Congenital androgen insensitivity due to a qualitatively abnormal androgen receptor.
Congenital androgen insensitivity due to a qualitatively abnormal androgen receptor.
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由于雄激素受体质量异常而导致先天性雄激素不敏感。
DOI：
10.1002/ajmg.1320100111
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发表时间：
1981
期刊：
影响因子：
--
通讯作者：
R. Summitt
中科院分区：
文献类型：
--
作者：
L. Pinsky;M. Kaufman;R. Summitt
在培养的生殖器皮肤成纤维细胞中，完全或不完全雄激素不敏感(AI)与特异性5-α-双氢睾酮受体活性缺乏相关，可能是由于受体的定性异常或受体后靶细胞对双氢睾酮敏感性的缺陷所致。我们研究了一名散发性完全性AI患者，其平均受体容量(Bmax)为34fmol/mg蛋白，另一名患者为不完全性AI，多个受累的母系亲属，平均Bmax为40(正常：15-50)。每一个都有正常的5α-还原酶活性。每种受体活性的下列性质都是正常的：平衡解离常数(Kd)，凝胶层析洗脱图谱，DHT-受体复合体的核转位，以及核复合体的0.4M KCl萃取率。在37°C预培养和42°C(与通常的37°C相比)下，“完全人工智能”患者细胞中的受体活性比7个对照细胞系中的任何一个细胞系中的受体活性下降(60%)得多(±20%)；相反，“不完全人工智能”患者细胞中的受体活性下降到一个可变的、可疑的异常程度。在37℃时，两组患者雄激素受体复合体的解离速率常数(k−1)分别为18×10−3min−1和5.9±0.32×10−3min−1(n=15)。因此，我们定义了两名具有不同临床程度的先天性AI患者的雄激素受体活性的新的质量缺陷，尽管雄激素结合水平正常。这些缺陷将被用作遗传学研究的标记和人类类固醇耐药癌症的分子模型。
Complete or incomplete androgen insensitivity (AI) not associated with deficient specific 5α-dihydrotestosterone (DHT)-receptor activity in cultured genital skin fibroblasts may result from a qualitative receptor abnormality or a postreceptor defect in target cell sensitivity to DHT. We have studied a sporadic patient with complete AI whose mean receptor capacity (Bmax) is 34 fmol/mg protein and a second with incomplete AI, multiple affected maternal relatives, and a mean Bmax of 40 (normal: 15 – 50). Each has normal 5α-reductase activity. The following qualities of the receptor activity are normal in each: Equilibrium dissociation constant (Kd), elution profile on gel chromatography, nuclear translocation of the DHT-receptor complex, and 0.4 M KCl extractability of the nuclear complex. When preincubated at 37°C and assayed at 42°C (compared with the usual 37°C) the receptor activity in cells of the “complete AI” patient decreased much more (60%) than that of any of 7 control cell lines (± 20%); the activity in cells of the “incomplete AI” patient, in contrast, decreased to a variable, questionably abnormal extent. When preincubated, assayed, and chased at 37°C with excess radioinert DHT, the androgen-receptor complexes in both patients dissociated with a rate constant (k−1) about 18 × 10−3 min−1 compared with a normal of 5.9 ± 0.32 × 10−3 min−1 (± SEM; n = 15). We have thus defined novel qualitative defects of the androgen receptor activity in two patients who have different clinical degrees of congenital AI despite normal levels of androgen binding. These defects will be useful as markers for genetic studies and as molecular models for steroid-resistant cancer in man.