Gonadal Determination and Adrenal Development Are Regulated by the Orphan Nuclear Receptor Steroidogenic Factor-1, in a Dose-Dependent Manner

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Abstract
The orphan nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) regulates the transcription of multiple genes involved in steroidogenesis, reproduction, and male sexual differenti- ation. A heterozygous loss-of-function SF-1 mutation (G35E) has been described in a patient with adrenal failure and com- plete 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 mu- tation. In functional assays, the R92Q mutant exhibited par- tial 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 homozy- gous 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 sen- sitivity of SF-1-dependent developmental pathways to gene dosage and function in humans. (J Clin Endocrinol Metab 87: 1829 -1833, 2002)

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