CFAP57 (WDR65) review notes

Deep research status

• just deep-research human CFAP57 --provider falcon failed: Edison API authentication
  error ("Failed to authenticate", HTTP 403 Forbidden).
• just deep-research human CFAP57 --provider perplexity failed: provider not available
  in this environment ("Provider 'perplexity' not available. Available: falcon, asta,
  openscientist").
• No deep-research file was written. Literature research was done manually (PubMed search
  for CFAP57 / FAP57 / WDR65) using the cached publications in publications/.

Identity

• UniProt Q96MR6, Cilia- and flagella-associated protein 57; alias WDR65. N-terminal WD40
  repeats (EML-like beta-propeller) and long C-terminal coiled coils; PANTHER
  PTHR32215:SF0. Chains i4/i5 in the human respiratory axoneme model PDB 8J07.
• Two transcripts: a long isoform needed in sperm and a short isoform; in mouse both are
  present in testis and trachea PMID:36752199.
• Disease: spermatogenic failure 95 (SPGF95, MIM:620917), MMAF. One PCD case report.
• Note: an older report linked a WDR65 missense variant to Van der Woude syndrome
  (PMID:21574244, not cached, not used); not relevant to ciliary function.

Literature findings (with provenance)

Chlamydomonas FAP57 (IDA8/BOP2)

• "IDA8 encodes flagellar-associated polypeptide (FAP)57/WDR65, a highly conserved WD
  repeat, coiled coil domain protein"; required "for targeting the assembly of a subset of
  inner dynein arms (IDAs) to a specific location in the 96 nm repeat"; "FAP57 forms an
  extended structure that interconnects multiple IDAs and regulatory complexes"
  PMID:31483737 (full text).
• "FAP57 is important for stabilizing the binding of IDA g (and to a lesser extent the
  binding of IDA d)"; "FAP57 is not required for docking of the N-DRC" PMID:31483737.
• Orthologues "have been identified in other organisms with motile cilia, but only in
  those species that assemble IDAs" PMID:31483737.

Human airway (PCD)

• Bustamante-Marin et al. 2020: homozygous CFAP57 nonsense variant causing exon 11 skipping
  in one PCD subject; "In normal human nasal epithelial cells, CFAP57 localizes throughout
  the ciliary axoneme"; mutant protein "is not incorporated into the axoneme"; "A reduced
  beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in
  human tracheobronchial epithelial cells (hTECs) recapitulates these findings"
  PMID:32764743 (full text).
• fap57 Chlamydomonas mutants "show reduced swimming velocity and altered waveforms"; the
  "g" (DHC7, DHC3) and "d" (DHC2) inner dyneins are reduced PMID:32764743.
• Only a single PCD subject has been reported; the PCD association is weaker than the
  sperm association.

Sperm (MMAF)

• Ma et al. 2023: two loss-of-function CFAP57 variants in three Pakistani MMAF families
  "who had no overt ciliary symptoms"; a mouse model of R958* recapitulates MMAF; "CFAP57
  deficiency disrupted the inner dynein arm (IDA) assembly in sperm flagella and that
  single-headed IDAs were more likely to be affected"; mutations affect only the long
  transcript PMID:36752199 (full text).
• "Ultrastructural analysis of the sperm flagella from CFAP57-mutated individuals revealed
  the presence of a normal 9 + 2 structure with only IDAs' absence" PMID:36752199.
• Chen et al. 2025: further biallelic variants; mutant mice recapitulate MMAF; CFAP57
  interacts with MYH10, and "both MYH10 and CFAP57 localize to the sperm flagella"
  PMID:41466333. The MYH10/IFT88 mechanism is single-study and not used for annotation.
• Tlili et al. 2026: homozygous nonsense variant in an Emirati asthenozoospermic man with
  no PCD signs PMID:41793497 (abstract only).
• CCDC113 interacts with CFAP57 in co-immunoprecipitation PMID:39671309.

Curation judgements

• GOA has only four CC rows (cilium x2, axoneme, sperm flagellum), no MF and no BP.
• Cilium (HPA IDA; ARBA IEA): MODIFY to GO:0031514 motile cilium; CFAP57 localizes to the
  axoneme of human airway motile cilia and to sperm flagella, and has no known role in
  primary cilia.
• Axoneme (IEA): ACCEPT. Sperm flagellum (Ensembl Compara IEA from mouse): ACCEPT, supported
  by human patient sperm data.
• NEW GO:0036159 inner dynein arm assembly: participation is structural (CFAP57 provides
  the docking/targeting structure for IDAs g and d). Comparator check (QuickGO,
  2026-10-16): CCDC39 and CCDC40, axonemal docking/ruler proteins that specify binding
  sites of IDAs and other complexes, carry this term by IMP.
• NEW GO:0003341 cilium movement: reduced beat frequency and altered waveform in patient
  nasal cells and hTEC knockdown, and in Chlamydomonas mutants. Comparator: CCDC39/CCDC40
  carry cilium movement (IMP).
• GO:0120316 sperm flagellum assembly not proposed: it has cilium movement among its GO
  ancestors, so proposing both would violate the ancestor/descendant rule. Cilium movement
  was preferred because the airway and Chlamydomonas data are direct measurements of
  ciliary beating. Raised as a question.
• NEW GO:0005200 structural constituent of cytoskeleton, consistent with CFAP61 review.

Review follow-up (2026-10-16, PR #5064 review)

• GO:0120316 sperm flagellum assembly ancestry, checked by an OLS hierarchicalAncestors
  query and the term graph endpoint (2026-10-16):
  https://www.ebi.ac.uk/ols4/api/ontologies/go/terms/http%253A%252F%252Fpurl.obolibrary.org%252Fobo%252FGO_0120316/hierarchicalAncestors.
  Direct parents: is_a GO:0044458 motile cilium assembly; is_a GO:0003006 developmental
  process involved in reproduction; part_of GO:0030317 flagellated sperm motility;
  part_of GO:0007286 spermatid development. GO:0030317 is_a GO:0060294 cilium movement
  involved in cell motility, which is_a GO:0003341 cilium movement. GO:0007286 is part_of
  GO:0048515 spermatid differentiation, which is part_of GO:0007283 spermatogenesis.
  So GO:0120316 is a descendant of cilium movement, flagellated sperm motility and
  spermatogenesis; the PR reviewer's doubt about the cilium movement and spermatogenesis
  paths was not borne out.
• Restored the full PMID:36752199 quote ("...a normal 9 + 2 structure with only IDAs'
  absence", curly apostrophe as in the cache); the earlier cut at "with only IDAs"
  inverted its meaning. Rechecked every supporting_text in the CFAP251, CFAP91 and CFAP57
  reviews against the text that follows it in the cache; no other meaning-changing
  truncation found.
• The GO:0120316 rationale in the cilium movement NEW row and in the suggested question
  now names the path explicitly (is_a motile cilium assembly; part_of flagellated sperm
  motility, which is_a cilium movement involved in cell motility, which is_a cilium
  movement).