Tsukada T, Inoue M, Tachibana S, Nakai Y, Takebe H
Department of Experimental Radiology, Kyoto University Faculty of Medicine, Japan.
J Clin Endocrinol Metab. 1994 Oct;79(4):1202-7. doi: 10.1210/jcem.79.4.7962294.
The molecular basis of androgen resistance was investigated in a patient with undervirilized male syndrome. Binding studies of the androgen receptors in the patient's genital skin fibroblasts revealed a normal binding capacity of 5 alpha-dihydrotestosterone, although the affinity to androgen was slightly lower than the normal control value. The androgen binding of the patient's receptor showed a moderate thermal instability when the assay temperature was raised from 30 to 41 C. Nucleotide sequencing analysis of the androgen receptor gene revealed a single nucleotide substitution in exon F, resulting in an amino acid alteration from leucine (CTC) to phenylalanine (TTC) at position 789 within the steroid-binding domain of androgen receptor. When expressed in COS-7 cells, the mutant androgen receptor harboring phenylalanine at position 789 showed thermolabile androgen-binding properties similar to those observed in the patient's genital skin fibroblasts. Cotransfection experiments with an androgen-inducible reporter gene demonstrated a decreased transactivational capability of the mutant receptor. These results indicate that this point mutation modified the receptor function and caused androgen resistance in this patient. This mutation caused the mildest form of all androgen insensitivity syndromes ever examined for mutations in the androgen receptor gene.
对一名男性化不足综合征患者的雄激素抵抗分子基础进行了研究。对患者生殖器皮肤成纤维细胞中的雄激素受体进行结合研究发现，5α - 双氢睾酮的结合能力正常，尽管其对雄激素的亲和力略低于正常对照值。当检测温度从30℃升高到41℃时，患者受体的雄激素结合表现出中度的热不稳定性。对雄激素受体基因进行核苷酸测序分析发现，外显子F中有一个单核苷酸替换，导致雄激素受体类固醇结合域内第789位的氨基酸从亮氨酸（CTC）变为苯丙氨酸（TTC）。当在COS - 7细胞中表达时，在第789位含有苯丙氨酸的突变雄激素受体表现出与在患者生殖器皮肤成纤维细胞中观察到的类似的热不稳定雄激素结合特性。用雄激素诱导报告基因进行的共转染实验表明，突变受体的反式激活能力降低。这些结果表明，该点突变改变了受体功能并导致该患者出现雄激素抵抗。该突变导致了所有曾检测雄激素受体基因突变的雄激素不敏感综合征中最轻微的一种形式。
