Loss-of-function mutations in<i>CEP78</i>cause male infertility in humans and mice
Xueguang Zhang, Rui Zheng, Chen Liang, Haotian Liu, Xiaozhen Zhang, Yongyi Ma, Mohan Liu, Wei Zhang, Yang Yang, Yang Yang, Man Liu, Chuan Jiang, Qingjia Ren, Yan Wang, Su‐Ren Chen, Yihong Yang, Yihong Yang, Ying Shen
Abstract
Centrosomal protein dysfunction might cause ciliopathies. However, the role of centrosomal proteins in male infertility remains poorly defined. Here, we identified a pathogenic splicing mutation in CEP78 in male infertile patients with severely reduced sperm number and motility, and the typical multiple morphological abnormalities of the sperm flagella phenotype. We further created Cep78 knockout mice, which showed an extremely low sperm count, completely aberrant sperm morphology, and approximately null sperm motility. The infertility of the patients and knockout mice could not be rescued by an intracytoplasmic sperm injection treatment. Mechanistically, CEP78 might regulate USP16 expression, which further stabilizes Tektin levels via the ubiquitination pathway. Cep78 knockout mice also exhibited impairments in retina and outer hair cells of the cochlea. Collectively, our findings identified nonfunctional CEP78 as an indispensable factor contributing to male infertility and revealed a role for this gene in regulating retinal and outer hair cell function in mice.