A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly

Abstract Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of male infertility, linked to defective spermiogenesis. Several flagella-associated proteins have been identified as crucial for the proper organization of the sperm flagellar axoneme. We identify a novel homozygous mutation in the CFAP58 gene (c.562C > T, p. R188*) that co-segregates with the multiple morphological abnormalities of the flagella (MMAF) phenotype in two unrelated consanguineous families from Pakistan. To validate the pathogenicity of this mutation, we developed a Cfap58 mutant mouse model to mimic the patient mutation. The Cfap58M/M mice exhibited infertility and recapitulated the MMAF phenotype observed in human patients. Transmission electron microscopy (TEM) analysis revealed the absence of the central pair (CP) of microtubules in the axonemal structure of sperm flagella. Further analysis demonstrated that the CFAP58 mutation disrupts CP assembly during spermiogenesis, leading to disorganization of axonemal proteins in both human and mouse sperm flagella. Our findings underscore the essential and conserved role of CFAP58 in sperm axoneme assembly and suggests that CFAP58 can serve as a genetic screening marker in the diagnosis and genetic counseling of MMAF and male infertility.