Abstract
Primary ovarian insufficiency (POI), or premature ovarian failure, is defined as the cessation of ovarian function before the age of 40. An insufficient ovarian follicle pool derived from primordial germ cells (PGCs) is an important cause of POI. Although the Nanos gene family is known to be required for PGC development and maintenance in diverse model organisms, the relevance of this information to human biology is not yet clear. In this study, we screened the coding regions of the NANOS1, NANOS2 and NANOS3 genes in 100 Chinese POI patients and identified four variants in the coding regions of these three genes, including one synonymous variant in NANOS3, one missense variant in each of NANOS1 and NANOS2 and one potentially relevant mutation (c.457C>T; p.Arg153Trp, heterozygous) in NANOS3. We demonstrated that the p.Arg153Trp substitution decreases the stability of NANOS3, potentially resulting in a hypomorph. Furthermore, an investigation of the relationship between the number of PGCs and the dosage of NANOS3 in mouse models showed that the population of PGCs is controlled by the level of NANOS3 protein. Taken together, our results provide new insight into the properties of the NANOS3 protein and establish that NANOS3 mutation is one possible cause of POI.