Gonadal determination and adrenal development are regulated by the orphan nuclear receptor steroidogenic factor-1, in a dose-dependent manner.

The orphan nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) regulates the transcription of multiple genes involved in steroidogenesis, reproduction, and male sexual differentiation. A heterozygous loss-of-function SF-1 mutation (G35E) has been described in a patient with adrenal failure and complete 46XY sex-reversal, indicating that haploinsufficiency of this factor is sufficient to cause a severe clinical phenotype. This mutation in the P-box region of the DNA-binding domain markedly impairs SF-1 binding to most response elements. In an infant with a similar clinical phenotype, we identified an SF-1 mutation (R92Q) in a highly conserved residue of the A-box, a region that functions as a secondary DNA-binding domain. Strikingly, the affected infant was homozygous for the R92Q mutation, but three relatives (parents, sister) were phenotypically normal despite being heterozygous for the mutation. In functional assays, the R92Q mutant exhibited partial loss of DNA binding and transcriptional activity when compared with the G35E P-box change, consistent with its phenotypic expression only when transmitted as a homozygous trait. Taken together, these two naturally-occurring SF-1 mutations reveal the relative functional importance of the P-box and A-box regions for monomeric binding by nuclear receptors. In addition, these patients reveal the exquisite sensitivity of SF-1-dependent developmental pathways to gene dosage and function in humans.