Variants in ZZS Complex-Associated Genes TEX11 and M1AP Are Responsible for Male Infertility and Nonobstructive...

Nonobstructive azoospermia (NOA) is the most severe form of male infertility, with genetic factors contributing to approximately 30% of cases. However, only a small fraction of all NOA cases can be explained by the current genetic findings. ZZS complex participates in meiotic recombination and is necessary for spermatogenesis.

To expand the variant spectrum of ZZS complex-associated genes in male infertility and validate the pathogenicity of identified variants in patients with NOA.

A total of 108 Chinese NOA patients were recruited, whole-exome sequencing (WES) and subsequent genetic analysis were performed to identify candidate pathogenic variants. Reverse-transcript PCR (RT-PCR) and quantitative reverse-transcript PCR (RT-qPCR) were performed to detect the mRNA expression of TEX11 and M1AP. Hematoxylin and eosin staining and immunofluorescence staining were performed on testicular sections obtained from patients' biopsies.

Five variants in ZZS complex-associated genes TEX11 and M1AP were identified from five NOA patients. These variants were either rare or absent in public human genetic databases and were predicted to be deleterious. Further functional analysis revealed that the mRNA expression levels of TEX11 and M1AP were significantly reduced in four of the affected patients. Hematoxylin and eosin staining revealed the loss of postmeiosis cells in seminiferous tubules of these patients. Immunofluorescence staining further confirmed the loss of spermatids and the zygotene arrest of meiosis.

Collectively, our findings provide compelling evidence for the pathogenicity of these five variants in the development of NOA. These results not only expand the genetic landscape of NOA but also offer valuable insights for future clinical screening and diagnostic strategies.