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Asthenoteratozoospermia is a common cause of male infertility. To further define the genetic causes underlying asthenoteratozoospermia, we performed whole-exome sequencing in a cohort of Han Chinese men with asthenoteratozoospermia. Homozygous deleterious variants of MYCBPAP were first identified in two unrelated Chinese cases. Replication analyses in a French cohort revealed an additional asthenoter-atozoospermia-affected case harboring a homozygous nonsense variant in MYCBPAP. All of the identified MYCBPAP variants were absent or extremely rare in the public human genome databases. Further functional assays indicated remarkably reduced abundance of MYCBPAP in the spermatozoa from MYCBPAP-associated cases. Subsequently, we generated a Mycbpap knockout (Mycbpap -/- ) mouse model, which also exhibited male infertility with reduced sperm motility and abnormal morphologies in sperm heads and flagella. Further investigations demonstrated that Mycbpap -/- male mice presented disrupted acrosome biogenesis and abnormally elongated manchette during spermiogenesis. Intriguingly, proteomic analyses indicated that the proteins related to spermatogenesis, acrosomal and flagellar functions were significantly down-regulated in the testes from Mycbpap -/- male mice. Endogenous immunoprecipitation combined with mass spectrometry revealed interactions of MYCBPAP with a ribosome elimination related protein ARMC3 and central apparatus proteins including CFAP65 and CFAP70. Furthermore, MYCBPAP-associated male infertility in humans and mice could be partially overcome by using intracytoplasmic sperm injections. Collectively, these findings illustrate the essential role of MYCBPAP in normal spermatogenesis and homozygous deleterious variants in MYCBPAP can be considered as a genetic diagnostic indicator for infertile men with asthenoteratozoospermia. Our study will provide effective guidance for genetic counseling, clinical diagnosis and assisted reproduction treatments of MYCBPAP-associated male infertility., Competing Interests: Compliance and ethics. The authors declare that they have no conflict of Interest. Ethics approval for this study was obtained from the ethics committees of all participating institutions, and written informed consents were secured from all participants. All animal experiments were carried out in accordance with the recommendations of the US National Institutes of Health’s Guide for the Care and Use of Laboratory Animals and approved by the animal ethics committee at Fudan University., (© 2024. Science China Press.)

Spermatogenesis defects concern millions of men worldwide, yet the vast majority remains undiagnosed. Here we report men with primary infertility due to multiple morphological abnormalities of the sperm flagella with severe disorganization of the sperm axoneme, a microtubule-based structure highly conserved throughout evolution. Whole-exome sequencing was performed on 78 patients allowing the identification of 22 men with bi-allelic mutations in DNAH1 (n = 6), CFAP43 (n = 10), and CFAP44 (n = 6). CRISPR/Cas9 created homozygous CFAP43/44 male mice that were infertile and presented severe flagellar defects confirming the human genetic results. Immunoelectron and stimulated-emission-depletion microscopy performed on CFAP43 and CFAP44 orthologs in Trypanosoma brucei evidenced that both proteins are located between the doublet microtubules 5 and 6 and the paraflagellar rod. Overall, we demonstrate that CFAP43 and CFAP44 have a similar structure with a unique axonemal localization and are necessary to produce functional flagella in species ranging from Trypanosoma to human.