Sequence variation at the human FOXO3 locus: A study of premature ovarian failure and primary amenorrhea

Teresa D. Gallardo, George B. John, Karen Bradshaw, Corrine Welt, Renee Reijo-Pera, Peter H. Vogt, Philippe Touraine, Silvia Bione, Daniela Toniolo, Lawrence M. Nelson, Andrew R. Zinn, Diego H. Castrillon

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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. METHODS and 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.

Original languageEnglish (US)
Pages (from-to)216-221
Number of pages6
JournalHuman Reproduction
Issue number1
StatePublished - Jan 2008


  • FOXO3
  • Female infertility
  • Menopause
  • Premature ovarian failure
  • Primary amenorrhea

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynecology


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