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

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=10

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.850052

DOI=10.3389/fcell.2022.850052

ISSN=2296-634X

ABSTRACT=<p>The <italic>SEPTIN12</italic> gene has been associated with male infertility. Male <italic>Septin12</italic><sup>+/−</sup> chimera mice were infertile, supporting the prevailing view that <italic>SEPTIN12</italic> haploinsufficiency causes male infertility. In this study, we identified a heterozygous mutation on <italic>SEPTIN12</italic>, c.72C&gt;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 <italic>SEPTIN12</italic> in FF and oocyte activation, we constructed <italic>Septin12</italic> knockout mice. Surprisingly, <italic>Septin12</italic><sup>−/−</sup> male mice, but not <italic>Septin12</italic><sup>+/−</sup> 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 <italic>Septin12</italic><sup><italic>−/−</italic></sup> sperm, indicating that FF caused by male <italic>Septin12</italic> deficiency is overcome by AOA. Mechanistically, loss of PLCζ around the acrosome might be the reason for FF of <italic>Septin12</italic><sup><italic>−/−</italic></sup> sperm. Taken together, our data indicated that homozygous knockout of <italic>Septin12</italic>, but not <italic>Septin12</italic> haploinsufficiency, leads to male infertility and FF.</p>