{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTOX1 is a multifunctional transcription factor that plays a critical role in placental development by regulating trophoblast differentiation, epithelial‐mesenchymal transition, and invasion. Functional studies have shown that the risk variant Y153H can directly limit first‐trimester extravillous trophoblast invasion via upregulation of cell–cell adhesion molecules such as alpha‑T‑catenin (CTNNA3) in an Akt‐dependent manner, while differential DNA methylation and parental imprinting of STOX1 further modulate its expression during placentation. Expression analyses across gestation and in cellular models also reveal that aberrant STOX1 levels are linked with diminished cytokine (e.g. IL‑6, IL‑8) and immune regulator (e.g. CD24) production, thereby impairing utero‑placental vascular remodeling. Furthermore, emerging evidence suggests that STOX1 may participate in broader inflammatory signaling pathways, as illustrated by its association with conditions such as lumbar disc herniation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n \nDisputes regarding the genetic association of STOX1 with pre-eclampsia have been raised by several population studies. Early reports proposed mutations in STOX1 as causative for pre-eclampsia, yet subsequent investigations in Dutch, Finnish, and other cohorts found similar allele frequencies between affected and control groups, suggesting that STOX1 variants alone may not confer a dominant risk for the disorder."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n \nExperimental models overexpressing STOX1 have provided further insights into its role in mediating maternal vascular pathology. In mouse models of severe pre-eclampsia, STOX1 overexpression induces endothelial dysfunction, inflammatory gene network alterations, and cardiac hypertrophy, phenocopying the cardiovascular complications observed in pre-eclamptic women."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n \nNotably, the functions of STOX1 extend beyond placental biology into the realm of neurodegeneration. In neural cells, particularly via the STOX1A isoform, overexpression has been associated with enhanced amyloid-beta precursor processing, increased tau phosphorylation at Alzheimer’s disease–related epitopes, and downregulation of genes such as CNTNAP2, thereby implicating STOX1 in the pathogenesis of late-onset Alzheimer’s disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marie van Dijk, Jan van Bezu, Daan van Abel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The STOX1 genotype associated with pre-eclampsia leads to a reduction of trophoblast invasion by alpha-T-catenin upregulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddq152"}], "href": "https://doi.org/10.1093/hmg/ddq152"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20400461"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20400461"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Marie van Dijk, Sascha Drewlo, Cees B M Oudejans "}, {"type": "b", "children": [{"type": "t", "text": "Differential methylation of STOX1 in human placenta."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Epigenetics (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4161/epi.5.8.13084"}], "href": "https://doi.org/10.4161/epi.5.8.13084"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20716964"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20716964"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marie van Dijk, Cees B M Oudejans "}, {"type": "b", "children": [{"type": "t", "text": "STOX1: Key player in trophoblast dysfunction underlying early onset preeclampsia with growth retardation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Pregnancy (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1155/2011/521826"}], "href": "https://doi.org/10.1155/2011/521826"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21490791"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21490791"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Y M Zhao, H Y Ding, H Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Expression and significance of STOX1 in villi and placenta at different stages of normal gestation]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhonghua Yi Xue Za Zhi (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3760/cma.j.issn.0376-2491.2019.13.009"}], "href": "https://doi.org/10.3760/cma.j.issn.0376-2491.2019.13.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30955313"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30955313"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Y M Zhao, Y C Duan, J L Zhu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "[Correlation between the expression of STOX1 in placenta of patients with early onset preeclampsia]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhonghua Yi Xue Za Zhi (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3760/cma.j.issn.0376-2491.2019.21.015"}], "href": "https://doi.org/10.3760/cma.j.issn.0376-2491.2019.21.015"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31189268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31189268"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xuejun Yang, Feng Li, Daqi Xin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Investigation of the STOX1 polymorphism on lumbar disc herniation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Genomic Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mgg3.1038"}], "href": "https://doi.org/10.1002/mgg3.1038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31724315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31724315"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Zhifang Li, Guiju Zhou, Fangbiao Tao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "circ-ZUFSP regulates trophoblasts migration and invasion through sponging miR-203 to regulate STOX1 expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.06.117"}], "href": "https://doi.org/10.1016/j.bbrc.2020.06.117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32807495"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32807495"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Seyda Akin, Ergun Pinarbasi, Aslihan Esra Bildirici, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "STOX1"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " promotor region -922 T > C polymorphism is associated with Early-Onset preeclampsia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Obstet Gynaecol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/01443615.2022.2141612"}], "href": "https://doi.org/10.1080/01443615.2022.2141612"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36369889"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36369889"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Marei Sammar, Clara Apicella, Peter Altevogt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modeling Preeclampsia In Vitro: Polymorphic Variants of STOX1-A/B Genes Can Downregulate CD24 in Trophoblast Cell Lines."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms232415927"}], "href": "https://doi.org/10.3390/ijms232415927"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36555567"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36555567"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Katja Kivinen, Hanna Peterson, Leena Hiltunen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evaluation of STOX1 as a preeclampsia candidate gene in a population-wide sample."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.ejhg.5201788"}], "href": "https://doi.org/10.1038/sj.ejhg.5201788"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17290274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17290274"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "A L Berends, A M Bertoli-Avella, C J M de Groot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STOX1 gene in pre-eclampsia and intrauterine growth restriction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BJOG (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-0528.2007.01414.x"}], "href": "https://doi.org/10.1111/j.1471-0528.2007.01414.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17617193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17617193"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Virginie Rigourd, Caroline Chauvet, Sonia T Chelbi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STOX1 overexpression in choriocarcinoma cells mimics transcriptional alterations observed in preeclamptic placentas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0003905"}], "href": "https://doi.org/10.1371/journal.pone.0003905"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19079545"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19079545"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "M H Fenstad, M P Johnson, M Løset, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STOX2 but not STOX1 is differentially expressed in decidua from pre-eclamptic women: data from the Second Nord-Trondelag Health Study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Hum Reprod (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/molehr/gaq064"}], "href": "https://doi.org/10.1093/molehr/gaq064"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20643876"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20643876"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Aurélien Ducat, Ludivine Doridot, Rosamaria Calicchio, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endothelial cell dysfunction and cardiac hypertrophy in the STOX1 model of preeclampsia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep19196"}], "href": "https://doi.org/10.1038/srep19196"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26758611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26758611"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Marie van Dijk, Jan van Bezu, Ankie Poutsma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The pre-eclampsia gene STOX1 controls a conserved pathway in placenta and brain upregulated in late-onset Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-2010-1265"}], "href": "https://doi.org/10.3233/JAD-2010-1265"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20110611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20110611"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Daan van Abel, Omar Michel, Rob Veerhuis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Direct downregulation of CNTNAP2 by STOX1A is associated with Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Alzheimers Dis (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3233/JAD-2012-120472"}], "href": "https://doi.org/10.3233/JAD-2012-120472"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22728895"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22728895"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Daan van Abel, Omar Abdulhamid, Wiep Scheper, et al. "}, {"type": "b", "children": [{"type": "t", "text": "STOX1A induces phosphorylation of tau proteins at epitopes hyperphosphorylated in Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurosci Lett (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neulet.2012.09.017"}], "href": "https://doi.org/10.1016/j.neulet.2012.09.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22995177"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22995177"}]}]}]}