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Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea. (Articolo in rivista)

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Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea. (Articolo in rivista) (literal)

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Gallardo TD; John GB; Bradshaw K; Welt C; Reijo-Pera R; Vogt PH; Touraine P; Bione S; Toniolo D; Nelson LM; Zinn AR; Castrillon DH. (2008)
Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea.
in Human reproduction (Oxf., Print); Oxford University Press, Oxford (Regno Unito)
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Gallardo TD; John GB; Bradshaw K; Welt C; Reijo-Pera R; Vogt PH; Touraine P; Bione S; Toniolo D; Nelson LM; Zinn AR; Castrillon DH. (literal)

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Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA; Department of Obstetrics and Gynecology, UT Southwestern Medical Center, Dallas, TX, USA; Department of Reproductive Endocrinology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, CA, USA; Department of Gynecologic Endocrinology & Reproductive Medicine, University of Heidelberg Heidelberg, Germany, USA; AP-HP, Department of Endocrinology and Reproductive Medicine, Pitié-Salpêtrière Hospital, Paris, France; Department of Human Genetics and Genomics, Institute of Molecular Genetics, Pavia, Italy; Department of Molecular Biology and Genomics, San Raffaele Scientific Institute, Milano, Italy; National Institute of Child Health & Human Development, National Institutes of Health, Bethesda, MD, USA; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA. (literal)

Titolo

Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea. (literal)

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. 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. (literal)

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