CFAP206

CFAP206 is a microtubule-docking adapter protein that localizes to the basal body and axoneme of motile cilia and sperm flagella, where it associates with the base of radial spoke 2 (RS2) in a CFAP91-dependent manner and is essential for stable assembly and positioning of radial spokes and inner dynein arms (PMID:32376681, PMID:36552811). Loss of CFAP206 abolishes axonemal localization of radial spoke proteins WDR66 and RSPH1 and causes flagellar ultrastructural defects, impaired mucociliary clearance, and hydrocephalus in mouse and Xenopus models, with its expression transcriptionally regulated by FOXJ1 (PMID:32376681). Bi-allelic truncating variants in human CFAP206 cause male infertility through multiple morphological abnormalities of the sperm flagellum (MMAF), with severely reduced embryo development even after ICSI (PMID:34255152).

1. 2020 High

   Establishing that CFAP206 is a ciliary structural component required for radial spoke formation and motile cilia function resolved its cellular role: it localizes to basal bodies and axonemes, and its loss produces hydrocephalus, male infertility, and impaired mucociliary clearance without laterality defects, placing it specifically in the motile (not nodal) cilia pathway.

   Evidence Xenopus CRISPR crispants, mouse knockout, electron tomography, immunolocalization, ciliary beat frequency and bead transport assays

   PMID:32376681

   Open questions at the time

   • Precise position within the radial spoke repeat was not determined
   • Direct binding partners on the axonemal microtubule were not identified
   • Mechanism by which ciliary beat frequency increases despite impaired transport was unexplained
2. 2021 High

   Linking CFAP206 to human disease and defining it as a microtubule-docking adapter for radial spokes and inner dynein arms established the molecular consequence of its loss: absence of WDR66 and RSPH1 from patient sperm axonemes, proving CFAP206 is required upstream for radial spoke complex recruitment.

   Evidence Human exome sequencing identifying bi-allelic truncating variants, immunostaining of patient sperm, CRISPR-Cas9 mouse knockout, sperm ultrastructure analysis, ICSI embryo development assay

   PMID:34255152

   Open questions at the time

   • Whether CFAP206 directly contacts WDR66/RSPH1 or acts indirectly was not resolved
   • Mechanism of poor ICSI outcomes beyond flagellar defects was not explored
   • No rescue experiment was performed in human or mouse systems
3. 2022 Medium

   Positioning CFAP206 specifically at the RS2 base and showing its stable docking depends on CFAP91 refined the assembly hierarchy, establishing that CFAP91 acts upstream of CFAP206 in RS2 biogenesis.

   Evidence Tetrahymena CFAP91 knockout with proteomic and fluorescence analysis of radial spoke components

   PMID:36552811

   Open questions at the time

   • Whether CFAP91–CFAP206 interaction is direct or mediated by other RS2 components was not tested
   • This dependency was shown only in Tetrahymena; conservation in vertebrates was not confirmed
   • Structural basis for CFAP206 docking at the RS2 base is unknown

• The direct protein–protein interaction network of CFAP206 on the axonemal microtubule, its structural basis of docking at RS2, and whether it plays additional roles in inner dynein arm positioning independent of radial spokes remain unresolved.
• No atomic or cryo-EM structure of CFAP206 or its complex exists
• No biochemical reconstitution of CFAP206–radial spoke interactions has been performed
• Whether CFAP206 loss contributes to primary ciliary dyskinesia beyond male infertility is undetermined