Screening for mutations in the steroidogenic acute regulatory protein and steroidogenic factor-1 genes, and in CYP11A and dosage-sensitive sex reversal-adrenal hypoplasia gene on the X chromosome, gene-1 (DAX-1), in hyperandrogenic hirsute women

Abnormalities in adrenal and/or ovarian steroidogenesis are found in most p atients with hirsutism. The rate-limiting step in the synthesis of steroids in the ovary and the adrenal is the conversion of cholesterol into pregnen olone by cholesterol side-chain cleavage enzyme (P450scc), encoded by the g ene CYP11A, after cholesterol is introduced into the mitochondria by the st eroidogenic acute regulatory protein (StAR). DAX-1 is a repressor of StAR g ene expression, and steroidogenic factor-1 (SF-1) is a regulator of CYP11A, DAX-1, and StAR gene. Mutations in any of these factors resulting in gain of function, or loss of repression, of StAR or P450scc might contribute to the steroidogenic abnormalities present in hirsute patients. In the present study we have screened, using heteroduplex analysis, the gen es encoding StAR and SF-1 as well as DAX-1 and CYP11A for mutations in geno mic DNA from 19 women presenting with hirautism and increased serum androge n levels. When variants were found, analysis was extended to a larger group of hyperandrogenic patients and nonaffected women. Two variants were ident ified in the SF-1 gene. A G -->C change in exon 6, resulting in an Arg(365) pro mutation, was found in 1 of 45 patients, but not in controls. Also, a G ly(146)Ala missense mutation, resulting from a G -->C change in exon 4, was found in 2 of 48 patients and in 2 of 50 nonaffected individuals. We ident ified a C -->T base pair change at position -33 of the StAR gene. Three of 48 patients and 3 of 43 controls presented this variant. No mutations were found in coding regions of the StAR gene. Analysis of CYP11A-coding regions identified a G -->A change in exon 3, resulting in a Val(179)Ile missense mutation. This mutation was found in 1 of 29 patients studied and was not p resent in 50 controls. Finally, analysis of DAX-1 showed no variant in any of the women studied. In conclusion, mutations in StAR, SF-1, CYP11A, and DAX-1 are seldom found in hirsute patients and do not explain the steroidogenic abnormalities foun d in these women.