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By using complementary  in vitro  and  ex vivo  approaches, we show that the risk allele (Y153H) of the pre-eclampsia susceptibility gene  STOX1  negatively regulates trophoblast invasion by upregulation of the cell–cell adhesion protein α-T-catenin ( CTNNA3 ). This is effectuated at the crucial epithelial–mesenchymal transition of proliferative into invasive extravillous trophoblast. This STOX1– CTNNA3  interaction is direct and includes Akt-mediated phosphorylated control of nucleo-cytoplasmic shuttling and ubiquitin-mediated degradation as shared with the  FOX  multigene family. This, to our knowledge, is the first time a genotype associated with pre-eclampsia has been shown to directly limit first trimester extravillous trophoblast invasion, the earliest hallmark of pre-eclampsia.

The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by α-T-catenin upregulation