Abstract
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.
Highlights
Infertility is a worldwide health concern, approximately affecting 15% of couples (Jiao et al, 2021)
All the patients had asthenozoospermia, with
Sperm morphological analysis was performed for P1-P9, and revealed that less than 3.3% of spermatozoa were morphologically normal according to World Health Organization (WHO) guidelines (Table 1)
Summary
Infertility is a worldwide health concern, approximately affecting 15% of couples (Jiao et al, 2021). Cilia- and flagella-associated protein 61 (CFAP61), CFAP91 and CFAP251 are the mammalian orthologs of C. reinhardtii CSC proteins (Dymek and Smith, 2007). All these three genes showed high expressions in testis, with lower levels in the respiratory system, thyroid, female reproductive system, etc., in humans (GTEx Consortium, 2013; Fagerberg et al, 2014), suggesting a potentially important role of CSC for sperm flagella. The signals of CSC proteins CFAP61 and CFAP251 were absent from flagella of the patients These observations suggested that these variants in CFAP61 are pathogenic for MMAF and human male infertility
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