SPATA22 heterozygous variants drive premature ovarian insufficiency: mechanism of granulosa cells dysfunction and therapeutic potential of N-acetylcysteine (NAC) treatment.

BACKGROUND

Premature ovarian insufficiency (POI) is a prevalent reproductive endocrine disorder, with genetic pathogenesis remaining largely elusive. SPATA22 is a known meiotic regulator in germ cells, while its function in ovarian somatic granulosa cells (GCs) and causal link to POI remain entirely uncharacterized.

METHODS

Whole-exome sequencing (WES) was performed in 608 idiopathic POI patients, with Sanger sequencing validating the identified SPATA22 variants in the affected pedigree. Pathogenicity and therapeutic potential were verified via in vivo phenotypic analysis of Spata22+/- mice, in vitro functional assays of primary mouse GCs, oocyte-GCs co-culture, and in vitro fertilization (IVF) embryo development assays, with N-acetylcysteine (NAC) intervention.

RESULTS

Two heterozygous pathogenic SPATA22 variants were identified in a POI pedigree with four affected infertile individuals. SPATA22 defects caused GCs dysfunction, accumulated DNA damage, oxidative stress, ovarian insufficiency, impaired fertility in mice. The antioxidant NAC effectively rescued GCs defects, and partially restored Spata22+/- mice fertility, ovarian function, co-cultured oocyte competence and embryo development potential.

CONCLUSIONS

The present study identifies SPATA22 as a causative gene for human POI, provides the first definitive demonstration of a non-canonical somatic function of SPATA22 in GCs, and offers a promising therapeutic strategy for SPATA22-related POI.