Bi-allelic variants in cause male infertility with asthenoteratozoospermia in humans and mice.

Study Question: Are there other pathogenic genes for asthenoteratozoospermia (AT)?

Summary Answer: is a novel candidate gene for AT in humans and mice.

What Is Known Already: AT is a major cause of male infertility. Several genes underlying AT have been reported; however, the genetic aetiology remains unknown in a majority of affected men.

Study Design Size Duration: A total of 432 patients with AT were recruited in this study. mutations were identified by whole-exome sequencing (WES). knockout mice were generated using the genome editing tool. The morphology and motility of sperm from knockout mice were investigated. The entire study was conducted over 3 years.

Participants/materials Setting Methods: WES was performed on 432 infertile patients with AT. In addition, two lines of knockout mice were generated. Haematoxylin and eosin (H&E) staining, transmission electron microscopy (TEM), immunostaining, and computer-aided sperm analysis (CASA) were performed to investigate the morphology and motility of the spermatozoa. ICSI was used to overcome the infertility of one patient and of the knockout mice.

Main Results And The Role Of Chance: biallelic variants were identified in three patients from three unrelated families. H&E staining revealed various morphological abnormalities in the flagella of sperm from the patients, and TEM and immunostaining further showed the loss of the central pair of microtubules, a dislocated mitochondrial sheath and fibrous sheath, as well as a partial absence of the inner dynein arms. In addition, the two knockout mouse lines demonstrated AT. One patient and the knockout mice showed good treatment outcomes after ICSI.

Large Scale Data: N/A.

Limitations Reasons For Caution: This is a preliminary report suggesting that defects in can lead to asthenoteratozoospermia in humans and mice. The pathogenic mechanism needs to be further examined in a future study.

Wider Implications Of The Findings: Our findings show that is a novel candidate gene for AT in humans and mice and provide crucial insights into the biological underpinnings of this disorder. The findings may also be beneficial for counselling affected individuals.

Study Funding/competing Interests: This work was supported by grants from National Natural Science Foundation of China (82201773, 82101961, 82171608, 32322017, 82071697, and 81971447), National Key Research and Development Program of China (2022YFC2702604), Scientific Research Foundation of the Health Committee of Hunan Province (B202301039323, B202301039518), Hunan Provincial Natural Science Foundation (2023JJ30716), the Medical Innovation Project of Fujian Province (2020-CXB-051), the Science and Technology Project of Fujian Province (2023D017), China Postdoctoral Science Foundation (2022M711119), and Guilin technology project for people's benefit (20180106-4-7). The authors declare no competing interests.