Variants in Homologous Recombination Genes EXO1 and RAD51 Related with Premature Ovarian Insufficiency

Context: Premature ovarian insufficiency (POI) is characterized by cessation of menstruation before 40 years of age and elevated serum level of FSH (>25 IU/L). Recent studies have found a few causative genes responsible for POI enriched in meiotic recombination and DNA damage repair pathways. Objective: To investigate the role of variations in homologous recombination genes played in POI pathogenesis. Methods: The whole exome sequencing was performed in 50 POI patients with primary amenorrhea. Functional characterizations of the novel variants were carried out in budding yeast and human cell line. Results: We identified 8 missense variants in 7 homologous recombination genes, including EXO1, RAD51, RMI1, MSH5, MSH2, MSH6, and MLH1. The mutation p.Thr52Ser in EXO1 impaired the meiotic process of budding yeast and p.Glu68Gly in RAD51-altered protein localization in human cells, both of them impaired the efficiency of homologous recombination repair for DNA double-stranded breaks in human cells. Conclusions: Our study first linked the variants of EXO1 and RAD51 with POI and further highlighted the role of DNA repair genes in ovarian dysgenesis.