No abstract

Acephalic spermatozoa syndrome (ASS) is a rare and severe type of teratozoospermia characterized by the predominance of headless spermatozoa in the ejaculate. However, knowledge about the causative genes associated with ASS in humans is limited. Loss‐of‐function of SPATA20 has been suggested to result in the separation of the sperm head and flagellum in mice, whereas there have been no cases reporting SPATA20 variants leading to human male infertility. In this study, a nonsense mutation in SPATA20 (c.619C > T, p.Arg207*) was first identified in an ASS patient. Moreover, this variant contributed to the degradation of SPATA20 and was associated with decreased expression of SPATA6, which plays a vital role in the assembly of the sperm head‐tail conjunction in humans. In addition, the infertility caused by loss‐of‐function mutation of SPATA20 might not be rescued by intracytoplasmic sperm injection (ICSI). Collectively, our findings suggested that SPATA20 might be required for sperm head‐tail conjunction formation in humans, the nonfunction of which may lead to male infertility related to ASS. The discovery of the loss‐of‐function mutation in SPATA20 enriches the gene variant spectrum of human ASS, further contributing to improved diagnosis, genetic counseling and prognosis for male infertility.

The testis-specific adenosine deaminase domain-containing (ADAD) protein family, including ADAD1 and ADAD2, has been confirmed to be essential in mouse male fertility. However, the roles of ADAD1 and ADAD2 in human reproductive biology are unclear. Herein, whole exome sequencing (WES) was conducted for 337 infertile patients to detect pathogenic variants in ADAD1 and ADAD2. Importantly, a novel deleterious biallelic variant of NM_001159285.2:c.1408G > T (p.V470F) and NM_001159285.2:c.1418A > G (p.E473G) in ADAD1 and a pathogenic homozygous missense variant of NM_001145400.2:c.1381C > T (p.R461W) in ADAD2 were identified in this infertile cohort with frequencies of 0.29% (1/337) and 0.59% (2/337), respectively. Electron microscopy revealed an abnormal morphology and severely disorganized ultrastructure of sperm from the patients. Immunofluorescence and western blotting showed a sharp decrease in ADAD1 and ADAD2 expression in sperm from the patients. Mechanistically, bioinformatics analysis suggested that ADAD2 interacts with DNAH17. Furthermore, we demonstrated that the expression of DNAH17 was markedly downregulated in the sperm of patients harboring ADAD2 variants. In addition, the expression of several autophagy regulators was significantly disrupted in the sperm of patients harboring ADAD2 variants. In conclusion, we identified novel ADAD1 and ADAD2 variants in three infertile patients from a large infertile cohort, first providing evidence that ADAD1 and ADAD2 variants might be a candidate genetic cause of human male infertility. Moreover, an important new dimension to our understanding of the genotype–phenotype correlations between the ADAD gene family and male infertility in humans has been uncovered, providing valuable information for the genetic diagnosis of male infertility.

No abstract