Disorders of sex development (DSD) are a group of rare congenital conditions in which the development of chromosomal, gonadal or anatomical sex is atypical. A subgroup termed 46,XX DSD covers disorders of ovarian development and maintenance, characterized by abnormal ovarian development, premature loss of ovarian function or even testis development in XX individuals. The molecular causes of 46,XX DSD have been elucidated in only a minority of c ases.
We recently proposed NR5A1 as a novel gene for 46,XX (ovo)testicular DSD (XX-(O)T DSD), an ultra-rare condition at the end of the 46,XX DSD spectrum. In addition, we demonstrated that haploinsufficiency of FOG2 and GATA4 is a novel cause of primary ovarian insufficiency (POI), a frequent cause of female infertility.
In this project we aim to (1) determine spatiotemporal expression patterns of the genes under study; (2) unravel the pathogenetic mechanisms of NR5A1-associated 46,XX DSD and (3) unravel the pathogenetic mechanisms of FOG2- and GATA4-associated POI by both in vitro and in vivo studies.
Overall, this study will scrutinize the pathogenetic mechanisms underlying ovarian development and functioning. This fundamental knowledge will provide new insight in 46, XX DSD and disorders impairing female fertility, such as primary ovarian insufficiency (POI), representing an important
burden in healthcare. These advances will ultimately improve management of individuals with these conditions.