Homozygous Loss of Septin12, but not its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure

Haixia Chen; Peng Li; Xiaoling Du; Yiding Zhao; Lingling Wang; Ye Tian; Xueru Song; Ling Shuai; Xiaohong Bai; Lingyi Chen

doi:10.3389/fcell.2022.850052

Homozygous Loss of Septin12, but not its Haploinsufficiency, Leads to Male Infertility and Fertilization Failure

Front Cell Dev Biol. 2022 Apr 25:10:850052. doi: 10.3389/fcell.2022.850052. eCollection 2022.

Authors

Affiliations

¹ Tianjin Key Laboratory of Female Reproductive Health and Eugenics, Reproductive Medicine Center, Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China.
² Tianjin Union Medical Center, State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Sciences, Frontiers Science Center for Cell Responses, National Demonstration Center for Experimental Biology Education and College of Life Sciences, Nankai University, Institute of Translational Medicine, Tianjin, China.
³ State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.

Abstract

The SEPTIN12 gene has been associated with male infertility. Male Septin12 ^+/- chimera mice were infertile, supporting the prevailing view that SEPTIN12 haploinsufficiency causes male infertility. In this study, we identified a heterozygous mutation on SEPTIN12, c.72C>A (p.Cys24Ter) in the male partner of a patient couple, who had a previous fertilization failure (FF) after intracytoplasmic sperm injection (ICSI) and became pregnant after ICSI together with artificial oocyte activation (AOA). To investigate the role of SEPTIN12 in FF and oocyte activation, we constructed Septin12 knockout mice. Surprisingly, Septin12 ^-/- male mice, but not Septin12 ^+/- male mice, are infertile, and have reduced sperm counts and abnormal sperm morphology. Importantly, AOA treatment enhances the 2-cell embryo rate of ICSI embryos injected with Septin12 ^-/- sperm, indicating that FF caused by male Septin12 deficiency is overcome by AOA. Mechanistically, loss of PLCζ around the acrosome might be the reason for FF of Septin12 ^-/- sperm. Taken together, our data indicated that homozygous knockout of Septin12, but not Septin12 haploinsufficiency, leads to male infertility and FF.

Keywords: SEPTIN12; calcium oscillation; fertilization failure; male infertility; oocyte activation.