Androgen Receptor Exon 1 Mutation Causes Androgen Insensitivity by Creating Phosphorylation Site and Inhibiting Melanoma Antigen-A11 Activation of NH2- and Carboxyl-terminal Interaction-dependent Transactivation
Androgen Receptor Exon 1 Mutation Causes Androgen Insensitivity by Creating Phosphorylation Site and Inhibiting Melanoma Antigen-A11 Activation of NH2- and Carboxyl-terminal Interaction-dependent Transactivation
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DOI：
10.1074/jbc.m111.336081
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发表时间：
2012-03-30
影响因子：
4.8
通讯作者：
Wilson, Elizabeth M.
中科院分区：
文献类型：
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作者：
Lagarde, William H.;Blackwelder, Amanda J.;Wilson, Elizabeth M.
X连锁人类雄激素受体（AR）基因中自然发生的种系突变通过破坏患有雄激素不敏感综合征的男性的AR功能，导致外生殖器不完全男性化。几乎所有引起雄激素不敏感综合征的 AR 错义突变都位于高度结构化的 DNA 和配体结合域中。在本报告中，我们研究了与 AR 外显子 1 错义突变 R405S 相关的功能缺陷，该突变导致部分雄激素不敏感。 46,XX 杂合母体携带者具有野生型 Arg-405 CGC 等位基因，但传播编码 Ser-405 的 AGC 突变等位基因。出生时，46,XY先证者有阴囊裂、尿道下裂和小阴茎，符合临床3期部分雄激素不敏感。 CV1 细胞中表达的 AR-R405S 的雄激素依赖性转录活性低于野生型 AR，并且在依赖于黑色素瘤抗原 A11 的共调节因子效应的雄激素依赖性 AR NH2 和羧基相互作用转录测定中难以进行。该突变产生了 Ser-405 磷酸化位点，通过 AR-R405S NH2 末端片段的凝胶迁移可以明显看出，双带在用 lambda-磷酸酶处理后转变为野生型单带。 R405S 突变的有害影响与黑色素瘤抗原 A11 和 p300 所需的 AR WXXLF 基序 (WHTLF437)-W-433 的接近有关，以刺激与 AR NH2 和羧基末端相互作用相关的转录活性。我们得出的结论是，黑色素瘤抗原 A11 对 AR NH2 和羧基末端相互作用的共调节作用放大了正常人类男性子宫内性别发育所需的对 p300 的雄激素依赖性转录反应。
Naturally occurring germ line mutations in the X-linked human androgen receptor (AR) gene cause incomplete masculinization of the external genitalia by disrupting AR function in males with androgen insensitivity syndrome. Almost all AR missense mutations that cause androgen insensitivity syndrome are located in the highly structured DNA and ligand binding domains. In this report we investigate the functional defect associated with an AR exon 1 missense mutation, R405S, that caused partial androgen insensitivity. The 46,XX heterozygous maternal carrier had a wild-type Arg-405 CGC allele but transmitted an AGC mutant allele coding for Ser-405. At birth, the 46,XY proband had a bifid scrotum, hypospadias, and micropenis consistent with clinical stage 3 partial androgen insensitivity. Androgen-dependent transcriptional activity of AR-R405S expressed in CV1 cells was less than wild-type AR and refractory in androgen-dependent AR NH2- and carboxyl interaction transcription assays that depend on the coregulator effects of melanoma antigen-A11. This mutation created a Ser-405 phosphorylation site evident by the gel migration of an AR-R405S NH2-terminal fragment as a double band that converted to the wild-type single band after treatment with lambda-phosphatase. Detrimental effects of the R405S mutation were related to the proximity of the AR WXXLF motif (WHTLF437)-W-433 required for melanoma antigen-A11 and p300 to stimulate transcriptional activity associated with the AR NH2- and carboxyl-terminal interaction. We conclude that the coregulator effects of melanoma antigen-A11 on the AR NH2- and carboxyl-terminal interaction amplify the androgen-dependent transcriptional response to p300 required for normal human male sex development in utero.