CCDC113の機能喪失変異は、ヒトとマウスの両方で男性不妊を引き起こす

Although genetic factors contribute significantly to male infertility, the underlying mechanisms remain incompletely understood. Coiled-coil domain-containing protein 113 (CCDC113) encodes a coiled-coil domain-containing protein critical for the assembly of cilia and flagella. Using whole-exome sequencing, we identified biallelic CCDC113 mutations in two unrelated families affected by oligoasthenoteratozoospermia. The mutations (c.901A>C; p.K301Q and c.404A>C; p.E135A) cosegregated with infertility phenotypes and were associated with defective sperm flagella. Functional analyses demonstrated that these mutations led to less stable CCDC113 protein and severely disrupted axonemal structures in spermatozoa from our three human patients. We generated Ccdc113 knockout mice, which recapitulated the human infertility phenotypes, including abnormal sperm morphology, impaired motility, and defective spermatogenesis. Importantly, one patient achieved successful pregnancy by intracytoplasmic sperm injection, highlighting the translational potential of genetic diagnostics. These findings suggest that CCDC113 is essential for male fertility and contribute to the understanding of the genetic landscape of infertility, offering novel insights into its diagnosis and management.