title: Limited contribution of NR5A1 (SF-1) mutations in women with primary ovarian insufficiency (POI).
abstract: 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.
  
  
  METHODS
  Cross-sectional cohort study.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  Well-phenotyped women (n = 386) with secondary amenorrhea and diagnosed with POI, including women with familial POI (n = 77).
  
  
  METHODS
  None.
  
  
  METHODS
  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.
  
  
  RESULTS
  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%.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Reproductive Medicine and Gynecology, University Medical Center Utrecht, Utrecht, The Netherlands. f.janse@umcutrecht.nl
authors.forename: Femi
authors.initials: F
authors.lastname: Janse
authors.forename: Larissa M
authors.initials: LM
authors.lastname: de With
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Duran
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
authors.forename: Angelique J
authors.initials: AJ
authors.lastname: Goverde
authors.forename: Cornelius B
authors.initials: CB
authors.lastname: Lambalk
authors.forename: Joop S E
authors.initials: JS
authors.lastname: Laven
authors.forename: Bart C J M
authors.initials: BC
authors.lastname: Fauser
authors.forename: Jacques C
authors.initials: JC
authors.lastname: Giltay
mesh_terms: D000293:Adolescent; D000328:Adult; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation / Q000235:genetics*; D016649:Primary Ovarian Insufficiency / Q000453:epidemiology / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D055815:Young Adult
chemical_list: C515057:NR5A1 protein, human; D022821:RNA Splice Sites; D054339:Steroidogenic Factor 1