Yong E L, Tut T G, Ghadessy F J, Prins G, Ratnam S S
Department of Obstetrics and Gynaecology, National University of Singapore, Singapore.
Mol Cell Endocrinol. 1998 Feb;137(1):41-50. doi: 10.1016/s0303-7207(97)00229-3.
Genetic defects of the human androgen receptor (AR) can cause a wide spectrum of androgen insensitivity syndromes (AIS) ranging from phenotypic females in those with complete AIS; ambiguous genitalia in partial AIS; to male infertility in minimal AIS. The majority of these defects are due to point mutations resulting in amino acid substitutions. It is however unclear why certain mutations result in partial AIS, whereas others in the same exon cause the complete syndrome. We present a case of partial AIS due to a point mutation affecting codon 758 of the AR ligand-binding domain (LBD) that changed the sense of the codon from asparagine to threonine (N758T). The mutant receptor displayed normal binding affinity to DHT but abnormal dissociation kinetics in both patient's fibroblasts and transfected COS-7 cells. The mutant AR was thermolabile, and resulted in approximately 50% reduction in receptor transactivation capacity when examined with a reporter gene incorporating an androgen-response-element. Although the 3-D structure of AR LBD is not known, the homologous region in a member of the steroid receptor superfamily, retinoid-X receptor (RXR-alpha), has been crystallized, allowing comparison of aligned amino-acid sequences of RXR-alpha and AR. The mutation, N758T, lies in a predicted linker region between the fifth alpha-helix (H5) and the first beta-strand (S1). Generally, mutations leading to partial AIS tend to cluster in the predicted linker regions located between the structural helices of the AR LBD. Most strikingly, the predicted linker regions contain over 70% of the mutant ARs associated with prostate cancer in the LBD. The occurrence of mutations associated with both partial AIS and prostate cancer in the same predicted linker regions, suggest that this clustering is not coincidental and that the predicted linker regions are likely to have important, but subtle, roles in defining androgen binding and ligand specificity.
人类雄激素受体（AR）的基因缺陷可导致一系列广泛的雄激素不敏感综合征（AIS），从完全性AIS患者的女性表型，到部分性AIS患者的生殖器模糊，再到轻度AIS患者的男性不育。这些缺陷大多是由导致氨基酸替换的点突变引起的。然而，尚不清楚为何某些突变会导致部分性AIS，而同一外显子中的其他突变却会导致完全性综合征。我们报告了一例因点突变影响AR配体结合域（LBD）密码子758而导致的部分性AIS病例，该突变使密码子的编码从天冬酰胺变为苏氨酸（N758T）。在患者的成纤维细胞和转染的COS-7细胞中，突变受体对双氢睾酮（DHT）显示出正常的结合亲和力，但解离动力学异常。突变型AR不耐热，当用包含雄激素反应元件的报告基因检测时，受体反式激活能力降低约50%。尽管AR LBD的三维结构尚不清楚，但类固醇受体超家族成员视黄酸X受体（RXR-α）中的同源区域已被结晶，从而可以比较RXR-α和AR的比对氨基酸序列。N758T突变位于预测的第五个α螺旋（H5）和第一个β链（S1）之间的连接区域。一般来说，导致部分性AIS的突变往往聚集在AR LBD结构螺旋之间的预测连接区域。最引人注目的是，预测的连接区域包含了LBD中与前列腺癌相关的超过70%的突变型AR。在相同的预测连接区域中同时出现与部分性AIS和前列腺癌相关的突变，表明这种聚集并非偶然，并且预测的连接区域在定义雄激素结合和配体特异性方面可能具有重要但微妙的作用。
