Experimental and molecular support for Cfap70 as a causative gene of multiple morphological abnormalities of the flagella with male infertility

Multiple Morphological Abnormalities of the Flagella (MMAF), a severe form of asthenozoospermia, can lead to male infertility. Recent studies have implicated an association between human CFAP70 deficiency and MMAF, however, the underlying biological mechanism and supporting experimental evidence in animal models remains unclear. To address this gap, we used CRISPR/Cas9 technology to generate Cfap70-deficient mice to investigate the relationship between Cfap70 deficiency and MMAF. Our findings show that the loss of CFAP70 leads to MMAF and spermiogenesis defects. Specifically, the lack of CFAP70 impairs sperm flagellum biogenesis and head shaping during spermiogenesis. Late-step spermatids from Cfap70-deficient mouse testis exhibited club-shaped sperm heads and abnormal disassembly of the manchette. Furthermore, we found that CFAP70 interacts with DNAI1 and with DNAI2; Cfap70 deficiency also reduces the level of AKAP3 in sperm flagella, indicating that CFAP70 may participate in the flagellum assembly and transport of flagellar components. These findings provide compelling evidence implicating Cfap70 as a causative gene of MMAF, and highlight the consequences of CFAP70 loss on flagellum biogenesis.

CFAP70; MMAF; flagellum assembly; male infertility.