03277nas a2200445   4500008004100000022001400041245015900055210006900214260001600283300000900299490000800308520183200316653001002148653000902158653001102167653004102178653002302219653003002242653004602272653001802318653003402336653001702370653001102387653001602398653002002414653001302434653004402447653001202491653003402503653002402537100002302561700002502584700001602609700002302625700001302648700001402661700001602675700001302691856012702704       2015                        eng d  a1879-003800aDeregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.0 aDeregulation of key signaling pathways involved in oocyte matura  c2015 Oct 15  a52-70 v5713 a<p>FMR1 premutation female carriers are at risk for Fragile X-associated primary ovarian insufficiency (FXPOI). Insights from knock-in mouse model have recently demonstrated that FXPOI is due to an increased rate of follicle depletion or an impaired development of the growing follicles. Molecular mechanisms responsible for this reduced viability are still unknown. In an attempt to provide new data on the mechanisms that lead to FXPOI, we report the first investigation involving transcription profiling of total blood from FMR1 premutation female carriers with and without FXPOI. A total of 16 unrelated female individuals (6 FMR1 premutated females with FXPOI; 6 FMR1 premutated females without FXPOI; and 4 no-FXPOI females) were studied by whole human genome oligonucleotide microarray (Agilent Technologies). Fold change analysis did not show any genes with significant differential gene expression. However, functional profiling by gene set analysis showed large number of statistically significant deregulated GO annotations as well as numerous KEGG pathways in FXPOI females. These results suggest that the impairment of fertility in these females might be due to a generalized deregulation of key signaling pathways involved in oocyte maturation. In particular, the vasoendotelial growth factor signaling, the inositol phosphate metabolism, the cell cycle, and the MAPK signaling pathways were found to be down-regulated in FXPOI females. Furthermore, a high statistical enrichment of biological processes involved in cell death and survival were found deregulated among FXPOI females. Our results provide new strategic approaches to further investigate the molecular mechanisms and potential therapeutic targets for FXPOI not focused in a single gene but rather in the set of genes involved in these pathways. </p>10aAdult10aAged10aFemale10aFragile X Mental Retardation Protein10aFragile X Syndrome10aGene Expression Profiling10aGene Expression Regulation, Developmental10aGene ontology10aGenome-Wide Association Study10aHeterozygote10aHumans10aMiddle Aged10aModels, Genetic10amutation10aOligonucleotide Array Sequence Analysis10aOocytes10aPrimary Ovarian Insufficiency10aSignal Transduction1 aAlvarez-Mora, M, I1 aRodriguez-Revenga, L1 aMadrigal, I1 aGarcía-García, F1 aDuran, M1 aDopazo, J1 aEstivill, X1 aMilà, M  uhttp://clinbioinfosspa.es/content/deregulation-key-signaling-pathways-involved-oocyte-maturation-fmr1-premutation-carriers