A NANOS3 mutation linked to protein degradation causes premature ovarian insufficiency

G Shi,Y Cao,X Wu,Z Dong,Y Xu,Z Liu,B Wang,S Zhou

doi:10.1038/cddis.2013.368

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.

Highlights

(PGCs), a transient population of germline stem cells that undergo several rounds of cell proliferation[2] and subsequently arrest at prophase I
We speculated that there is a relationship between Primary ovarian insufficiency (POI) and defects in NANOS genes, as POI is largely dependent on the size of the pool of PGCs
We sequenced all coding regions of the NANOS1, NANOS2 and NANOS3 genes in 100 Chinese POI patients. This analysis identified a total of four variants in the coding regions of these three genes, including one synonymous variant in NANOS3 and one missense variant in each of NANOS1, NANOS2 and NANOS3 (Table 1)

Summary

Results and Discussion

We sequenced all coding regions of the NANOS1, NANOS2 and NANOS3 genes in 100 Chinese POI patients. This analysis identified a total of four variants in the coding regions of these three genes, including one synonymous variant in NANOS3 and one missense variant in each of NANOS1, NANOS2 and NANOS3 (Table 1). The affected woman was 23 years old, heterozygotes for the variant, unmarried and the offspring of consanguineous parents Her mother was 45 years old, premenopausal and had a normal menstrual cycle. She had elevated follicle-stimulating hormone (4124.89 U/l) and luteinising hormone (443.17 U/l) on several examinations, with the cessation of periods. Using co-transfected GFP as a reporter, we confirmed that the reduction in hNANOS3 protein level was not due to variability in the transfection efficiency (Figure 1b)

Location dbSNP ID

Cell Death and Disease

Neo allele

Materials and Methods

Primer ID Sequence