). Reduced CFAP410 produces fewer and shorter primary cilia, defective sonic hedgehog signalling, and impaired neuromuscular junction formation, all reversible by re-expression (PMID:39703094). Disease-associated missense and structural mutations destabilize the protein, alter its localization and ubiquitination, and weaken the NEK1 interaction, linking CFAP410 to ALS and spondylometaphyseal dysplasia phenotypes (PMID:27548899, PMID:37901396, PMID:39255848, PMID:40933646).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2015 Medium

    Established that CFAP410 acts in DNA damage repair within the NEK1 pathway rather than as an isolated factor, defining its first functional partner.

    Evidence siRNA knockdown with HR/NHEJ reporter assays and NEK1 overexpression rescue in human cells

    PMID:26290490

    Open questions at the time
    • Did not define the physical interaction interface
    • Mechanism by which CFAP410 promotes HR specifically was not resolved
  2. 2015 Medium

    Localized CFAP410 to specific ciliary substructures of photoreceptors, anchoring it to the basal body/connecting cilium compartment.

    Evidence Immunohistochemistry on human, pig, and mouse retinal sections

    PMID:26294103

    Open questions at the time
    • Did not establish ciliary function mechanistically
    • No link to a molecular pathway at the cilium
  3. 2016 Medium

    Extended ciliary localization to cone and rod connecting cilia and tied CFAP410 to ciliogenesis and chondrocyte differentiation, broadening its tissue relevance.

    Evidence Immunolocalization in retina plus functional data in chondrocytes; mutant expression assays showing reduced stability and altered localization

    PMID:26974433 PMID:27548899

    Open questions at the time
    • Did not identify the degradation machinery acting on mutants
    • Connection between cartilage and ciliary roles unresolved
  4. 2020 High

    Defined how CFAP410 levels are regulated, showing FBXO3 ubiquitylates it for degradation while NEK1 phosphorylation stabilizes it, and that an ALS mutant escapes this control.

    Evidence Reciprocal Co-IP, ubiquitylation and phosphorylation assays, and neurite outgrowth in mESC-derived motor neurons

    PMID:32891887

    Open questions at the time
    • The SCF complex composition beyond FBXO3 not detailed
    • Phosphosites mediating FBXO3 escape not fully mapped
  5. 2023 High

    Characterized the endogenous NEK1–CFAP410 complex at structural resolution, mapping a C-terminal interaction domain on NEK1 and linking complex integrity to both ciliogenesis and HR.

    Evidence Endogenous reciprocal Co-IP, AlphaFold modelling, ciliogenesis and HR assays with pathogenic mutants

    PMID:37188479

    Open questions at the time
    • Interface modelled by AlphaFold, not crystallographically resolved as a complex
    • How the same complex partitions between cilium and DNA repair unresolved
  6. 2023 Medium

    Confirmed that additional pathogenic CFAP410 variants destabilize the protein and alter its ubiquitination, generalizing the proteostatic mechanism of disease mutations.

    Evidence Co-IP, western blotting, immunofluorescence, and cell cycle analysis in HEK293T cells

    PMID:37901396

    Open questions at the time
    • Did not test FBXO3/NEK1 dependence for these specific variants
    • Functional ciliary consequence not assayed
  7. 2024 High

    Solved the bimodular architecture, showing the CTD forms a tetrameric helical bundle essential for basal body localization and the NTD is an LRR fold whose mutations destabilize binding-partner interactions.

    Evidence X-ray crystallography across three organisms plus L224P localization assays in T. brucei; 1.0-Å NTD structure with disease-mutation analysis

    PMID:39255848 PMID:40018707

    Open questions at the time
    • Identity of NTD surface-patch binding partners not experimentally confirmed
    • Structure of the full-length protein or partner complexes not determined
  8. 2024 Medium

    Demonstrated multi-organ pathogenicity of the V58L variant, linking it to DNA damage response defects, mitochondrial dysfunction, altered excitability, and reduced NEK1 protein.

    Evidence iPSC-derived motor neurons vs isogenic controls, zebrafish model, apoptosis/DNA damage/mitochondrial assays, NEK1 western blot

    PMID:39227882

    Open questions at the time
    • Mechanism linking V58L to mitochondrial dysfunction unclear
    • How V58L downregulates NEK1 post-transcriptionally not defined
  9. 2025 High

    Connected CFAP410 loss to a ciliary signalling axis in motor neurons, showing reduced cilia impair SHH signalling, CRABP1 expression, and NMJ formation, all rescued by re-expression.

    Evidence iPSC-derived motor neurons, siRNA knockdown, SHH reporter assays, compartmentalized NMJ co-culture, overexpression rescue

    PMID:39703094

    Open questions at the time
    • Whether SHH defect is upstream or parallel to NMJ phenotype not fully resolved
    • Relationship to the DNA-repair role in the same cells not integrated
  10. 2025 Medium

    Showed in an endogenous knock-in model that ALS variants impair the NEK1 interaction and increase DNA damage susceptibility without altering cilia frequency, dissociating the genome-maintenance from the ciliary phenotype.

    Evidence Knock-in mESCs, neural differentiation, DNA damage assays, Co-IP for Nek1 interaction

    PMID:40933646

    Open questions at the time
    • Why cilia were unaffected here but affected in other models unresolved
    • Quantitative contribution of NEK1-binding loss to DNA damage not isolated
  11. 2026 Low

    Proposed a context-specific oncogenic role via JAK2/STAT3 activation in prostate cancer, expanding CFAP410 function beyond cilia and DNA repair.

    Evidence Co-IP, western blotting, proliferation/migration assays, TUNEL, and xenograft model in prostate cancer cells

    PMID:41612237

    Open questions at the time
    • Co-IP without reciprocal validation; direct interaction unconfirmed
    • JAK2/STAT3 activation inferred only from downstream target western blots
    • No mechanistic link to the established ciliary/NEK1 functions

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CFAP410 mechanistically integrates its basal body/ciliogenesis role with NEK1-dependent homologous recombination in the same cell remains unresolved.
  • No model explains the partition of the CFAP410–NEK1 complex between cilium and nucleus
  • NTD binding partners beyond NEK1 unidentified
  • Structure of the assembled CFAP410–NEK1 complex not experimentally determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005815 microtubule organizing center 3 GO:0005929 cilium 3 GO:0005829 cytosol 1
Pathway
R-HSA-73894 DNA Repair 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-162582 Signal Transduction 1
Partners
FBXO3NEK1
Complex memberships
CFAP410-NEK1 complexSCF-FBXO3 ubiquitin ligase (substrate)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 C21ORF2 (CFAP410) interacts with NEK1 kinase, and C21ORF2-depleted cells show impaired homologous recombination (but not non-homologous end joining) after ionizing radiation. Overexpression of NEK1 rescued the DNA repair defect in C21ORF2-knockdown cells, placing C21ORF2 in the same pathway as NEK1 for DNA damage repair. siRNA knockdown, colony survival assay, HR/NHEJ reporter assays, NEK1 overexpression rescue Acta biochimica et biophysica Sinica Medium 26290490
2015 C21ORF2 (CFAP410) protein localizes to ciliary structures of photoreceptor cells, specifically the daughter basal body, the centriole adjacent to the basal body, and the connecting cilium, as determined by immunohistochemistry in human, pig, and mouse retinas. Immunohistochemistry on mammalian (human, pig, mouse) retinal sections The British journal of ophthalmology Medium 26294103
2016 C21ORF2 (CFAP410) protein localizes to the connecting cilium of cone and rod photoreceptors, and is implicated in cartilage differentiation in chondrocytes based on functional data. Immunolocalization in retinal tissue; functional data in chondrocyte cells PloS one Medium 26974433
2016 Missense mutations in the leucine-rich repeat C-terminal (LRRCT) domain of C21ORF2 (CFAP410) reduce protein stability and alter cytoplasmic localization of mutant proteins compared to wild type in vitro, and C21ORF2 is required for ciliogenesis in retinal photoreceptors. In vitro expression assays, immunofluorescence, western blotting of mutant constructs in cell lines Investigative ophthalmology & visual science Medium 27548899
2020 FBXO3 (substrate receptor of an SCF ubiquitin ligase complex) binds and ubiquitylates C21ORF2, targeting it for proteasomal degradation. NEK1-mediated phosphorylation of C21ORF2 attenuates its interaction with FBXO3, thereby stabilizing C21ORF2. The ALS-associated V58L mutant of C21ORF2 is hyperphosphorylated by NEK1, escapes FBXO3-mediated ubiquitylation, and accumulates together with NEK1. Expression of C21ORF2(V58L) in mouse ESC-derived motor neurons impaired neurite outgrowth. Co-immunoprecipitation, ubiquitylation assays, phosphorylation assays, motor neuron differentiation from mESCs, neurite outgrowth measurement iScience High 32891887
2023 Endogenous NEK1 and C21ORF2 form a tight complex in human cells. A C-terminal interaction domain (CID) on NEK1 is necessary for association with C21ORF2, and pathogenic mutations in this region disrupt the complex. AlphaFold modelling predicts an extended binding interface between the leucine-rich repeat domain of C21ORF2 and the NEK1-CID. NEK1 mutations that inhibit kinase activity or weaken NEK1-C21ORF2 association severely compromise ciliogenesis. C21ORF2, like NEK1, is required for homologous recombination. Endogenous Co-immunoprecipitation, AlphaFold structural modelling, ciliogenesis assays, HR repair assays, pathogenic mutant analysis Life science alliance High 37188479
2023 CFAP410 pathogenic variants (p.Tyr107His and p.Pro116Leu) reduce protein stability and alter the ubiquitination level of CFAP410, as measured by co-IP and western blotting in HEK293T cells, suggesting the ubiquitin-proteasome pathway mediates CFAP410 degradation. Co-immunoprecipitation, western blotting, immunofluorescence, cell cycle analysis in HEK293T cells Frontiers in medicine Medium 37901396
2024 The C-terminal domain (CTD) of CFAP410 forms a tetrameric helical bundle, as determined by crystal structures from Homo sapiens, Trypanosoma brucei, and Chlamydomonas reinhardtii. The tetrameric assembly is essential for correct basal body localization of CFAP410; the ALS/spondylometaphyseal dysplasia-associated L224P mutation disassembles the tetramer and disrupts basal body localization in T. brucei. X-ray crystallography (crystal structures from three organisms), functional localization assays with L224P mutant in T. brucei Open biology High 39255848
2025 C21ORF2 localizes to the basal body of the primary cilium in human motor neurons. ALS-associated mutations alter this basal body localization. Reduction of C21ORF2 levels causes fewer primary cilia and reduced ciliary length, leading to defective sonic hedgehog (SHH) signalling, reduced CRABP1 expression, and impaired neuromuscular junction formation. Overexpression of C21ORF2 in mutant motor neurons rescued ciliary frequency and length, CRABP1 expression, and NMJ formation. iPSC-derived motor neuron cultures, immunofluorescence, siRNA knockdown, SHH pathway reporter assays, compartmentalized co-culture NMJ assay, rescue by overexpression Brain : a journal of neurology High 39703094
2024 The ALS-associated C21ORF2-V58L variant causes increased apoptosis in mouse neurons, movement defects in zebrafish, and in iPSC-derived motor neurons: defects in DNA damage response, mitochondrial dysfunction, and changes in neuronal excitability. V58L induces post-transcriptional downregulation of NEK1 protein levels. iPSC-derived motor neurons (patient vs isogenic controls), zebrafish model, apoptosis assays, DNA damage response assays, mitochondrial assays, western blotting for NEK1 Acta neuropathologica communications Medium 39227882
2025 Knock-in of ALS-associated Cfap410 variants in mouse ESCs results in impaired interaction with Nek1 and increased susceptibility to DNA damage in ESCs, neural progenitors, and differentiated neurons, without significant effects on primary cilia frequency. Gene editing (knock-in) in mESCs, neural differentiation, DNA damage assays, Co-immunoprecipitation for Nek1 interaction iScience Medium 40933646
2025 CFAP410 adopts a bimodular architecture. The 1.0-Å resolution crystal structure of the N-terminal domain (NTD) of T. brucei CFAP410 reveals a leucine-rich repeat fold with a conserved surface patch. Disease-causing mutations in the NTD destabilize the structure and are predicted to disrupt interactions with binding partners. X-ray crystallography (1.0-Å resolution), structural analysis of disease-causing mutations Frontiers in cell and developmental biology High 40018707
2026 C21ORF2 promotes activation of the JAK2/STAT3 signaling pathway in prostate cancer cells, upregulating downstream targets c-MYC, Cyclin A1, Bcl-2, and Cleaved caspase-3. Co-immunoprecipitation demonstrated interaction between C21ORF2 and downstream targets; C21ORF2 showed negative correlation with KCTD5. In vivo xenograft models validated C21ORF2's role in tumor growth. Co-immunoprecipitation, western blotting, CCK-8 proliferation assay, Transwell assay, TUNEL staining, subcutaneous xenograft mouse model BMC cancer Low 41612237

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 The NEK1 interactor, C21ORF2, is required for efficient DNA damage repair. Acta biochimica et biophysica Sinica 64 26290490
2015 C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium. The British journal of ophthalmology 40 26294103
2016 Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations. PloS one 38 26974433
2013 Safety assessment and probiotic evaluation of Enterococcus faecium YF5 isolated from sourdough. Journal of food science 32 23488799
2016 Identification of Novel Mutations in the LRR-Cap Domain of C21orf2 in Japanese Patients With Retinitis Pigmentosa and Cone-Rod Dystrophy. Investigative ophthalmology & visual science 29 27548899
2020 An Amyotrophic Lateral Sclerosis-Associated Mutant of C21ORF2 Is Stabilized by NEK1-Mediated Hyperphosphorylation and the Inability to Bind FBXO3. iScience 26 32891887
1998 Characterization of a novel gene, C21orf2, on human chromosome 21q22.3 and its exclusion as the APECED gene by mutation analysis. Genomics 25 9465297
2017 Homozygous variant in C21orf2 in a case of Jeune syndrome with severe thoracic involvement: Extending the phenotypic spectrum. American journal of medical genetics. Part A 23 28422394
2003 Reduction of chromatin assembly factor 1 p60 and C21orf2 protein, encoded on chromosome 21, in Down syndrome brain. Journal of neural transmission. Supplementum 20 15068244
2023 Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases. Life science alliance 16 37188479
2025 C21ORF2 mutations point towards primary cilia dysfunction in amyotrophic lateral sclerosis. Brain : a journal of neurology 10 39703094
2024 ALS-associated C21ORF2 variant disrupts DNA damage repair, mitochondrial metabolism, neuronal excitability and NEK1 levels in human motor neurons. Acta neuropathologica communications 9 39227882
2023 C21orf2 variants causing inherited retinal disease: A review of what we know and a report of two new suspected cases. Clinical case reports 9 36950666
2018 Prediction of structural consequences for disease causing variants in C21orf2 protein using computational approaches. Journal of biomolecular structure & dynamics 8 29343210
2023 Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma. Frontiers in medicine 6 37901396
2021 A homozygous in-frame duplication within the LRRCT consensus sequence of CFAP410 causes cone-rod dystrophy, macular staphyloma and short stature. Ophthalmic genetics 6 34915818
2024 The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body. Open biology 3 39255848
2025 Concurrent novel mutations in PAX3 and CFAP410 in a patient with Waardenburg syndrome type 1 associated with Retinitis Pigmentosa. Ophthalmic genetics 2 40044632
2025 The Molecular Intersection of NEK1, C21ORF2, Cyclin F, and VCP in ALS Pathogenesis. Genes 2 40282367
2025 Functional variants of CFAP410 affect the DNA damage response leading to motor neuron degeneration - Implications for ALS. iScience 1 40933646
2024 Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration. Research square 1 38405922
2024 Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration. Ophthalmic genetics 1 39232248
2024 Coding and non-coding variants in the ciliopathy gene CFAP410 cause early-onset non-syndromic retinal degeneration. NPJ genomic medicine 1 39516462
2022 A polymorphic transcriptional regulatory domain in the amyotrophic lateral sclerosis risk gene CFAP410 correlates with differential isoform expression. Frontiers in molecular neuroscience 1 36131690
2026 C21orf2 as a potential regulator of JAK2/STAT3 signaling in prostate cancer cell proliferation and apoptosis: an exploratory study. BMC cancer 0 41612237
2025 CFAP410 has a bimodular architecture with a conserved surface patch on its N-terminal leucine-rich repeat motif for binding interaction partners. Frontiers in cell and developmental biology 0 40018707
2025 Variants in CFAP410 cause a range of retinal and skeletal phenotypes. NPJ genomic medicine 0 40246852

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