A Homozygous CCDC146 Mutation Cause Oligo-astheno-terato-zoospermia in Human and Mice

Infertility is a significant health concern. Crucial factors directly linked to male fertility include the number and quality of sperm. Oligo-astheno-terato-zoospermia (OAT), characterized by reduced sperm motility and concentration in semen, and morphological abnormalities in sperm heads and flagella. Although variants in several genes have been identified in OAT cases, the genetic etiologies and pathogenetic mechanisms of OAT remain inadequately understood. In this study, we identified a homozygous nonsense mutation (c.916C>T p.Arg306*) in the Coiled-Coil Domain Containing 146 (CCDC146) gene in an infertile man with OAT. The mutation in CCDC146 results in the production of a truncated CCDC146 protein (1-305 aa), retaining only two out of five coiled-coil domains. To validate the pathogenicity of the CCDC146 mutation, we generated a mouse model (Ccdc146 mut/mut) with a similar mutation to that of the patient. Consistently, the Ccdc146 mut/mut mice exhibited infertility characterized by significantly reduced sperm counts, diminished motility, and multiple defects in sperm heads and flagella. The levels of axonemal proteins, including DNAH17, DNAH1, and SPAG6, were significantly reduced in sperm of Ccdc146 mut/mut mice. Moreover, we observed that both human and mouse CCDC146 could interact with intraflagellar transport protein 20 (IFT20). However, the mutated human and mouse CCDC146 lost this interaction, leading to the degradation of IFT20. Collectively, our findings indicate that a novel homozygous nonsense mutation in CCDC146 is deleterious and causes male infertility, potentially by disrupting axonemal protein transportation. These findings offer valuable insights for genetic counseling regarding CCDC146 mutant-associated infertility in human males.