MOLECULAR-BASIS OF ANDROGEN RESISTANCE IN A FAMILY WITH A QUALITATIVE ABNORMALITY OF THE ANDROGEN RECEPTOR AND RESPONSIVE TO HIGH-DOSE ANDROGEN THERAPY
MOLECULAR-BASIS OF ANDROGEN RESISTANCE IN A FAMILY WITH A QUALITATIVE ABNORMALITY OF THE ANDROGEN RECEPTOR AND RESPONSIVE TO HIGH-DOSE ANDROGEN THERAPY
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DOI：
10.1172/jci115147
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发表时间：
1991-04-01
影响因子：
15.9
通讯作者：
WILSON, JD
中科院分区：
文献类型：
--
作者：
MCPHAUL, MJ;MARCELLI, M;WILSON, JD
我们研究了一个男性化严重缺陷并伴有受体功能定性缺陷的家族中突变雄激素受体的性质。 该家族中的雄激素受体基因包含两个结构改变：外显子5中2444位的单核苷酸取代（腺苷->鸟苷），将酪氨酸761转化为半胱氨酸残基;外显子1中缩短的谷氨酰胺均聚片段，编码12个谷氨酰胺，而不是通常的20-22个谷氨酰胺。 使用聚合酶链反应扩增富含谷氨酰胺的片段进行了家族研究，结果表明先证者的妹妹不携带突变等位基因。 这两个突变对雄激素受体功能的影响进行了研究，通过引入的变化，单独和组合，到cDNA编码的正常人雄激素受体和分析后产生的受体蛋白质转染到真核细胞的cDNA。 761位半胱氨酸残基的存在导致二氢睾酮从受体蛋白快速解离。 然而，显着的热不稳定性的转染受体蛋白，是证明只有在引入雄激素受体cDNA含有部分缺失的谷氨酰胺均聚物片段和半胱氨酸残基的位置761。 同样，只有当两种改变都存在时，受体刺激报告基因的能力才显著降低，这表明缩短的谷氨酰胺均聚片段放大了由酪氨酸至半胱氨酸取代引起的受体功能受损。
We have examined the nature of the mutant androgen receptor in a family with a severe defect in virilization associated with a qualitative defect in receptor function. The androgen receptor gene in this family contains two structural alterations: a single nucleotide substitution at position 2444 in exon 5 (adenosine --> guanosine) that converts tyrosine 761 to a cysteine residue and a shortened glutamine homopolymeric segment in exon 1 that encodes 12 rather than the usual 20-22 glutamines. A family study was performed using polymerase chain reaction amplification of the glutamine-rich segment, and it was shown that the sister of the proband does not carry the mutant allele. The effects of these two mutations on the function of the androgen receptor were studied by introducing the changes, individually and in combination, into cDNAs encoding the normal human androgen receptor and analyzing the receptor protein produced after transfection of the cDNAs into eukaryotic cells. The presence of a cysteine residue at position 761 causes rapid dissociation of dihydrotestosterone from the receptor protein. Marked thermolability of the transfected receptor protein, however, was demonstrable only upon introduction of an androgen receptor cDNA containing both the partial deletion of the glutamine homopolymeric segment and a cysteine residue at position 761. Likewise, the ability of the receptor to stimulate a reporter gene is strikingly diminished only when both alterations are present, suggesting that the shortened glutamine homopolymeric segment amplifies the impairment of receptor function caused by the tyrosine to cysteine substitution.