title: Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea.
abstract: BACKGROUND
  The forkhead transcription factor Foxo3 is a master regulator and potent suppressor of primordial follicle activation. Loss of Foxo3 function in the mouse leads to premature ovarian failure (POF) due to global follicle activation.
  
  
  RESULTS
  Here, we show that the mouse Foxo3 locus is haploinsufficient, and that Foxo3-/+ females undergo early reproductive senescence consistent with an increased rate of primordial follicle utilization. Then, to determine if heterozygous or homozygous polymorphisms or mutations of the human orthologue FOXO3 contribute to POF or idiopathic primary amenorrhea (PA), we sequenced the exons and flanking splice sequences of the gene in a large number of women with idiopathic POF (n = 273) or PA (n = 29). A total of eight single-nucleotide polymorphisms (SNPs) were identified, revealing a substantial amount of genetic variation at this locus. Allelic frequencies in control samples excluded several of these variants as causal. For the remaining variants, site-directed mutagenesis was performed to assess their functional impact. However, these rare sequence variants were not associated with significant decreases in FOXO3 activity.
  
  
  CONCLUSIONS
  Taken together, our findings suggest that, despite the potential for FOXO3 haploinsufficiency to cause ovarian failure, FOXO3 mutations or common SNPs are not a common cause of either POF or PA.
authors.affiliation: Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Teresa D
authors.initials: TD
authors.lastname: Gallardo
authors.forename: George B
authors.initials: GB
authors.lastname: John
authors.forename: Karen
authors.initials: K
authors.lastname: Bradshaw
authors.forename: Corrine
authors.initials: C
authors.lastname: Welt
authors.forename: Renee
authors.initials: R
authors.lastname: Reijo-Pera
authors.forename: Peter H
authors.initials: PH
authors.lastname: Vogt
authors.forename: Philippe
authors.initials: P
authors.lastname: Touraine
authors.forename: Silvia
authors.initials: S
authors.lastname: Bione
authors.forename: Daniela
authors.initials: D
authors.lastname: Toniolo
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nelson
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Zinn
authors.forename: Diego H
authors.initials: DH
authors.lastname: Castrillon
mesh_terms: D000328:Adult; D000568:Amenorrhea / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D005091:Exons; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005787:Gene Frequency; D014644:Genetic Variation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D016649:Primary Ovarian Insufficiency / Q000235:genetics*
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors