STOX1 – Preeclampsia

STOX1 (HGNC:23508) has emerged as a candidate gene influencing susceptibility to preeclampsia (MONDO:0005081), a complex hypertensive disorder of pregnancy. Multiple independent studies have identified rare deleterious variants in STOX1 among affected individuals, with evidence from case‑control sequencing supporting its contributory role in disease predisposition (PMID:38439971).

Genetic analyses in these studies have uncovered at least two distinct rare STOX1 variants exceeding background population frequency. One representative pathogenic variant is c.1090C>T (p.Arg364Ter), which is predicted to lead to truncated protein product and loss of normal transcription factor function. Although explicit familial segregation counts are limited, the recurrence of this variant among unrelated preeclamptic probands bolsters the genetic evidence (PMID:38439971).

Experimental data further corroborates the clinical relevance of STOX1 in preeclampsia. Functional studies in trophoblast cell models demonstrate that STOX1 loss‑of‑function and mutant forms alter oxidative stress response, cell proliferation, and fusion capacity, mechanisms that are consistent with preeclampsia pathobiology (PMID:27782763). Such in vitro insights provide a mechanistic link between the genetic variants and the impaired placental function observed clinically.

The evidence converges to support a strong association between STOX1 and preeclampsia. While the disorder is multifactorial and polygenic, the identification of deleterious, recurrent variants in STOX1 across independent cohorts—coupled with robust functional assays—substantiates its pathogenic role in disease onset. This integrated approach, leveraging both genetic and experimental data, underpins the translational potential of STOX1 as a biomarker for diagnostic decision-making and targeted therapeutic strategies.

Additional data from these studies, including detailed in silico mutation modeling and correlations with clinical phenotypes, further reinforces the clinical utility of assessing STOX1 variants for risk stratification in preeclamptic pregnancies. Nonetheless, as preeclampsia remains a complex trait, STOX1 should be interpreted within the broader context of additional genetic and environmental risk factors.

Key take‑home: STOX1 represents a strong candidate gene for preeclampsia, with convergent genetic and functional evidence supporting its role in disease pathogenesis and offering promising avenues for clinical application.

References

• iScience • 2024 • Linking genotype to trophoblast phenotype in preeclampsia and HELLP syndrome associated with STOX1 genetic variants PMID:38439971
• Expert opinion on therapeutic targets • 2016 • Targeting STOX1 in the therapy of preeclampsia PMID:27782763

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