Apparently normal ovarian differentiation in a prepubertal girl with transcriptionally inactive steroidogenic factor 1 (NR5A1/SF-1) and adrenocortical insufficiency

Steroidogenic factor 1 (NR5A1/SF-1) plays an essential role in the developm ent of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonada l axes, controlling expression of their many important genes. The recent de scription of a 46,XY patient bearing a mutation in the NR5A1 gene, causing male pseudohermaphroditism and adrenal failure, demonstrated the crucial ro le of SF-1 in male gonadal differentiation. The role of SF-1 in human ovari an development was, until now, unknown. We describe a phenotypically and ge notypically normal girl, with signs and symptoms of adrenal insufficiency a nd no apparent defect in ovarian maturation, bearing a heterozygote G-->T t ransversion in exon 4 of the NR5A1 gene that leads to the missense R255L in the SF-1 protein. The exchange does not interfere with protein translation and stability. Consistent with the clinical picture, R255L is transcriptio nally inactive and has no dominant-negative activity. The inability of the mutant (MUT) NR5A1/SF-1 to bind canonical DNA sequences might offer a possi ble explanation for the failure of the mutant protein to transactivate targ et genes. This is the first report of a mutation in the NR5A1 gene in a gen otypically female patient, and it suggests that NR5A1/SF-1 is not necessary for female gonadal development, confirming the crucial role of NR5A1/SF-1 in adrenal gland formation in both sexes.