Establishment of the concept of androgen insensitivity syndrome due to the abnormality of transcriptional cofactor and analysis of the responsible cofactor.

我们发现一个病人谁被诊断为表型和内分泌完全雄激素不敏感综合征（AIS），但谁没有雄激素受体（AR）基因异常。与对照组相比，患者成纤维细胞中正常的整个AR的反式激活明显降低，强烈表明该患者由于辅激活因子的异常而表现出AIS。本研究的目的是建立共激活因子疾病的概念和分离其共激活因子，并获得以下结果。在来自患者的原代培养的生殖器皮肤成纤维细胞中通过AR、糖皮质激素受体（GR）、它们的AF-1-或AF-2-截短的受体以及它们的嵌合受体的反式激活的研究揭示，来自AR的AF-1的激活信号的传递被破坏。已知的转录辅因子的共转染没有恢复患者受损的AR依赖性反式激活。在患者成纤维细胞中，具有约90 kDa的表观Mr的蛋白质与AR的GST融合AF-1的结合丧失。以AR-AF-1为诱饵，利用酵母双杂交系统分离到一个增强AR依赖的反式激活的cDNA，从而建立了一种新的类固醇激素不敏感症--共激活因子疾病，并分离到一种AR-AF-1特异性共激活因子。

We found a patient who was diagnosed phenotypically and endocrinologically as having complete androgen insensitivity syndrome (AIS), but who had no abnormality in the androgen receptor (AR) gene. Transactivation by the normal entire AR in the patient fibroblasts was markedly low compared with that in the controls, strongly suggesting that this patient manifests AIS due to the abnormality of coactivator. The aims of the present study were the establishment of the concept of a coactivator disease and the isolation of its coactivator, and the following results were obtained. Investigation of the transactivation by the AR, glucocorticoid receptor (GR), their AF-1- or AF-2-truncated receptors and their chimeric receptors in primary-cultured genital skin fibroblasts from the patient revealed that transmission of the activation signal from AF-1 of the AR was disrupted. Co-transfection of known transcriptional cofactors did not restore the impaired AR-dependent transactivation in the patient. The binding of a protein with an apparent Mr of about 90 kDa to GST-fused AF-1 of the AR was lost in the patient fibroblasts. A cDNA which enhances the AR-dependent transactivation was isolated by yeast two hybrid system using as AR-AF-1 as a bait.In conclusion, we have established a new form of steroid hormone insensitivity, a coactivator disease, and also isolated one of the AR-AF-1-specific coactivators.