CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful...

Multiple morphological abnormalities of the flagella (MMAF) are a recessive cause of male infertility characterized by severe flagellar defects. CFAP58 is a known MMAF-associated gene, but its underlying molecular mechanism remains unclear.

To define the molecular function of CFAP58 and how its loss leads to MMAF.

Whole-exome sequencing was performed to identify pathogenic variants in three unrelated infertile men. Sperm motility, protein expression, localization, and ultrastructure were evaluated using CASA, western blotting, immunofluorescence, and transmission electron microscopy. Intracytoplasmic sperm injection (ICSI) was performed to assess fertilization capacity.

Three novel CFAP58 loss-of-function variants were identified. CFAP58-deficient sperm displayed classic MMAF phenotypes with severely impaired motility. Ultrastructural analysis showed disruption of the "9 + 2" axoneme, loss of the central pair, and disorganization of accessory structures. Mechanistically, CFAP58 may contribute to the structural connection between radial spokes (RS) and doublet microtubules (DMTs); its absence leads to RS damage and axonemal instability. Notably, despite profound structural defects, fertilization and pregnancy were successfully achieved through ICSI using CFAP58-deficient sperm. DISCUSSION AND CONCLUSION: CFAP58 deficiency is associated with RS-DMT interface abnormalities and defective flagellar assembly, potentially contributing to MMAF. However, the retained fertilization competence of these sperm through ICSI underscores that assisted reproductive technology constitutes an effective therapeutic strategy for affected patients.