Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility

Multiple morphological abnormalities of the flagella (MMAF) can lead to male infertility due to impaired sperm motility and morphology. Calmodulin- and spoke-associated complex (CSC) are known for their roles in radial spoke (RS) assembly and ciliary motility in Chlamydomonas, while the role of cilia- and flagella-associated protein 61 (CFAP61), a mammalian ortholog of the CSC subunits, in humans is yet unknown. Here, we recruited three unrelated Pakistani families comprising of 11 infertile male patients diagnosed with MMAF. CFAP61 variants, c.451_452del (p.I151Nfs*4) in family 1 and c.847C > T (p.R283*) in family 2 and 3, were identified recessively co-segregating with the MMAF phenotype. Transmission electron microscopy analyses revealed severe disorganized axonemal ultrastructures, and missings of central pair, RSs, and inner dynein arms were also observed and confirmed by immunofluorescence staining in spermatozoa from patients. CFAP61 and CFAP251 signals were absent from sperm tails of the patients, which suggested the loss of functional CSC in sperm flagella. Altogether, our findings report that homozygous variants in CFAP61 are associated with MMAF and male infertility, demonstrating the essential role of this gene in normal sperm flagellum structure in humans.

Automated summary

In this study, homozygous variants in CFAP61 were found to be associated with Multiple morphological abnormalities of the flagella (MMAF) and male infertility. The study revealed severe disorganization of axonemal ultrastructures in spermatozoa from patients, along with the absence of certain key components. These findings emphasize the essential role of the CFAP61 gene in normal sperm flagellum structure in humans.