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

Lorenzo Costa; Luis Bermudez-Guzman; Ikram Benouda; Paul Laissue; Adrien Morel; Karen Marcela Jiménez; Thierry Fournier; Laurence Stouvenel; Céline Méhats; Francisco Miralles; Daniel Vaiman

doi:10.1016/j.isci.2024.109260

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

iScience. 2024 Feb 16;27(3):109260. doi: 10.1016/j.isci.2024.109260. eCollection 2024 Mar 15.

Authors

Affiliations

¹ Institut Cochin, Team 'From Gametes To Birth', INSERM U1016, CNRS UMR8104, Université de Paris, 24 rue du Faubourg St Jacques, 75014 Paris, France.
² Department of Human Genetics, University of Heidelberg, Heidelberg, Germany.
³ CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
⁴ Biopas Laboratoires, Orphan Diseases Unit, BIOPAS GROUP, Bogotá 111111, Colombia.
⁵ Universidad Del Rosario, School of Medicine and Health Sciences, Center for Research in Genetics and Genomics (CIGGUR), Institute of Translational Medicine (IMT), Bogotá, Colombia.
⁶ Université Paris Cité, INSERM, UMR-S1139, Pathophysiology & Pharmacotoxicology of the Human Placenta, Pre- & Post-natal Microbiota (3PHM), 75006 Paris, France.

Abstract

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.

Keywords: Cell biology; Human Genetics; Phenotyping; Pregnancy; Transcriptomics.