P-571 Mutations in FOXO3 mutation cause human premature ovarian insufficiency

Abstract

Abstract Study question Do variants in front fork transcription factor 3 (FOXO3) account for premature ovarian insufficiency (POI) in humans? Is there is a potential treatment for POI caused by FOXO3 mutations? Summary answer Heterozygous variants in FOXO3 cause human female infertility owing to POI by inducing oocyte apoptosis. What is known already Front fork transcription factor 3 (FOXO3) is a member of the forkhead box family of transcription factors. Previous study had reported that FOXO3 encodes an evolutionarily conserved primary regulator and an effective inhibitor of primordial follicle activation. The null mutants of Foxo3 or its ortholog in multiple organisms displayed POI owing to deficiencies in maintaining the ovarian reserve. However, whether FOXO3 variants can underline POI phenotype in humans were unclear, and the causal relationship has not yet been established with functional evidence. Study design, size, duration 107 primary infertility families with POI were recruited for pathogenic variants screening. The proband with and her parents were verified for FOXO3 variants. Participants/materials, setting, methods All the patients were diagnosed with POI were confirmed by clinical analyses. Exome sequencing and subsequent bioinformatic analyses were performed to screen for candidate pathogenic variants. The pathogenicity of identified variants was assessed and studied in vivo in mice carrying the equivalent mutations. Main results and the role of chance Novel heterozygous variant in FOXO3 was identified in the patient with POI. Mice modeling the Foxo3 variant identified in patients recapitulated the ovarian reserve defects of patients, confirming the pathogenicity of the identified variants. The mutation caused constitutive activation of FOXO3 lead to POI by inducing oocyte apoptosis, which will facilitate the genetic diagnosis of POI in patients and provide a potential therapeutic target for female fertility. Limitations, reasons for caution A limitation of the current study is the small sample size. More primary infertility patients with POI should be screened to enrich the pathogenetic mutations of FOXO3. Wider implications of the findings FOXO3 was detected as a novel gene underlie human POI, thus providing new targets for the molecular diagnosis and treatment. Trial registration number the National Natural Science Foundation of China (NSFC) (Grant number:82302083)