一个中国雄性激素不敏感综合征大家系中AR-Arg^(840)Cys突变的生物学效应

Resolving Pleiotropic Effects of an AR Arg^(840)Cys Mutant Detected in a Large Chinese AIS Family

雄性激素不敏感综合征在中国有一个患者大家系.遗传分析表明,雄性激素受体(AR)的Arg840Cys突变是引起本家系疾病的原因.家系中的患者个体呈现高度变异的表型特征.选择具有显著代表性的3个患者个体,成功建立了这些个体的生殖器皮肤成纤维细胞系(GSF),并研究了各细胞系的生长动力曲线和生长周期的分布,发现这些指标和个体病症的严重程度呈一定的正相关性.通过比较野生型与突变性AR的空间结构变化以及转激活能力的变化,结合个体表型的差异性,推测由于个体的基因背景差异,相关AR辅调控因子的表达也会存在着差异,可能最终导致该家系患者显著的表型变化.目前,已利用蛋白质双向电泳,观察到个体间差异表达的蛋白,并在其中寻找AR的辅调控因子,以期进一步阐明AR-Arg840Cys突变一因多效性的机制.

We created genital skin fibroblast cell lines directly from three patients in a Chinese family affected with androgen insensitivity syndrome（AIS）. The disease pedigree was characterized by that all patients in the family shared an identical Arg^840Cys mutant in androgen receptor（AR） but showed quite different phenotypes of the disease trait. We found that the cell growth curve and cell cycles established from these cell lines were significantly associated with severity of their donors＇ disease phenotype. Comparison was made in transcriptional activity and 3-D protein structure between a normal and mutant AR in the light of the mutant defecting. This revealed that although etiology of AIS is monogenic, the mutant may influence significantly several major aspects of the cells＇ biological characters in comparison to those of its wild allele. The observation highlights the significance of varying genetic backgrounds in shaping the divergent disease phenotypes. As an initial attempt to explore interaction between the defected AR and its co-regulators, we reported here also the experimental evidence of 2D-PAGE profiles that would be useful to guide a hunt for these co-regulators.