CFAP65, or cilia and flagella associated protein 65, is a fundamental protein in the development and formation of ciliated flagella. It is highly expressed in the testis and plays crucial roles in sperm development, with its associated pathways likely involving proteostatic systems during acrosome formation, manchette organization, and mitochondrial sheath (MS) assembly [1,2]. Genetic models, such as gene-knockout mouse models, have been essential in studying its functions.

In Cfap65 knockout (Cfap65-/-) mice, male mice exhibit severe asthenoteratospermia due to morphologically defective sperm heads and flagella. The sperm heads in step 9 spermatids show hyper-constriction along with abnormal manchette development, and acrosome biogenesis is abnormal in the maturation phase. Flagellar elongation is also severely affected, characterized by disrupted MS assembly. Additionally, proteomic analysis reveals a disrupted proteostatic system in the absence of CFAP65. Endogenous immunoprecipitation and immunostaining experiments suggest that CFAP65 may form a cytoplasmic protein network [1]. In humans, biallelic mutations in CFAP65 cause multiple morphological abnormalities of the sperm flagella (MMAF), leading to severely decreased sperm motility and male infertility [3,4,5,6].

In conclusion, Cfap65 is essential for sperm head shaping, acrosome biogenesis, and MS assembly during spermiogenesis. The study of Cfap65-knockout mouse models has significantly contributed to understanding male infertility caused by MMAF, providing insights into the complex molecular mechanisms underlying sperm development [1,3,4,5,6].

References:

1. Wang, Weili, Tian, Shixong, Nie, Hongchuan, Zhang, Feng, Tan, Yue-Qiu. . CFAP65 is required in the acrosome biogenesis and mitochondrial sheath assembly during spermiogenesis. In Human molecular genetics, 30, 2240-2254. doi:10.1093/hmg/ddab185. https://pubmed.ncbi.nlm.nih.gov/34231842/

2. Li, Yunze, Ran, Dongmei, Basnet, Shiva, Peng, Yifan, Du, Changzheng. 2024. The expression and clinical significance of CFAP65 in colon cancer. In BMC gastroenterology, 24, 222. doi:10.1186/s12876-024-03317-5. https://pubmed.ncbi.nlm.nih.gov/38992586/

3. Li, Weiyu, Wu, Huan, Li, Fuping, Cao, Yunxia, Zhang, Feng. 2019. Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice. In Journal of medical genetics, 57, 89-95. doi:10.1136/jmedgenet-2019-106344. https://pubmed.ncbi.nlm.nih.gov/31501240/

4. Wang, Weili, Tu, Chaofeng, Nie, Hongchuan, Lin, Ge, Tan, Yue-Qiu. 2019. Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations. In Journal of medical genetics, 56, 750-757. doi:10.1136/jmedgenet-2019-106031. https://pubmed.ncbi.nlm.nih.gov/31413122/

5. Zhang, Xueguang, Shen, Ying, Wang, Xiang, Zhang, Chaoliang, Yang, Yihong. 2019. A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella. In Clinical genetics, 96, 541-548. doi:10.1111/cge.13644. https://pubmed.ncbi.nlm.nih.gov/31571197/

6. Jiang, Chuan, Zhang, Xue-Guang, Wang, Xiang, Zhang, Chao-Liang, Yang, Yi-Hong. . [Homozygous CFAP65 mutation induces multiple morphological abnormalities of sperm flagella: A preliminary genetic study]. In Zhonghua nan ke xue = National journal of andrology, 27, 595-602. doi:. https://pubmed.ncbi.nlm.nih.gov/34914225/