Analysis of NR5A1 in 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility


      • The frequency of NR5A1 variants in premature ovarian insufficiency found in this study was is in keeping with prior studies.
      • The p.Val15Met variant is a cause of sporadic premature ovarian insufficiency with primary amenorrhea.
      • In silico predictions can contribute to incorrect variant curation.
      • A recurrent allele in African women with premature ovarian insufficiency has no detectable functional impact.
      • Women with diminished ovarian reserve can have rare non-synonymous NR5A1 variants, albeit with no detectable functional consequence.
      • NR5A1 variants may have a subtle impact on protein function and may cause mild ovarian deficiency.


      Ovarian deficiency, including diminished ovarian reserve and premature ovarian insufficiency, represents one of the main causes of female infertility. Little is known of the genetic basis of diminished ovarian reserve, while premature ovarian insufficiency often has a genetic basis, with genes affecting various processes. NR5A1 is a key gene required for gonadal function, and variants are associated with a wide phenotypic spectrum of disorders of sexual development, and are found in 0.26–8% of patients with premature ovarian insufficiency. As there is some debate about the extent of involvement of NR5A1 in the pathogenesis of ovarian deficiency, we performed an in-depth analysis of NR5A1 variants detected in a cohort of 142 patients with premature ovarian insufficiency, diminished ovarian reserve, or unexplained infertility associated with normal ovarian function. We identified rare non-synonymous protein-altering variants in 2.8 % of women with ovarian deficiency and no such variants in our small cohort of women with infertility but normal ovarian function. We observed previously reported variants associated with premature ovarian insufficiency in patients with diminished ovarian reserve, highlighting a genetic relationship between these conditions. We confirmed functional impairment resulting from a p.Val15Met variant, detected for the first time in a patient with premature ovarian insufficiency. The remaining variants were associated with preserved transcriptional activity and localization of NR5A1, indicating that rare NR5A1 variants may be incorrectly curated if functional studies are not undertaken, and/or that NR5A1 variants may have only a subtle impact on protein function and/or confer risk of ovarian deficiency via oligogenic inheritance.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Maturitas
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Gleicher N.
        • Kim A.
        • Weghofer A.
        • Kushnir V.A.
        • Shohat-Tal A.
        • Lazzaroni E.
        • et al.
        Hypoandrogenism in association with diminished functional ovarian reserve.
        Hum Reprod Oxf Engl. 2013; 28: 1084-1091
        • Iwase A.
        • Osuka S.
        • Goto M.
        • Murase T.
        • Nakamura T.
        • Takikawa S.
        • et al.
        Clinical application of serum anti-Müllerian hormone as an ovarian reserve marker: a review of recent studies.
        J. Obstet. Gynaecol. Res. 2018; 44: 998-1006
        • Mutlu M.F.
        • Erdem M.
        • Erdem A.
        • Yildiz S.
        • Mutlu I.
        • Arisoy O.
        • et al.
        Antral follicle count determines poor ovarian response better than anti-Müllerian hormone but age is the only predictor for live birth in in vitro fertilization cycles.
        J. Assist. Reprod. Genet. 2013; 30: 657-665
        • Victoria M.
        • Labrosse J.
        • Krief F.
        • Cédrin-Durnerin I.
        • Comtet M.
        • Grynberg M.
        Anti Müllerian Hormone: more than a biomarker of female reproductive function.
        J. Gynecol. Obstet. Hum. Reprod. 2019; 48: 19-24
        • Cohen J.
        • Chabbert-Buffet N.
        • Darai E.
        Diminished ovarian reserve, premature ovarian failure, poor ovarian responder--a plea for universal definitions.
        J. Assist. Reprod. Genet. 2015; 32: 1709-1712
        • Pastore L.M.
        • Christianson M.S.
        • Stelling J.
        • Kearns W.G.
        • Segars J.H.
        Reproductive ovarian testing and the alphabet soup of diagnoses: DOR, POI, POF, POR, and FOR.
        J. Assist. Reprod. Genet. 2018; 35: 17-23
        • Tucker E.J.
        • Grover S.R.
        • Bachelot A.
        • Touraine P.
        • Sinclair A.H.
        Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic Spectrum.
        Endocr. Rev. 2016; 37: 609-635
        • Wang T.-T.
        • Ke Z.-H.
        • Song Y.
        • Chen L.-T.
        • Chen X.-J.
        • Feng C.
        • et al.
        Identification of a mutation in GDF9 as a novel cause of diminished ovarian reserve in young women.
        Hum. Reprod. 2013; 28: 2473-2481
        • Pashaiasl M.
        • Ebrahimi M.
        • Ebrahimie E.
        Identification of the key regulating genes of diminished ovarian reserve (DOR) by network and gene ontology analysis.
        Mol. Biol. Rep. 2016; 43: 923-937
        • Bashamboo A.
        • McElreavey K.
        NR5A1/SF-1 and development and function of the ovary.
        Ann. Endocrinol. (Paris). 2010; 71: 177-182
        • Lourenço D.
        • Brauner R.
        • Lin L.
        • De Perdigo A.
        • Weryha G.
        • Muresan M.
        • et al.
        Mutations in NR5A1 associated with ovarian insufficiency.
        N. Engl. J. Med. 2009; 360: 1200-1210
        • Jeyasuria P.
        • Ikeda Y.
        • Jamin S.P.
        • Zhao L.
        • De Rooij D.G.
        • Themmen A.P.N.
        • et al.
        Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function.
        Mol. Endocrinol. Baltim. Md. 2004; 18: 1610-1619
        • Camats N.
        • Fernández-Cancio M.
        • Audí L.
        • Schaller A.
        • Flück C.E.
        Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin?.
        Eur. J. Hum. Genet. EJHG. 2018; 26: 1329-1338
        • Robevska G.
        • van den Bergen J.A.
        • Ohnesorg T.
        • Eggers S.
        • Hanna C.
        • Hersmus R.
        • et al.
        Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development.
        Hum. Mutat. 2018; 39: 124-139
        • Bashamboo A.
        • Ferraz-de-Souza B.
        • Lourenço D.
        • Lin L.
        • Sebire N.J.
        • Montjean D.
        • et al.
        Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.
        Am. J. Hum. Genet. 2010; 87: 505-512
        • Jiao X.
        • Qin Y.
        • Li G.
        • Zhao S.
        • You L.
        • Ma J.
        • et al.
        Novel NR5A1 missense mutation in premature ovarian failure: detection in han chinese indicates causation in different ethnic groups.
        PLoS One. 2013; 8e74759
        • Knarston I.M.
        • Robevska G.
        • van den Bergen J.A.
        • Eggers S.
        • Croft B.
        • Yates J.
        • et al.
        NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients.
        Hum. Mutat. 2019; 40: 207-216
        • Stenson P.D.
        • Ball E.V.
        • Mort M.
        • Phillips A.D.
        • Shiel J.A.
        • Thomas N.S.T.
        • et al.
        Human Gene Mutation Database (HGMD): 2003 update.
        Hum. Mutat. 2003; 21: 577-581
        • Landrum M.J.
        • Lee J.M.
        • Benson M.
        • Brown G.R.
        • Chao C.
        • Chitipiralla S.
        • et al.
        ClinVar: improving access to variant interpretations and supporting evidence.
        Nucleic Acids Res. 2018; 46 (D1062–7)
        • Sadedin S.P.
        • Dashnow H.
        • James P.A.
        • Bahlo M.
        • Bauer D.C.
        • Lonie A.
        • et al.
        Cpipe: a shared variant detection pipeline designed for diagnostic settings.
        Genome Med. 2015; 7: 68
        • Venselaar H.
        • Te Beek T.A.H.
        • Kuipers R.K.P.
        • Hekkelman M.L.
        • Vriend G.
        Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces.
        BMC Bioinformatics. 2010; 11: 548
        • Voican A.
        • Bachelot A.
        • Bouligand J.
        • Francou B.
        • Dulon J.
        • Lombès M.
        • et al.
        NR5A1 (SF-1) mutations are not a major cause of primary ovarian insufficiency.
        J. Clin. Endocrinol. Metab. 2013; 98: E1017-1021
        • Tucker E.J.
        • Jaillard S.
        • Grover S.R.
        • den Bergen J.
        • Robevska G.
        • Bell K.M.
        • et al.
        TP63‐truncating variants cause isolated premature ovarian insufficiency.
        Hum. Mutat. 2019;
        • Camats N.
        • Pandey A.V.
        • Fernández-Cancio M.
        • Andaluz P.
        • Janner M.
        • Torán N.
        • et al.
        Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals.
        J. Clin. Endocrinol. Metab. 2012; 97: E1294-1306
        • Lin L.
        • Philibert P.
        • Ferraz-de-Souza B.
        • Kelberman D.
        • Homfray T.
        • Albanese A.
        • et al.
        Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function.
        J. Clin. Endocrinol. Metab. 2007; 92: 991-999
        • Janse F.
        • de With L.M.
        • Duran K.J.
        • Kloosterman W.P.
        • Goverde A.J.
        • Lambalk C.B.
        • et al.
        Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI).
        Fertil. Steril. 2012; 97 (e2): 141-146
        • Sreenivasan R.
        • Ludbrook L.
        • Fisher B.
        • Declosmenil F.
        • Knower K.C.
        • Croft B.
        • et al.
        Mutant NR5A1/SF-1 in patients with disorders of sex development shows defective activation of the SOX9 TESCO enhancer.
        Hum. Mutat. 2018; 39: 1861-1874
        • Eggers S.
        • Smith K.R.
        • Bahlo M.
        • Looijenga L.H.J.
        • Drop S.L.S.
        • Juniarto Z.A.
        • et al.
        Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1.
        Eur. J. Hum. Genet. EJHG. 2015; 23: 486-493