Affinage

CFAP58

Cilia- and flagella-associated protein 58 · UniProt Q5T655

Length
872 aa
Mass
103.4 kDa
Annotated
2026-06-09
11 papers in source corpus 5 papers cited in narrative 5 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

CFAP58 is a testis-enriched cilia- and flagella-associated protein essential for sperm flagellar axoneme assembly and midpiece integrity, with bi-allelic loss-of-function variants causing multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility in humans and recapitulated in knockout and knock-in mice (PMID:32791035, PMID:40675161). The protein localizes throughout the sperm flagellum, concentrating at the mid-piece, and its loss reduces axonemal markers (SPAG6, SPEF2) and the mitochondrial sheath protein HSP60 while disrupting central pair microtubule assembly (PMID:32791035, PMID:40675161). Structurally, CFAP58 forms a heterodimer with CCDC146/MBO2 within a conserved L-shaped axonemal element that interconnects inner dynein arms with regulatory complexes and is required for normal ciliary waveform (PMID:38568782). Beyond the axoneme, CFAP58 acts in the intra-manchette/intra-flagellar transport pathway through physical interactions with IFT88 and CCDC42, stabilizing CCDC42 to support manchette-dependent sperm head shaping (PMID:38602507). CFAP58 co-localizes with ODF2/Cenexin and modulates Notch signaling during primary cilium elongation, extending its role to ciliogenesis beyond the male germline (PMID:31904090).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2020 High

    Establishing whether CFAP58 has an essential in vivo function addressed the unknown of its requirement for sperm formation, demonstrating it is causally linked to human male infertility via flagellar and mitochondrial sheath defects.

    Evidence Whole-exome sequencing of patients plus CRISPR/Cas9 knockout mice with TEM, IF, and immunoblotting

    PMID:32791035

    Open questions at the time
    • Did not resolve the molecular structure CFAP58 builds within the axoneme
    • Direct binding partners not yet defined
  2. 2020 Medium

    Identifying CFAP58 as an ODF2/Cenexin interactor and a Notch-pathway modulator addressed where it acts beyond the flagellum, linking it to primary cilium elongation and ciliogenesis.

    Evidence Mass spectrometry interactome, siRNA knockdown in astrocytes with Notch pharmacological modulation and IF

    PMID:31904090

    Open questions at the time
    • Notch link rests on pharmacological evidence only
    • Direct ODF2 binding interface not mapped
    • Single-lab, knockdown-based
  3. 2024 High

    Cryo-ET of the Chlamydomonas ortholog answered the structural question of how CFAP58 is organized in the axoneme, showing it heterodimerizes with CCDC146/MBO2 in an L-shaped element coupling inner dynein arms to regulatory complexes.

    Evidence Cryo-electron tomography, comparative proteomics, epitope tagging, and mbo mutant analysis in Chlamydomonas

    PMID:38568782

    Open questions at the time
    • Conservation of the L-shaped structure in mammalian sperm not directly demonstrated
    • Mechanism of waveform regulation not resolved
  4. 2024 Medium

    Defining CFAP58 interactions with IFT88 and CCDC42 addressed how its loss affects sperm head morphology, implicating it in the intra-manchette/intra-flagellar transport pathway as a stabilizer of CCDC42.

    Evidence Knockout mice with co-immunoprecipitation, IF, and TEM

    PMID:38602507

    Open questions at the time
    • Cargo role for CCDC42 inferred, not directly demonstrated
    • Co-IP without reciprocal/structural validation of interaction interfaces
  5. 2025 Medium

    A knock-in mouse modeling a patient nonsense mutation answered which axonemal substructure depends on CFAP58, showing it is required for central pair microtubule assembly during spermiogenesis.

    Evidence Whole-exome sequencing of patients and Cfap58 knock-in mutant mice with TEM and IF

    PMID:40675161

    Open questions at the time
    • Mechanistic link between CFAP58 and central pair nucleation unresolved
    • Not yet independently replicated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CFAP58's axonemal structural role, IFT/IMT transport function, and Notch modulation are mechanistically integrated remains unresolved.
  • No structural model of the mammalian CFAP58 complex
  • Direct binding interfaces with IFT88/CCDC42/CCDC146 not mapped
  • Mechanism connecting CFAP58 to central pair assembly unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0005198 structural molecule activity 1
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 1
Partners
CCDC146CCDC42IFT88ODF2
Complex memberships
CFAP58-CCDC146/MBO2 heterodimeraxonemal L-shaped structure

Evidence

Reading pass · 5 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Bi-allelic loss-of-function variants in CFAP58 cause axonemal and mitochondrial sheath malformations in human sperm flagella. CFAP58 localizes to the entire flagellum of control sperm, concentrated in the mid-piece. Loss of CFAP58 reduces abundance of axoneme ultrastructure markers SPAG6 and SPEF2 and mitochondrial sheath protein HSP60. Cfap58-knockout mice generated by CRISPR/Cas9 are male-infertile with severe flagellar defects, establishing CFAP58 as essential for sperm flagellogenesis. Whole-exome sequencing, immunofluorescence, immunoblotting, transmission electron microscopy, CRISPR/Cas9 knockout mice American journal of human genetics High 32791035
2020 CFAP58 is identified as a testis-enriched protein that co-localizes with Odf2/Cenexin at the sperm midpiece and primary cilia. Cfap58 knockdown in astrocytes impairs primary cilium elongation and sperm midpiece formation via modulation of the Notch signaling pathway. Cfap58 was identified as an interactor of Odf2/Cenexin by mass spectrometry interactome analysis. Mass spectrometry interactome analysis, siRNA knockdown, immunofluorescence, drug administration studies (Notch pathway modulation) Bioscience reports Medium 31904090
2024 CFAP58 (FAP58/CCDC147) forms a heterodimer with MBO2/CCDC146 that is part of a conserved L-shaped structure in the Chlamydomonas axoneme, varying between doublet microtubules. This structure interconnects inner dynein arms with multiple regulatory complexes and is required for normal ciliary waveform. Loss of FAP58 disrupts inner arm dynein b assembly. Comparative proteomics revealed overlapping protein defects with other motility mutants. Cryo-electron tomography, comparative proteomics, epitope tagging, Chlamydomonas mbo mutant analysis Molecular biology of the cell High 38568782
2024 CFAP58 loss in mice causes not only sperm tail defects but also disrupts the manchette structure, leading to abnormal sperm head shaping and increased spermatozoa apoptosis. CFAP58 physically interacts with IFT88 and CCDC42, and may act as a cargo protein stabilizing CCDC42 in the intra-manchette transport/intra-flagellar transport (IMT/IFT) pathway. Gene knockout mice, co-immunoprecipitation (CFAP58-IFT88 and CFAP58-CCDC42 interaction), immunofluorescence, TEM Development (Cambridge, England) Medium 38602507
2025 A homozygous nonsense mutation in CFAP58 (c.562C>T, p.R188*) disrupts central pair (CP) microtubule assembly in the sperm flagellar axoneme. Cfap58 mutant mice mimicking the patient mutation recapitulate the MMAF phenotype, and TEM shows absence of the central pair of microtubules, demonstrating CFAP58 is required for CP assembly during spermiogenesis. Whole-exome sequencing (human patients), Cfap58 knock-in mutant mouse model, transmission electron microscopy, immunofluorescence Human molecular genetics Medium 40675161

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice. American journal of human genetics 90 32791035
2021 Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders. Human reproduction (Oxford, England) 51 34089056
2021 Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer. Breast cancer research and treatment 32 34173924
2016 Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 27 26762739
2021 Prediction of bladder cancer outcome by identifying and validating a mutation-derived genomic instability-associated long noncoding RNA (lncRNA) signature. Bioengineered 21 33955803
2020 Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella. Clinical genetics 21 33314088
2020 The novel testicular enrichment protein Cfap58 is required for Notch-associated ciliogenesis. Bioscience reports 12 31904090
2024 CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice. Development (Cambridge, England) 8 38602507
2024 The MBO2/FAP58 heterodimer stabilizes assembly of inner arm dynein b and reveals axoneme asymmetries involved in ciliary waveform. Molecular biology of the cell 6 38568782
2025 Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes. The Journal of pathology 3 40317966
2025 A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly. Human molecular genetics 1 40675161

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