Pathogenic TP73 variants may lead to premature ovarian insufficiency by hyperactivating primordial follicles via the PI3K/AKT/FOXO3A pathway

Background

Premature ovarian insufficiency (POI) is characterized by primary or secondary amenorrhoea before the age of 40, alongside high levels of follicle-stimulating hormone (FSH) and reduced levels of estrogen, severely impairing female fertility. This study aimed to identify novel genetic factors contributing to POI.

Methods

We performed whole-exome sequencing and whole-genome sequencing on 93 patients with POI and 465 healthy female controls to identify variants in the TP73 gene. In-vitro culture models of mouse ovaries were utilized to evaluate the effects of identified TP73 variants on activation of primordial follicles.

Results

Two missense variants in TP73, p.R538C (NM_005427.4: c.1612C>T) and p.L560P (NM_005427.4: c.1679T>C), were identified. In mouse ovaries, overexpressing these variants significantly increased activation of primordial follicles. Transcriptomic analysis revealed 276 differentially expressed genes in the p.R538C group and 119 in the p.L560P group, with downregulation of key genes, including S100A8 and S100A9. Functional experiments demonstrated that these genes regulate the PI3K/AKT/FOXO3A signaling pathway, which was activated in mutant groups, resulting in the overactivation of primordial follicles.

Conclusion

Variants in TP73 appear to activate the PI3K/AKT/FOXO3A signaling pathway, leading to primordial follicle overactivation and accelerated depletion of the ovarian reserve, which may trigger POI. This research offers novel understanding of the genetic foundation of POI and identifies possible therapeutic targets for maintaining ovarian function.