Pathogenic variants in TSC2 might cause premature ovarian insufficiency through activated mTOR induced hyperactivation of primordial follicles

ObjectiveTo investigate the role of tuberous sclerosis complex (TSC) genes, including TSC1 and TSC2, in the pathogenesis of human premature ovarian insufficiency (POI).DesignGenetic and functional study.SettingUniversity-based reproductive medical center.Patient(s)Six patients from a cohort of 1,030 cases with idiopathic POI.Intervention(s)Variants in TSC1 and TSC2 were screened through the largest in-house database of whole exome sequencing performed in 1,030 patients with idiopathic POI. The pathogenic effects of the variants were further verified by functional studies.Main Outcome Measure(s)TSC1 or TSC2 variant and functional characteristics.Result(s)Five pathogenic heterozygous variants in TSC2 were identified in 6 patients with POI. Functional studies showed these variants impaired the repressive effect of TSC2 on mammalian target of rapamycin (mTOR) pathway by disrupting the formation of TSC complex or its GTPase-activating protein activity. Furthermore, in vitro ovarian culture assay showed that TSC2 p.R98Q led to hyperactivation of mTOR pathway thereby triggering primordial follicle activation.Conclusion(s)The present study identified pathogenic variants of TSC2 in patients with POI, firstly suggested defective TSC/mTOR pathway mediated hyperactivation of primordial follicle participating in the pathogenesis of POI, giving insights into new targets of genetic counseling and clinical prevention for POI. Considering the pivotal role of TSC2 variants in diagnosis of TSC syndrome, the present study also highlighted the importance of history collection and long-term follow-up for the TSC2 variants carriers. To investigate the role of tuberous sclerosis complex (TSC) genes, including TSC1 and TSC2, in the pathogenesis of human premature ovarian insufficiency (POI). Genetic and functional study. University-based reproductive medical center. Six patients from a cohort of 1,030 cases with idiopathic POI. Variants in TSC1 and TSC2 were screened through the largest in-house database of whole exome sequencing performed in 1,030 patients with idiopathic POI. The pathogenic effects of the variants were further verified by functional studies. TSC1 or TSC2 variant and functional characteristics. Five pathogenic heterozygous variants in TSC2 were identified in 6 patients with POI. Functional studies showed these variants impaired the repressive effect of TSC2 on mammalian target of rapamycin (mTOR) pathway by disrupting the formation of TSC complex or its GTPase-activating protein activity. Furthermore, in vitro ovarian culture assay showed that TSC2 p.R98Q led to hyperactivation of mTOR pathway thereby triggering primordial follicle activation. The present study identified pathogenic variants of TSC2 in patients with POI, firstly suggested defective TSC/mTOR pathway mediated hyperactivation of primordial follicle participating in the pathogenesis of POI, giving insights into new targets of genetic counseling and clinical prevention for POI. Considering the pivotal role of TSC2 variants in diagnosis of TSC syndrome, the present study also highlighted the importance of history collection and long-term follow-up for the TSC2 variants carriers.