Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency
Por:
M. ALVAREZ-MORA, L. RODRIGUEZ-REVENGA, I. MADRIGAL, F. GARCIA-GARCIA, M. DURAN, J. DOPAZO, X. ESTIVILL and M. MILA
Publicada:
15 oct 2015
Resumen:
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. (C) 2015 Elsevier B.V. All rights reserved.
Filiaciones:
M. ALVAREZ-MORA:
Hosp Clin Barcelona, CIBER Enfermedades Raras, E-08036 Barcelona, Spain
Hosp Clin Barcelona, Biochem & Mol Genet Dept, E-08036 Barcelona, Spain
IDIBAPS, Barcelona 08036, Spain
L. RODRIGUEZ-REVENGA:
Hosp Clin Barcelona, CIBER Enfermedades Raras, E-08036 Barcelona, Spain
Hosp Clin Barcelona, Biochem & Mol Genet Dept, E-08036 Barcelona, Spain
IDIBAPS, Barcelona 08036, Spain
I. MADRIGAL:
Hosp Clin Barcelona, CIBER Enfermedades Raras, E-08036 Barcelona, Spain
Hosp Clin Barcelona, Biochem & Mol Genet Dept, E-08036 Barcelona, Spain
IDIBAPS, Barcelona 08036, Spain
:
Ctr Invest Principe Felipe, Computat Genom Dept, Valenda 46012, Spain
M. DURAN:
Hosp Clin Barcelona, Dept Obstet & Gynecol, E-08036 Barcelona, Spain
:
Ctr Invest Principe Felipe, Computat Genom Dept, Valenda 46012, Spain
Ctr Invest Principe Felipe, INB, Funct Genom Node, Valenda 46012, Spain
Ctr Invest Principe Felipe, CIBER Enfermedades Raras, Valenda 46012, Spain
X. ESTIVILL:
Ctr Genom Regulat CRG, Bioinformat & Genom Program, Barcelona 08003, Spain
UPF, Barcelona 08005, Spain
Ctr Genom Regulat, CIBERESP, Barcelona 08003, Spain
Dexeus Womans Hlth, Genom & Personalized Med Sect, Barcelona 08028, Spain
M. MILA:
Hosp Clin Barcelona, CIBER Enfermedades Raras, E-08036 Barcelona, Spain
Hosp Clin Barcelona, Biochem & Mol Genet Dept, E-08036 Barcelona, Spain
IDIBAPS, Barcelona 08036, Spain
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