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Characterization of the androgen receptor (AR) in sexual differntiation to androgen insensitivity syndrome (AIS).

雄激素受体（AR）在雄激素不敏感综合征（AIS）性别分化中的特征。

基本信息

批准号：
09671654
负责人：
SHIMA Hiroki
金额：
$ 1.47万
依托单位：
Hyogo College of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09671654/
关键词：
androgen receptor androgen insensitivity syndrome gene mutation

项目摘要

The molecular basis of AIS was ultimately established by identification of mutations in the gene encoding the AR in individuals with various forms of this syndrome. We report point mutations in the AR gene of testicular feminization syndrome, and Reifenstein syndrome. These point mutations in the hormone binding domain of the AR were responsible for their thermolability in the radioreceptor assay using fibloblast cells derived from genitalia, which were confirmed through transactivation luciferase assay after transfection of the target genes into COS7 cells. The one mutant expression plasmid significantly decreased the transactivation activity in comparison with that of a wild type (58.5%, P<O.05), and two mutants expression plasmid (M807V, and R840H) significantly decreased the reporter gene activity in comparison with that of a wild type (64.5%, P<O.05). Transactivation assay with one of two mutations didn't show any difference of the reporter gene activity from that of a wild type. Although the replacement of one of two hydrophobic aminoacids for hydrophillic amino acid transfected into the one mutant expression plasmid significantly decreased the reporter gene activity in comparison with that of a wild type (34.8%, P<O.05). We suggest that the point mutation generating the replacement of hydrophobic amino acid for hydrophilic one could be one of the major causes for an ambiguous phenotype of genitalia in patients with ALS.We are undergoing differential display assay of the AR to investigate second message of the target gene.

AIS的分子基础最终是通过鉴定患有各种形式的这种综合征的个体中编码AR的基因的突变来建立的。我们报告了睾丸女性化综合征和赖芬斯坦综合征的AR基因点突变。AR的激素结合结构域中的这些点突变负责使用来自生殖器的成纤维细胞的放射受体测定中的热不稳定性，这在靶基因转染到COS 7细胞后通过反式激活荧光素酶测定得到证实。其中一个突变表达质粒的转录激活活性较野生型显著降低（58.5%，P<0.05），两个突变表达质粒（M807 V和R840 H）的报告基因活性较野生型显著降低（64.5%，P<0.05）。其中一个突变体的反式激活试验显示报告基因活性与野生型没有任何差异。将两个疏水性氨基酸中的一个替换为疏水性氨基酸后，报告基因的活性显著低于野生型（34.8%，P<0.05）。我们认为，点突变产生的疏水氨基酸取代为亲水的一个可能是一个重要的原因之一，在ALS患者的生殖器表型不明确。我们正在进行差异显示分析的AR的目的基因的第二信息。