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

我们发现了一名患者，他的表型和内分泌学诊断为完全雄激素不敏感综合征(AIS)，但雄激素受体(AR)基因没有异常。与对照组相比，患者成纤维细胞中正常完整AR的反式激活显著降低，强烈提示该患者由于辅活化子的异常而表现为AIS。本研究的目的是建立共激活型疾病的概念并分离其共激活型疾病，并取得了以下结果。在原代培养的生殖器皮肤成纤维细胞中，对AR、糖皮质激素受体(GR)、其AF-1或AF-2截短受体及其嵌合受体反式激活的研究表明，AR的AF-1激活信号的传递被中断。共转染已知的转录辅因子不能恢复患者受损的AR依赖的反式激活。在患者成纤维细胞中，一个表观MR约为90 kDa的蛋白质与AR的GST融合的AF-1结合丢失。利用酵母双杂交系统，以AS AR-AF-1为诱饵，分离到一个增强AR依赖反式激活的基因，从而建立了一种新的类固醇激素不敏感型共激活剂病，并分离到一种AR-AF-1特异性辅激活剂。

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.