title: Deregulation of key signaling pathways involved in oocyte maturation in FMR1 premutation carriers with Fragile X-associated primary ovarian insufficiency.
abstract: 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.
authors.affiliation: CIBER de Enfermedades Raras, Hospital Clínic, 08036 Barcelona, Spain; Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) 08036 Barcelona, Spain. Electronic address: misabel_alvarez@hotmail.com.
authors.forename: M I
authors.initials: MI
authors.lastname: Alvarez-Mora
authors.affiliation: CIBER de Enfermedades Raras, Hospital Clínic, 08036 Barcelona, Spain; Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) 08036 Barcelona, Spain. Electronic address: lbodi@clinic.ub.es.
authors.forename: L
authors.initials: L
authors.lastname: Rodriguez-Revenga
authors.affiliation: CIBER de Enfermedades Raras, Hospital Clínic, 08036 Barcelona, Spain; Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) 08036 Barcelona, Spain. Electronic address: imadbajo@clinic.ub.es.
authors.forename: I
authors.initials: I
authors.lastname: Madrigal
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain. Electronic address: fgarcia@cipf.es.
authors.forename: F
authors.initials: F
authors.lastname: Garcia-Garcia
authors.affiliation: Obstetrics and Gynecology Department Hospital Clinic, 08036 Barcelona, Spain. Electronic address: mduran@clinic.ub.es.
authors.forename: M
authors.initials: M
authors.lastname: Duran
authors.affiliation: Computational Genomics Department, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain; Functional Genomics Node, INB, Centro de Investigación Príncipe Felipe, Valencia, Spain; CIBER de Enfermedades Raras, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain. Electronic address: jdopazo@cipf.es.
authors.forename: J
authors.initials: J
authors.lastname: Dopazo
authors.affiliation: Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), 08005 Barcelona, Spain; Hospital del Mar Medical Research Institute (IMIM), 08003 Barcelona, Spain; CIBER de Epidemiología y Salud Pública (CIBERESP), Centre for Genomic Regulation, 08003 Barcelona, Spain; Genomics and Personalized Medicine Section, Dexeus Woman's Health, 08028 Barcelona, Spain. Electronic address: xavier.estivill@crg.eu.
authors.forename: X
authors.initials: X
authors.lastname: Estivill
authors.affiliation: CIBER de Enfermedades Raras, Hospital Clínic, 08036 Barcelona, Spain; Biochemistry and Molecular Genetics Department, Hospital Clinic, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) 08036 Barcelona, Spain. Electronic address: mmila@clinic.ub.es.
authors.forename: M
authors.initials: M
authors.lastname: Milà
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D063990:Gene Ontology; D055106:Genome-Wide Association Study / Q000379:methods; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D009865:Oocytes / Q000254:growth & development / Q000378:metabolism*; D016649:Primary Ovarian Insufficiency / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human
keywords: FMR1 premutation; FXPOI; Female infertility; Oocyte maturation