Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.
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.
['Alvarez-Mora|M I|MI|', 'Rodriguez-Revenga|L|L|', 'Madrigal|I|I|', 'Garcia-Garcia|F|F|', 'Duran|M|M|', 'Dopazo|J|J|', 'Estivill|X|X|', 'Milà|M|M|']
D000328:Adult D000368:Aged D005260:Female D051860:Fragile X Mental Retardation Protein D005600:Fragile X Syndrome D020869:Gene Expression Profiling D018507:Gene Expression Regulation, Developmental D063990:Gene Ontology D055106:Genome-Wide Association Study D006579:Heterozygote D006801:Humans D008875:Middle Aged D008957:Models, Genetic D009154:Mutation D020411:Oligonucleotide Array Sequence Analysis D009865:Oocytes D016649:Primary Ovarian Insufficiency D015398:Signal Transduction
Oocyte maturation FMR1 premutation FXPOI Female infertility