Sequence variant of POU5F1 as risk factor for premature ovarian insufficiency by mis-regulating transcription

Premature ovarian insufficiency (POI) is a severe disease that leads to female infertility. Previous studies have suggested that genetic mutations are one of the causes of POI. In order to explore novel pathogenic genes associated with POI, we performed whole-exome sequencing on 111 patients with POI. A rare stop codon variant (NM_002701: c.876 T > G: p.Y292*) of the POU5F1 gene was identified in one patient. The POU5F1 gene encodes the OCT4 protein, which has been reported to play an essential role in the specification and proliferation of primordial germ cells. In this study, we constructed wild-type (WT) and truncated mutant plasmids of the POU5F1 gene, transfected cells with them respectively, and carried out RNA sequencing analysis. We found that 681 genes were differentially expressed between the groups expressing the POU5F1-WT and truncated mutant plasmids. Gene ontology analysis revealed that these genes were enriched in biological processes such as germ cell development, gonadal development, follicle-regulated growth to maturity, ovulation from ovarian follicle, and negative regulation of the BMP signaling pathway. Quantitative real-time PCR confirmed that the genes LIN28A, NANOG, TRIM49D1, FRG2C, KLHL10, and HOXB4 were significantly differentially expressed between the groups expressing the POU5F1-WT and truncated mutant plasmids. This study is the first to discover that the POU5F1 gene may be associated with POI, and suggests that the rare truncated mutation of the POU5F1 gene may be one of the genetic pathogenic factors of POI.