A homozygous loss‐of‐function mutation in CEP250 is associated with acephalic spermatozoa syndrome in humans

Abstract Background The presence of predominantly headless sperm in semen is a hallmark of acephalic spermatozoa syndrome, which is primarily caused by gene mutations in humans. Purpose To identify genetic causes for acephalic spermatozoa syndrome. Methods Polymerase chain reaction and Sanger sequencing were performed to define mutations in SUN5 and PMFBP1 . Whole‐exome sequencing was performed on the patients to identify pathogenic mutations for infertility. Western blotting and immunofluorescence analysis detected the expression level and localization of CEP250. Co‐immunoprecipitation detected the protein‐protein interactions. Cep250‐KI mice were generated by the CRISPR‐Cas9 system. Results Here, 10 patients diagnosed with acephalic spermatozoa syndrome were recruited, and a homozygous loss‐of‐function mutation in CEP250 (NM_007186: c. 4710_4723del: p. E1570fs*39) was identified from a consanguineous Han Chinese family. Immunofluorescence experiments revealed a decreased CEP250 signal in the neck region of the patient's sperm compared with the normal. Co‐immunoprecipitation results indicated reduced interaction between SUN5/PMFBP1 and mutant CEP250 compared with the wild‐type, possibly due to the absence of complete 2272–2442 amino acids. Besides, the patient can be effectively treated with intracytoplasmic sperm injections. Nevertheless, Cep250‐KI male mice exhibit non‐obstructive azoospermia, which indicates the different functions in CEP250 between human and mouse spermatogenesis. Conclusion Collectively, CEP250 may represent a novel pathogenic gene for acephalic spermatozoa syndrome in humans, and we provide precise genetic diagnosis and treatment strategies for the patient.