<i>CEP131</i> Deficiency Leads to Multiple Morphological Abnormalities of the Sperm Flagellum‐Associated Male Infertility via Impaired CEP290 Interaction

BACKGROUND: Multiple morphological abnormalities of the sperm flagellum (MMAF) is a phenotypically severe but genetically heterogeneous subtype of asthenoteratozoospermia. The genetic etiology of MMAF patients is still largely unknown. OBJECTIVES: To identify novel genetic factors contributing to MMAF-related male infertility and evaluate the therapeutic efficacy of intracytoplasmic sperm injection in affected patients. MATERIALS AND METHODS: A cohort of 124 infertile males with typical MMAF were recruited. Novel pathogenic variants were identified through whole-exome sequencing and Sanger sequencing. Bioinformatics analysis revealed the effects of these variants. Sperm morphology and ultrastructural defects were observed using Papanicolaou staining and transmission electron microscopy. The expression and localization of relevant proteins were analyzed by immunofluorescence. CEP131 interaction proteins were identified via co-immunoprecipitation. The impact of pathogenic variants on fertilization and embryonic development was evaluated by intracytoplasmic sperm injection. RESULTS: We identified bi-allelic CEP131 mutations in four patients with MMAF for the first time. These mutations are highly deleterious and rare in the human population. These mutations affect the expression of centrosome-related proteins CEP131, CEP290, and PCM1, and lead to centrosomal malformations. CEP131 interacts with CEP290 to regulate the formation of the sperm flagellum. Unfortunately, two patients were treated with ICSI but none of them obtained transferable blastocysts due to embryonic development arrest. CONCLUSION: This study provides the first evidence that CEP131 mutations cause MMAF and male infertility due to impairing sperm flagellar formation by interacting with CEP290. ICSI treatment showed a poor prognosis in our cases due to embryonic development arrest.