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首页> 外文期刊>Molecular and Cellular Endocrinology >A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation.
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A novel mutation F826L in the human androgen receptor in partial androgen insensitivity syndrome; increased NH2-/COOH-terminal domain interaction and TIF2 co-activation.

机译：部分雄激素不敏感综合征中人类雄激素受体中的新突变F826L;增加NH2- / COOH-末端域相互作用和TIF2共激活。

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摘要

A novel mutation F826L located within the ligand binding domain (LBD) of the human androgen receptor (AR) was investigated. This mutation was found in a boy with severe penoscrotal hypospadias (classified as 46,XY DSD). The AR mutant F826L appeared to be indistinguishable from the wild-type AR, with respect to ligand binding affinity, transcriptional activation of MMTV-luciferase and ARE2-TATA-luciferase reporter genes, protein level in genital skin fibroblasts (GSFs), and sub-cellular distribution in transfected cells. However, an at least two-fold higher NH2-/COOH-terminal domain interaction was found in luciferase and GST pull-down assays. A two-fold increase was also observed for TIF2 (transcription intermediary factor 2) co-activation of the AR F826L COOH-terminal domain. This increase could not be explained by a higher stability of the mutant protein, which was within wild-type range. Repression of transactivation by the nuclear receptor co-repressor (N-CoR) was not affected by the AR F826L mutation. The observed properties of AR F826L would be in agreement with an increased activity rather than with a partial defective AR transcriptional activation. It is concluded that the penoscrotal hypospadias in the present case is caused by an as yet unknown mechanism, which still may involve the mutant AR.
机译：研究了位于人类雄激素受体（AR）配体结合域（LBD）内的新型突变F826L。在患有严重的阴囊尿道下裂（分类为46，XY DSD）的男孩中发现了这种突变。就配体结合亲和力，MMTV-萤光素酶和ARE2-TATA-萤光素酶报告基因的转录激活，生殖器皮肤成纤维细胞（GSFs）中的蛋白质水平而言，AR突变体F826L与野生型AR似乎没有区别。转染细胞中的细胞分布。但是，在萤光素酶和GST下拉试验中发现至少NH2- / COOH-末端域相互作用高两倍。还观察到AR F826L COOH末端域的TIF2（转录中介因子2）共激活增加了两倍。这种增加不能用突变蛋白的更高稳定性来解释，突变蛋白在野生型范围内。核受体共阻遏物（N-CoR）抑制反式激活不受AR F826L突变的影响。 AR F826L的观察到的特性与增加的活性一致，而不是与AR转录激活的部分缺陷相一致。可以得出结论，本案中的阴囊尿道下裂是由尚不清楚的机制引起的，其仍可能涉及突变体AR。

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