Response to treatment in patients with partial androgen insensitivity due to mutations in the DNA-binding domain of the androgen receptor
Response to treatment in patients with partial androgen insensitivity due to mutations in the DNA-binding domain of the androgen receptor
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DOI：
10.1159/000023519
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发表时间：
2000-01-01
期刊：
影响因子：
--
通讯作者：
Wedell, A
中科院分区：
文献类型：
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作者：
Giwercman, YL;Nikoshkov, A;Wedell, A
雄激素不敏感综合征是一种由雄激素受体功能缺陷引起的疾病，其特征是核型男性不同程度的男性化不足。我们在雄激素受体基因中发现了四个突变，位于编码蛋白质 DNA 结合域的区域。在对雄激素完全不敏感的患者中发现了两种突变，R607X 和 R615G，而另外两种突变，S578T 和 A596T，在部分不敏感的患者中发现。受体在 COS 细胞中瞬时表达后，在体外测定了三种错义突变的功能后果。所有突变体均表现出正常的雄激素结合能力，但刺激雄激素反应报告基因转录的能力异常。 R615G 消除了反式激活，而 S578T 和 A596T 部分功能失常。A596T 的功能（而非 S578T）在体外高雄激素浓度下正常化，反映了体内情况。因此，雄激素受体 DNA 结合域发生特定突变的患者可能会受益于雄激素治疗。版权所有 (C) 2000 S. Karger AG，巴塞尔。
The androgen insensitivity syndrome is a disorder caused by deficient function of the androgen receptor, characterized by varying degrees of undermasculinization in karyotypic males. We have identified four mutations in the androgen receptor gene, in the region encoding the DNA-binding domain of the protein. Two mutations, R607X and R615G, were found in patients with complete insensitivity to androgens, whereas the other two, S578T and A596T, were found in patients with partial insensitivity. The functional consequences of the three missense mutations were assayed in vitro after transient expression of the receptors in COS cells. All mutants showed normal androgen binding but abnormal abilities to stimulate transcription of an androgen-responsive reporter gene. R615G abolished transactivation whereas S578T and A596T were partially malfunctional, The function of A596T, but not of S578T, was normalized at high androgen concentrations in vitro, reflecting the in vivo situation. Thus, patients with specific mutations in the DNA-binding domain of the androgen receptor may benefit from androgen treatment. Copyright (C) 2000 S. Karger AG, Basel.