Disección molecular de la etiología de la falla ovárica prematura por secuenciación directa y NGS: estudio de la implicación de los genes CITED2, CDKN1B, FOXO4, BMP15 y ADAMTS19

Abstract

Premature ovarian failure (POF) is a frequent disease, affecting 1% of women under 40 years old (Coulam et al, 1986). Clinically, POF women are affected by primary or secondary amenorrhoea and increased plasma levels of gonadotrophins (e.g. FSH and LH). POF can be originated from a variety of mechanisms leading to a decrease in the number of follicles, to the increase of follicular atresia or to follicle maturation failure (Beck-Peccoz et al, 2006). POF has been associated with different etiologies, but in the majority of the cases the cause remains unknown. The prevalence of idiopathic cases suggests the existence of genetic and environmental aetiological factors (Maclaran et al, 2011). The inherent molecular complexity of sex determination, folliculogenesis and ovulation underlines that hundreds of genes might be related to POF phenotype (Laissue, 2015). In this context, direct sequencing of single genes and large scale genomic approaches are complementary tools for identifying new POF molecular actors. The present PhD thesis focused on the use of direct sequencing, NGS and functional in vitro tests allowing the identification and validation of new POF causative sequence variants.