Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI)

The prevalence of NR5A1 mutations in a large cohort of well-phenotyped women with secondary amenorrhea and diagnosed with POI was only 1.4%, which is substantially lower than previously reported.


Femi Janse, M.D., Larissa M. de With, M.D., Karen J. Duran, Ph.D., Wigard P. Kloosterman, Ph.D., Angelique J. Goverde, M.D., Ph.D., Cornelius B. Lambalk, M.D., Ph.D., Joop S.E. Laven, M.D., Ph.D., Bart C.J.M. Fauser, M.D., Ph.D., Jacques C. Giltay, M.D., Ph.D., the Dutch Primary Ovarian Insufficiency Consortium

Vol 97, Issue 1 , Pages 141-146.e2



To evaluate the significance of NR5A1 mutations in a large, well-phenotyped cohort of women with primary ovarian insufficiency (POI). Mutations in the NR5A1 gene (SF-1) were previously described in disorders of sexual development and adrenal insufficiency. Recently, a high frequency of NR5A1 gene mutations was reported in a small group of women with POI.


Cross-sectional cohort study.


University hospital.


Well-phenotyped women (n = 386) with secondary amenorrhea and diagnosed with POI, including women with familial POI (n = 77).



Main Outcome Measure(s):

The entire coding region and splice sites of the NR5A1 gene were PCR-amplified and sequenced. The pathogenicity of identified mutations was predicted in silico by assessing Align-GVGD class and Grantham score.


Sequencing was successful in 356 patients with POI. In total, 9 mutations were identified in 10 patients. Five of these mutations concerned novel nonconservative mutations occurring in 5 patients. Prediction of effect on protein function showed low to intermediate pathogenicity for all nonconservative mutations. The overall NR5A1 gene mutation rate was 1.4%.


The current study demonstrates that mutations in the NR5A1 gene are rare in women with POI. Primary ovarian insufficiency remains unexplained in the great majority of patients; therefore, continued efforts are needed to elucidate its underlying genetic factors.

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