Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation.
Cushing's disease preceded by generalized glucocorticoid resistance: clinical consequences of a novel, dominant-negative glucocorticoid receptor mutation.
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库欣病先于全身糖皮质激素抵抗：新型显性失活糖皮质激素受体突变的临床后果。
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发表时间：
1996
期刊：
影响因子：
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通讯作者：
G. Chrousos
中科院分区：
文献类型：
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作者：
M. Karl;S. Lamberts;J. Koper;D. Katz;N. Huizenga;T. Kino;B. Haddad;M. Hughes;G. Chrousos
全身性糖皮质激素抵抗与下丘脑-垂体-肾上腺轴的慢性过度激活有关，以补偿受损的糖皮质激素受体功能。我们报告一个独特的散发性全身性糖皮质激素抵抗患者，他在33岁时出现不孕不育和高血压，38岁时发展为脑垂体性库欣病。白细胞结合研究显示糖皮质激素受体的亲和力正常，但结合部位减少了50%。地塞米松不能抑制患者淋巴细胞的胸腺嘧啶核苷掺入。他在糖皮质激素受体基因上有一种新的杂合性错义突变(异亮氨酸559到天冬酰胺559)。突变型受体在体外对野生型受体诱导基因转录的能力表现出强烈的显性-负性效应。单细胞聚合酶链式反应显示，患者所有培养的淋巴母细胞和成纤维细胞以及50%的精子中都存在这种突变；他的父母和七个兄弟姐妹中没有这种突变。因此，这种新的突变既是从头开始的，也存在于生殖系中。该患者的垂体促肾上腺皮质激素瘤免疫组织化学染色显示P53蛋白积聚，表明肿瘤细胞中存在P53基因的体细胞致癌突变。对淋巴母细胞和皮肤成纤维细胞培养的P53异常的调查没有显示任何异常。因此，一种新的糖皮质激素受体新胚系突变具有很强的显性-负活性，导致了严重的散发性全身性糖皮质激素抵抗，这在促肾上腺皮质激素腺瘤形成之前。后者可能是由于慢性促肾上腺皮质激素过度刺激，糖皮质激素负反馈减少，以及至少一个随后的细胞周期控制的躯体缺陷的综合作用所致。
Generalized glucocorticoid resistance is associated with chronic hyperactivation of the hypothalamic-pituitary-adrenal axis, compensating for impaired glucocorticoid receptor function. We report a unique patient with sporadic generalized glucocorticoid resistance who, at age 33, presented with infertility and hypertension and, at 38, developed pituitary Cushing's disease. Leukocyte-binding studies revealed normal affinity of the glucocorticoid receptor but a reduction of binding sites by 50%. [3H]thymidine incorporation by this patient's lymphocytes was not suppressible by dexamethasone. He had a novel heterozygous missense mutation in the glucocorticoid receptor gene (isoleucine 559 to asparagine 559). The mutant receptor exhibited a strong dominant-negative effect on the ability of the wild-type receptor to induce gene transcription in vitro. The mutation was present in all of the patient's cultured lymphoblasts and fibroblasts as well as in 50% of his sperm, as demonstrated by single-cell polymerase chain reaction; it was not present in his parents and seven siblings. This novel mutation was thus both de novo and present in the germ line. Immunohistochemical staining of this patient's pituitary corticotropinoma revealed accumulation of p53 protein, indicating the presence of a putative somatic oncogenic mutation in the p53 gene in the tumor cells. Investigation of the lymphoblast and skin fibroblast cultures for p53 abnormalities did not show any aberration. Thus, a novel de novo germ line mutation of the glucocorticoid receptor with strong dominant-negative activity caused severe sporadic generalized glucocorticoid resistance, which preceded corticotroph adenoma formation. The latter probably was due to the combined effects of chronic corticotroph hyperstimulation, decreased glucocorticoid negative feedback, and at least one subsequent somatic defect in the control of the cell cycle.