Department of Obstetrics/Gynecology, Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China.
Sci Adv. 2022 Oct 7;8(40):eabn0968. doi: 10.1126/sciadv.abn0968.
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 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 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. 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.
中心体蛋白功能障碍可能导致纤毛病。然而，中心体蛋白在男性不育中的作用仍未明确界定。在这里，我们在严重少精子症和运动能力下降的男性不育患者中发现了一个在 中的致病剪接突变，以及精子鞭毛表型的典型多种形态异常。我们进一步创建了 敲除小鼠，其显示出极低的精子数、完全异常的精子形态和几乎为零的精子运动能力。患者和敲除小鼠的不育症不能通过胞质内精子注射治疗来挽救。从机制上讲，CEP78 可能调节 USP16 的表达，进而通过泛素化途径稳定 Tektin 水平。 敲除小鼠也表现出视网膜和耳蜗外毛细胞的损伤。总之，我们的研究结果确定了功能失调的 CEP78 是导致男性不育的不可或缺的因素，并揭示了该基因在调节小鼠视网膜和外毛细胞功能中的作用。
