Objective: 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. Design: Cross-sectional cohort study. Setting: University hospital. Patient(s): Well-phenotyped women (n = 386) with secondary amenorrhea and diagnosed with POI, including women with familial POI (n = 77). Intervention(s): None. 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. Result(s): 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%. Conclusion(s): 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.

NR5A1, POI, Primary ovarian insufficiency, SF-1, steroidogenic factor 1
dx.doi.org/10.1016/j.fertnstert.2011.10.032, hdl.handle.net/1765/68524
Fertility and Sterility
Department of Gynaecology & Obstetrics

Janse, F, de With, L.M, Duran, K, Kloosterman, W.P, Goverde, A.J, Lambalk, C.B, … Giltay, J.C. (2012). Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI). Fertility and Sterility, 97(1). doi:10.1016/j.fertnstert.2011.10.032