Analysis of BMP15-Induced Transcriptome in Human Granulosa Cells for the Identification of Novel Candidate Genes for Primary Ovarian Insufficiency

Primary Ovarian Insufficiency (POI) is a female fertility disorder which affects 1% of women before 40 years of age and manifests with amenorrhea, elevation of serum gonadotrophins and low estrogens. POI has a strong genetic component with incomplete penetrance. Several candidate genes have been described so far, however, its etiopathogenesis is mostly unknown. In order to discover the POI-related causative mechanisms, microarray transcriptome analysis in human granulosa cells (hGCs) stimulated with recombinant human BMP15 (rhBMP15) and next generation sequencing analysis (NGS) on the identified differentially expressed genes in a selected group of patients with POI were conducted on NGS Illumina platform. In the present study, we obtained 19 differentially expressed genes upon rhBMP15 stimulation in hGCs. Results: showed that all identified genes were upregulated and associated to pluripotency, inhibition of apoptosis, cell proliferation, BMP signaling and apoptosis. Moreover, we identified nine POI patients bearing six rare variants in 5 of the BMP15-induced genes (SAMD11, SMAD6, ID1, USP35, GPCR137C). The BMP15-induced transcriptome analysis in hGCs contributed the understanding of BMP15 role as transcriptional regulator, through the activation of transcriptional repressors, by inducing pathways inhibiting the ovarian follicle maturation, thus possibly maintaining an undifferentiated state of hGCs. These findings lead to the identification of novel candidate genes for POI.