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CFAP74

Cilia- and flagella-associated protein 74 · UniProt Q9C0B2

Length
1584 aa
Mass
178.6 kDa
Annotated
2026-06-09
13 papers in source corpus 6 papers cited in narrative 6 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

CFAP74 is a cilia- and flagella-associated protein required for the structural integrity and motile function of motile cilia and sperm flagella across multiple tissues (PMID:32555313, PMID:39362668, PMID:36459505). In spermatozoa it localizes along the entire length of the flagellum, and its loss or pathogenic variation is associated with multiple morphological abnormalities of sperm flagella, including a thinner midpiece, disorganized mitochondrial sheath, and axonemal defects (PMID:32555313, PMID:41117181). In respiratory cilia, pathogenic CFAP74 variants cause primary ciliary dyskinesia characterized by a defective C1d projection of the ciliary central apparatus and insufficient mucociliary clearance, despite grossly normal ciliary ultrastructure and beating (PMID:39362668). CFAP74 is also required for left-right body patterning: knockdown disrupts Kupffer's vesicle organogenesis and ciliogenesis and perturbs early left-right signaling and cardiac looping (PMID:36459505). During spermiogenesis, Cfap74 mRNA is a translational target of CEP112-mediated RNA granule phase separation (PMID:39349455), and the CFAP74 protein physically associates with CFAP119 within the flagellar assembly interaction network (PMID:40759592). Beyond these localization, interaction, and loss-of-function phenotype data, the precise biochemical role of CFAP74 within the central apparatus has not been mechanistically resolved in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2020 Medium

    Established that CFAP74 is genetically required for normal sperm flagellar morphology by linking biallelic variants to loss of the protein and the MMAF phenotype.

    Evidence Whole-exome sequencing and immunofluorescence on patient sperm

    PMID:32555313

    Open questions at the time
    • No mechanistic placement within axonemal structure
    • No in vitro reconstitution of CFAP74 function
    • Functional consequence for ciliary motility not assessed
  2. 2022 Medium

    Showed CFAP74 acts in left-right patterning by demonstrating that its loss disrupts Kupffer's vesicle ciliogenesis and downstream laterality signaling.

    Evidence Zebrafish morpholino knockdown with in situ hybridization, immunostaining, and high-speed cilia videomicroscopy

    PMID:36459505

    Open questions at the time
    • Morpholino specificity not corroborated by genetic mutant
    • Molecular role of CFAP74 within cilia not defined
    • Link between sperm and node ciliary defects unresolved
  3. 2024 Medium

    Defined the structural correlate of CFAP74 dysfunction in respiratory cilia by tying pathogenic variants to a defective C1d central-apparatus projection and impaired clearance.

    Evidence High-throughput sequencing, in vitro ciliary transport assays, TEM, and high-speed videomicroscopy in PCD individuals

    PMID:39362668

    Open questions at the time
    • How CFAP74 builds or stabilizes the C1d projection unknown
    • Discordance between normal beat/ultrastructure and impaired clearance unexplained
    • No biochemical characterization of CFAP74 within central apparatus
  4. 2024 Medium

    Placed Cfap74 mRNA within post-transcriptional control of spermiogenesis by identifying it as a translational target of CEP112-driven RNA granule phase separation.

    Evidence Multi-omics, TRICK reporter assay, co-IP/MS, and in vitro phase separation assay

    PMID:39349455

    Open questions at the time
    • Effect of dysregulated Cfap74 translation on protein function not tested
    • Finding centers on CEP112 rather than CFAP74 protein mechanism
    • Timing of CFAP74 protein deposition in flagellum not mapped
  5. 2025 Medium

    Demonstrated CFAP74 localizes along the entire flagellum and that some missense variants impair flagellar ultrastructure without abolishing protein expression or localization.

    Evidence Immunofluorescence, scanning and transmission electron microscopy, whole-exome sequencing in patients

    PMID:41117181

    Open questions at the time
    • Mechanism by which localization-competent variants cause defects unknown
    • No structure-function mapping of variant residues
    • Single lab without reconstitution
  6. 2025 Low

    Began defining the CFAP74 interaction network by validating a direct physical interaction with CFAP119 relevant to flagellum development.

    Evidence Co-immunoprecipitation validating an in silico predicted interaction

    PMID:40759592

    Open questions at the time
    • Single co-IP without reciprocal pull-down or orthogonal validation
    • Study focused on CFAP119, not CFAP74
    • Functional consequence of the interaction untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct biochemical activity of CFAP74 within the central apparatus and how it stabilizes the C1d projection remain unresolved.
  • No structural model of CFAP74 in the axoneme
  • No comprehensive interactome beyond CFAP119
  • No reconstitution linking molecular activity to the C1d defect

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CFAP119

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Biallelic missense mutations in CFAP74 (compound heterozygous variants in two unrelated patients) result in absence of CFAP74 protein in sperm as confirmed by immunofluorescence, associated with the MMAF (multiple morphological abnormalities of sperm flagella) phenotype and potential PCD, establishing CFAP74 as required for normal sperm flagellar morphology. Whole-exome sequencing, immunofluorescence on patient sperm samples Journal of human genetics Medium 32555313
2024 Pathogenic variants in CFAP74 cause primary ciliary dyskinesia with a defective C1d projection of the ciliary central apparatus; affected individuals exhibit insufficient ciliary clearance demonstrated by in vitro ciliary transport assays, despite normal ciliary ultrastructure by TEM and normal ciliary beating by high-speed videomicroscopy. High-throughput sequencing, in vitro ciliary transport assays, transmission electron microscopy, high-speed videomicroscopy The European respiratory journal Medium 39362668
2022 Morpholino-mediated knockdown of cfap74 in zebrafish caused abnormalities in cardiac looping, disrupted expression of early left-right signaling molecules, and impaired Kupffer's vesicle organogenesis and ciliogenesis, establishing CFAP74 as required for left-right patterning via ciliogenesis. Zebrafish morpholino knockdown, whole-mount in situ hybridization, immunostaining, high-speed cilia video microscopy PLoS genetics Medium 36459505
2025 CFAP74 localizes along the entire flagellum of spermatozoa as shown by immunofluorescence; missense variants in CFAP74 (c.2452C>T and c.3044T>C compound heterozygous, or homozygous c.3532G>A) do not disrupt protein expression or subcellular localization but are associated with flagellar ultrastructural defects including thinner midpiece, disorganized mitochondrial sheath, and axonemal abnormalities. Immunofluorescence, scanning electron microscopy, transmission electron microscopy, whole-exome sequencing Annals of human genetics Medium 41117181
2025 CFAP119 physically interacts with CFAP74 as validated by co-immunoprecipitation, placing CFAP74 within a protein interaction network relevant to sperm flagellum development. Co-immunoprecipitation (in vitro validation of in silico predicted interaction) The world journal of men's health Low 40759592
2024 CEP112 forms RNA granules during spermiogenesis that enrich CFAP74 mRNA among target mRNAs, and CEP112 orchestrates translational regulation of Cfap74 mRNA; this places CFAP74 as a translational target of CEP112-mediated phase separation during spermatid development. Multi-omics analyses, TRICK reporter assay, co-immunoprecipitation with mass spectrometry, in vitro liquid-liquid phase separation assay Nature communications Medium 39349455

Source papers

Stage 0 corpus · 13 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Biallelic mutations of CFAP74 may cause human primary ciliary dyskinesia and MMAF phenotype. Journal of human genetics 45 32555313
2013 Analysis of differentially expressed genes and microRNAs in alcoholic liver disease. International journal of molecular medicine 37 23337955
2024 CEP112 coordinates translational regulation of essential fertility genes during spermiogenesis through phase separation in humans and mice. Nature communications 19 39349455
2023 Genome-Wide Scan of Wool Production Traits in Akkaraman Sheep. Genes 17 36980985
2024 Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus. The European respiratory journal 15 39362668
2022 LOF variants identifying candidate genes of laterality defects patients with congenital heart disease. PLoS genetics 9 36459505
2021 Comparative methylation and RNA-seq expression analysis in CpG context to identify genes involved in Backfat vs. Liver diversification in Nanchukmacdon Pig. BMC genomics 8 34743693
2020 Comparison of whole exome sequencing in circulating tumor cells of primitive and metastatic nasopharyngeal carcinoma. Translational cancer research 7 35117778
2020 HNRNPCL1, PRAMEF1, CFAP74, and DFFB: Common Potential Biomarkers for Sporadic and Suspected Lynch Syndrome Endometrial Cancer. Cancer management and research 5 33177874
2023 Genomic selection pressure discovery using site-frequency spectrum and reduced local variability statistics in Pakistani Dera-Din-Panah goat. Tropical animal health and production 3 37750990
2025 Identification of a Novel Biallelic CFAP119 Variant in an Infertile Man with Asthenoteratozoospermia. The world journal of men's health 1 40759592
2025 Establishing the causative link between CFAP221 variants and asthenoteratozoospermia in humans. Journal of assisted reproduction and genetics 0 40272718
2025 CFAP74 Variants Could Cause Male Infertility With the Asthenoteratozoospermia Phenotype. Annals of human genetics 0 41117181

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