Weidemann W, Linck B, Haupt H, Mentrup B, Romalo G, Stockklauser K, Brinkmann A O, Schweikert H U, Spindler K D
Department of Endocrinology and Developmental Biology, Heinrich Heine University of Düsseldorf.
Clin Endocrinol (Oxf). 1996 Dec;45(6):733-9. doi: 10.1046/j.1365-2265.1996.8600869.x.
Androgen insensitivity syndromes (AIS) in subjects with 46, XY karyotype and normal or even elevated androgen blood levels are characterized by various aberrations in male differentiation and virilization. AIS is often accompanied by a broad spectrum of abnormal binding characteristics of the androgen receptor (AR). In order to investigate the correlation between the degree of virilization defect and the type of androgen binding abnormalities and/or the nature of the mutation in the AR gene, we determined androgen binding characteristics of the AR protein and the sequence of the AR gene in clinically and biochemically well characterized patients with various degrees of androgen resistance.
The activity of 5 alpha-reductase and the binding of androgen to its receptor (KD-values, Bmax, thermolability) were determined in genital skin fibroblasts from 20 patients with various degrees of defects in virilization (2 CAIS, complete AIS; 18 PAIS, partial AIS patients). The AR gene of these 20 subjects was characterized by PCR-SSCP analysis. In case of aberrant electrophoretic mobility the corresponding exon was sequenced.
The 2 patients with CAIS and 7 with PAIS showed a mutation in the AR gene. In two, the mutation was in the DNA binding domain, and in all others in the ligand binding domain. In 11 patients with severe virilization defects no abnormal behaviour was detected in the PCR-SSCP. Transcriptional activation studies of two mutant ARs revealed that an approximately tenfold higher androgen concentration (methyltrienolone) is necessary to achieve maximal response as compared to the wild type AR.
There is no obvious relation between the degree of androgen resistance and the binding parameters of the AR and/or the nature of mutation in the AR gene. Androgen insensitivity syndrome can occur despite normal androgen binding and presumably non-mutated AR genes. Even if there is abnormal binding of androgen and/or a mutation in the AR gene there is no clear-cut relationship between these parameters and the degree of virilization defects. Thus, in a proportion of patients, neither the determination of binding parameters of the AR nor the detection of mutations in the AR gene are sufficient to understand the mechanisms underlying the androgen insensitivity syndrome.
46, XY核型且雄激素血水平正常甚至升高的个体中的雄激素不敏感综合征（AIS），其特征为男性分化和男性化过程存在各种异常。AIS常伴有雄激素受体（AR）广泛的异常结合特性。为了研究男性化缺陷程度与雄激素结合异常类型和/或AR基因突变性质之间的相关性，我们在临床和生化特征明确的不同程度雄激素抵抗患者中，测定了AR蛋白的雄激素结合特性及AR基因序列。
在20例不同程度男性化缺陷患者（2例完全性雄激素不敏感综合征，CAIS；18例部分性雄激素不敏感综合征，PAIS患者）的生殖器皮肤成纤维细胞中，测定5α-还原酶活性及雄激素与其受体的结合情况（解离常数KD值、最大结合容量Bmax、热稳定性）。通过PCR-SSCP分析对这20名受试者的AR基因进行特征分析。若电泳迁移率异常，则对相应外显子进行测序。
2例CAIS患者和7例PAIS患者的AR基因存在突变。其中2例突变位于DNA结合域，其他所有突变均位于配体结合域。11例严重男性化缺陷患者的PCR-SSCP未检测到异常行为。对两个突变AR的转录激活研究表明，与野生型AR相比，达到最大反应所需的雄激素（甲基三烯olone）浓度大约高10倍。
雄激素抵抗程度与AR的结合参数和/或AR基因突变性质之间无明显关联。即使雄激素结合正常且AR基因可能未发生突变，仍可发生雄激素不敏感综合征。即使存在雄激素结合异常和/或AR基因突变，这些参数与男性化缺陷程度之间也无明确关系。因此，在一部分患者中，测定AR的结合参数或检测AR基因突变，均不足以理解雄激素不敏感综合征的潜在机制。
