Research Article: Novel NR5A1 Missense Mutation in Premature Ovarian Failure: Detection in Han Chinese Indicates Causation in Different Ethnic Groups

Date Published: September 20, 2013

Publisher: Public Library of Science

Author(s): Xue Jiao, Yingying Qin, Guangyu Li, Shidou Zhao, Li You, Jinlong Ma, Joe Leigh Simpson, Zi-Jiang Chen, Qing-Yuan Sun.


The etiology of most premature ovarian failure (POF) cases is usually elusive. Although genetic causes clearly exist and a likely susceptible region of 8q22.3 has been discovered, no predominant explanation exists for POF. More recently, evidences have indicated that mutations in NR5A1 gene could be causative for POF. We therefore screened for mutations in the NR5A1 gene in a large cohort of Chinese women with non-syndromic POF.

Mutation screening of NR5A1 gene was performed in 400 Han Chinese women with well-defined 46,XX idiopathic non-syndromic POF and 400 controls. Subsequently, functional characterization of the novel mutation identified was evaluated in vitro.

A novel heterozygous missense mutation [c.13T>G (p.Tyr5Asp)] in NR5A1 was identified in 1 of 384 patients (0.26%). This mutation impaired transcriptional activation on Amh, Inhibin-a, Cyp11a1 and Cyp19a1 gene, as shown by transactivation assays. However, no dominant negative effect was observed, nor was there impact on protein expression and nuclear localization.

This novel mutation p.Tyr5Asp, in a novel non-domain region, is presumed to result in haploinsufficiency. Irrespectively, perturbation in NR5A1 is not a common explanation for POF in Chinese.

Partial Text

Premature ovarian failure (POF), also termed primary ovarian insufficiency (POI), refers to cessation of normal ovarian function before the age of 40 years. Approximately 1% of the population has POF prior to age 40 and only 0.1% or less before age 30 [1], [2]. The etiology of POF is highly heterogeneous. Chromosomal abnormalities account for 12% of cases [3], and the familial aggregation often associated with POF indicates a genetic contribution. Causative mutations in several genes (e.g., NOBOX, FIGLA, BMP15 and GDF9) have been identified in non-syndromic POF [4]–[8], but none of these genes are perturbed in more than a small minority of POF cases, in a given ethnic group. More recently, our genome-wide association study (GWAS) of POF discovered a significantly susceptible region of 8q22.3; however, it was concluded as an important yet undefined long distance regulatory region affecting oogenesis [9]. Therefore, the underlying explanation for POF remains largely unknown (idiopathic).

In our large cohort of Chinese patients known to have well-defined 46,XX non-syndromic POF, a novel heterozygous missense mutation was identified (1/384, 0.26%). The c.13T>G transition located in exon 2, outside any classic domains of SF1, resulted in a p.Tyr5Asp mutation. The highly conserved tyrosine residue was located adjacent to the first zinc finger of DBD, a region that contributed to specific recognition and interaction with promoter responsive elements in target genes. In vitro transactivation assays using Amh, Inhibin-a, Cyp11a1 and Cyp19a1 promoters showed impaired transactivation activity of the p.Y5D mutant, and thus confirmed its deleterious effect. However, a dominant negative effect was not observed (Fig. 2), consistent with previous reports [22], [24], [25].