Endocrine Abstracts

NR5A1, a member of the nuclear receptor superfamily, is a key transcriptional regulator of genes involved in the hypothalamic–pituitary–gonadal steroidogenic axis. Newborn mice deficient in NR5A1 lack both gonads and adrenal glands and have impaired expression of pituitary gonadotrophins. NR5A1 is expressed in foetal and adult Sertoli and Leydig cells of testis. NR5A1 is also expressed in multiple cell types in the foetal, postnatal, prepubertal and mature ovary. Up until 2008, 18 NR5A1 mutations were described in the human. Three of these were identified in individuals with adrenal insufficiency, two associated with 46,XY DSD and the third a 46,XX female with conserved ovarian function. Other mutations were associated with various anomalies of testis development with no evidence of adrenal failure. We have identified further 19 mutations in NR5A1 including mutations in 4 familial cases having individuals with 46,XY DSD as well as primary ovarian insufficiency (POI). A further analysis of 25 sporadic cases of POI revealed two additional mutations. Functional analysis revealed that each mutant protein had altered transactivational properties on gonadal promoters. These data reveal novels insights into the role of NR5A1 in ovarian developmental and function and indicate that mutations of the NR5A1 gene may be a significant cause of human ovarian insufficiency. Further work in our lab continues to unveil additional gonadal phenotypes associated with mutations in NR5A1, adding to the complexity of role of NR5A1 in development and function of mammalian gonad.