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- W855682095 abstract "Single germline mutations found in women with primary ovarian insufficiency (POI), besides mouse models have provided substantial understanding into the factors involved in differentiation and ovarian development. POI is characterized by amenorrhea with elevated gonadotropin levels, and affects 1% of women before the age of 40 years.Several transcription factors involved in ovary development and folliculogenesis are mutated in reproductive disorders. We have shown a high prevalence of POI cases harboring mutations in the Newborn oogenesis homeobox (NOBOX) gene, which encodes a homeodomain-Containing transcription factor expressed preferentially in oocyte. NOBOX plays a critical role in early folliculogenesis and its absence leads to sterility. In addition to its oocyte localization, we show here that NOBOX is also expressed in granulosa cells (GCs), those surrounding the germ cell. Since NOBOX and FOXL2, a master regulator of GC development (belonging to forkhead family), are co-Expressed in GCs. Here, using several molecular approaches, we have demonstrated that NOBOX and FOXL2 indeed physically interact leading to a down-Regulation of their transactivation capacity. Altogether, these observations highlight a novel role for NOBOX in interaction with FOXL2, and suggest that they may be antagonistic transcription regulators. POI encompasses a heterogeneous spectrum of conditions, through two major mechanisms, follicle dysfunction and follicle depletion. Genetic component such as X chromosome abnormalities, deletions, FMR1 premutations, BMP15 variants, were identified as the first genetic causes of the pathophysiology. Today, the genetic origin of POI is supported by the existence of monogenic forms in humans and animal models but the relevance of several loci for POI pathogenesis should not be ruled out. By means of a next-Generation sequencing , a multiplex (PGM-Ion Torrent technology) sequencing of 19 genes was undertaken in a cohort of 100 nonsyndromic women with POI. In 26 patients, we reported 10 gene defects, among them, missense mutations in 4 new candidates were detected. Our aggregate data suggest that point mutations in these candidate genes are causative of the disease by prediction analysis assays. Two to three gene defects can synergize to produce a more severe phenotype in POI patients than either alone. This study identifies for the first time in a large proportion of POI patients specific sets of germline mutations that, together, may account for this disease. Thus, oligogenicity also has implications for genetic counseling regarding POI." @default.
- W855682095 created "2016-06-24" @default.
- W855682095 creator A5071770110 @default.
- W855682095 date "2014-11-21" @default.
- W855682095 modified "2023-09-24" @default.
- W855682095 title "Etude de nouveaux acteurs de la physiopathologie ovarienne" @default.
- W855682095 hasPublicationYear "2014" @default.
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