Calvo R M, Asunción M, Tellería D, Sancho J, San Millán J L, Escobar-Morreale H F
Department of Endocrinology, Hospital Ramón y Cajal, Madrid 28034, Spain.
J Clin Endocrinol Metab. 2001 Apr;86(4):1746-9. doi: 10.1210/jcem.86.4.7424.
Abstract Abnormalities in adrenal and/or ovarian steroidogenesis are found in most patients with hirsutism. The rate-limiting step in the synthesis of steroids in the ovary and the adrenal is the conversion of cholesterol into pregnenolone by cholesterol side-chain cleavage enzyme (P450scc), encoded by the gene CYP11A, after cholesterol is introduced into the mitochondria by the steroidogenic acute regulatory protein (StAR). DAX-1 is a repressor of StAR gene 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 genes encoding StAR and SF-1 as well as DAX-1 and CYP11A for mutations in genomic DNA from 19 women presenting with hirsutism and increased serum androgen levels. When variants were found, analysis was extended to a larger group of hyperandrogenic patients and nonaffected women. Two variants were identified 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 Gly(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 identified 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 present 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 found in these women.
大多数多毛症患者存在肾上腺和/或卵巢类固醇生成异常。卵巢和肾上腺中类固醇合成的限速步骤是，在类固醇生成急性调节蛋白（StAR）将胆固醇转运至线粒体后，由CYP11A基因编码的胆固醇侧链裂解酶（P450scc）将胆固醇转化为孕烯醇酮。DAX-1是StAR基因表达的抑制因子，类固醇生成因子-1（SF-1）是CYP11A、DAX-1和StAR基因的调节因子。这些因子中任何一个发生突变，导致StAR或P450scc功能增强或抑制作用丧失，都可能导致多毛症患者出现类固醇生成异常。在本研究中，我们采用异源双链分析技术，对19例多毛症且血清雄激素水平升高的女性的基因组DNA中编码StAR、SF-1、DAX-1和CYP11A的基因进行了突变筛查。发现变异后，分析范围扩大至更多高雄激素血症患者和未受影响的女性。在SF-1基因中鉴定出两个变异。45例患者中有1例在第6外显子发生G→C改变，导致Arg(365)Pro突变，而对照组未发现。此外，48例患者中有2例以及50例未受影响个体中有2例在第4外显子发生G→C改变，导致Gly(146)Ala错义突变。我们在StAR基因第-33位发现一个C→T碱基对改变。48例患者中有3例以及43例对照组中有3例出现该变异。在StAR基因编码区未发现突变。对CYP11A编码区的分析发现第3外显子有一个G→A改变，导致Val(179)Ile错义突变。该突变在29例研究患者中有1例出现，50例对照组中未出现。最后，对DAX-1的分析显示，所研究的任何女性均未出现变异。总之，多毛症患者很少发现StAR、SF-1、CYP11A和DAX-1的突变，这些突变无法解释这些女性中发现的类固醇生成异常。
