Linking genotype to trophoblast phenotype in preeclampsia and HELLP syndrome associated with STOX1 genetic variants

• Published in: iScience 2024-03, Vol.27 (3), p.109260-109260, Article 109260
• Main Authors: Costa, Lorenzo, Bermudez-Guzman, Luis, Benouda, Ikram, Laissue, Paul, Morel, Adrien, Jiménez, Karen Marcela, Fournier, Thierry, Stouvenel, Laurence, Méhats, Céline, Miralles, Francisco, Vaiman, Daniel
• Format: Article
• Language: English
• Subjects: Cell biology; Human Genetics; Life Sciences; Phenotyping; Pregnancy; Transcriptomics
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.109260

Preeclampsia is a major hypertensive pregnancy disorder with a 50% heritability. The first identified gene involved in the disease is STOX1, a transcription factor, whose variant Y153H predisposes to the disease. Two rare mutations were also identified in Colombian women affected by the hemolysis, elevated liver enzyme, low platelet syndrome, a complication of preeclampsia (T188N and R364X). Here, we explore the effects of these variants in trophoblast cell models (BeWo) where STOX1 was previously invalidated. We firstly showed that STOX1 knockout alters response to oxidative stress, cell proliferation, and fusion capacity. Then, we showed that mutant versions of STOX1 trigger alterations in gene profiles, growth, fusion, and oxidative stress management. The results also reveal alterations of the STOX interaction with DNA when the mutations affected the DNA-binding domain of STOX1 (Y153H and T188N). We also reveal here that a major contributor of these effects appears to be the E2F3 transcription factor. [Display omitted] •The KO of STOX1 in BeWo cells induces a higher fusogenic capacity•STOX1 acts through the regulation of the E2F3 transcription factor•The R364X mutant has altered oxidative stress, proliferation, and fusion•hCG secretion is altered in BeWo cells overexpressing STOX1 mutants Pregnancy; Human Genetics; Phenotyping; Cell biology; Transcriptomics