A novel mutation in the human androgen receptor suggests a regulatory role for the hinge region in amino-terminal and carboxy-terminal interactions
A novel mutation in the human androgen receptor suggests a regulatory role for the hinge region in amino-terminal and carboxy-terminal interactions
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DOI：
10.1210/jc.2008-0737
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发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Hughes, I. A.
中科院分区：
文献类型：
--
作者：
Deeb, A.;Jaeaeskelaeinen, J.;Hughes, I. A.
背景：雄激素不敏感综合征（AIS）是由雄激素受体（AR）的分子缺陷引起的。在临床上，部分AIS具有可变的表型。许多机制可以解释AIS的表型。AR作用的一个关键步骤是N端和C端的相互作用。目的：AR铰链区的作用不如受体的其他部分那么清楚。我们的目的是研究这一地区的N/C-termini interaction.Patient和方法的作用：我们报告一个严重的男性化不足和外源性雄激素反应不良的患者。进行雄激素结合，并对AR基因进行测序。在COS-1细胞中重建突变并转染。研究了反式激活。使用哺乳动物双杂交测定研究N/C-末端相互作用。结果：雄激素结合正常，在AR铰链区发现一个新的突变（Arg 629 Trp）。突变体AR反式激活比野生型（WT）高40%。当WT N和C端结构域共转染时，转录增加3倍;当包括AR的突变区域时，没有反应发生（P < 0.001）。突变体AR的细胞表现出相当的核定位的WT AR。结论：在铰链区的突变受损的N/C-结构域的相互作用，在正常的AR结合和核定位的存在下。它导致出生时严重的男性化不足和对雄激素的抵抗。这些发现证实了铰链区在AR功能中的独特调节作用。
Context: The androgen insensitivity syndrome (AIS) is caused by molecular defects in the androgen receptor (AR). Clinically, the partial AIS has a variable phenotype. Many mechanisms explain the phenotype in the AIS. A crucial step in AR action is the interaction of the N and C termini.Objective: The role of the hinge region of the AR is not as well understood as other parts of the receptor. We aim to study the role of this region in the N/C-termini interaction.Patient and Method: We report a patient with severe undermasculinization and poor response to exogenous androgens. Androgen binding was performed, and the AR gene was sequenced. The mutation was recreated and transfected in COS-1 cells. Transactivation was studied. N/C-termini interaction was studied using a mammalian two-hybrid assay. A nuclear localization study was performed.Results: Androgen binding was normal, and a novel mutation (Arg629Trp) in the AR hinge region was identified. Mutant AR transactivation was 40% higher compared with wild type (WT). A3-fold increase in transcription occurred when both WT N and C-terminal domains were cotransfected; no response occurred when the mutated region of the AR was included (P < 0.001). Cells with mutant AR showed a comparable nuclear localization to the WT AR.Conclusions: A mutation in the hinge region impaired N/C-domain interaction in the presence of normal AR binding and nuclear localization. It resulted in severe undermasculinization at birth and resistance to androgens. The findings confirm a unique regulatory role for the hinge region in AR function.