CCDC146, a coiled-coil domain-containing protein, is predominantly expressed in the testes and is essential for sperm flagellum biogenesis and male fertility. It functions in microtubule-related processes as it is associated with centrosomes and microtubule-based organelles. It may be involved in pathways related to intraflagellar transport, which is crucial for the formation and maintenance of cilia and flagella [1,2].

Gene knockout studies in mice have been pivotal in understanding CCDC146's function. Ccdc146 knockout male mice are infertile. The knockout impairs spermiogenesis due to flagellum and manchette organization defects, leading to a multiple morphological abnormalities of the flagella (MMAF)-like phenotype. CCDC146 interacts with CCDC38, CCDC42, IFT88, and IFT20. Its knockout decreases the protein levels of ODF2, IFT88, and IFT20 [1]. In humans, pathogenic bi-allelic mutations in CCDC146 are identified in infertile patients with MMAF, and a homozygous nonsense mutation in CCDC146 in an infertile male patient with oligoasthenoteratozoospermia (OAT) was found. The mouse model with a similar mutation showed reduced sperm counts, motility, and axonemal protein levels, and the interaction between CCDC146 and IFT20 was lost in the mutated version [2,3].

In conclusion, CCDC146 is essential for sperm flagellum biogenesis and male fertility. The gene knockout mouse models have revealed its role in male infertility-related diseases such as MMAF and OAT, highlighting its significance in understanding the genetic etiology of these conditions.

References:

1. Ma, Yanjie, Wu, Bingbing, Chen, Yinghong, Zhao, Jianguo, Li, Wei. 2023. CCDC146 is required for sperm flagellum biogenesis and male fertility in mice. In Cellular and molecular life sciences : CMLS, 81, 1. doi:10.1007/s00018-023-05025-x. https://pubmed.ncbi.nlm.nih.gov/38038747/

2. Muroňová, Jana, Kherraf, Zine Eddine, Giordani, Elsa, Ray, Pierre F, Arnoult, Christophe. 2024. Lack of CCDC146, a ubiquitous centriole and microtubule-associated protein, leads to non-syndromic male infertility in human and mouse. In eLife, 12, . doi:10.7554/eLife.86845. https://pubmed.ncbi.nlm.nih.gov/38441556/

3. Ye, Jing-Wei, Abbas, Tanveer, Zhou, Jian-Teng, Shi, Qing-Hua, Shi, Bao-Lu. . Homozygous CCDC146 mutation causes oligoasthenoteratozoospermia in humans and mice. In Zoological research, 45, 1073-1087. doi:10.24272/j.issn.2095-8137.2024.019. https://pubmed.ncbi.nlm.nih.gov/39245651/