Familial glucocorticoid receptor haploinsufficiency by non-sense mediated mRNA decay, adrenal hyperplasia and apparent mineralocorticoid excess.
Familial glucocorticoid receptor haploinsufficiency by non-sense mediated mRNA decay, adrenal hyperplasia and apparent mineralocorticoid excess.
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DOI：
10.1371/journal.pone.0013563
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发表时间：
2010-10-22
期刊：
影响因子：
3.7
通讯作者：
Lombès M
中科院分区：
文献类型：
--
作者：
Bouligand J;Delemer B;Hecart AC;Meduri G;Viengchareun S;Amazit L;Trabado S;Fève B;Guiochon-Mantel A;Young J;Lombès M
原发性糖皮质激素抵抗（OMIM 138040）是一种罕见的遗传性疾病，由于糖皮质激素受体（GR）的遗传改变，导致对糖皮质激素作用的全身性部分不敏感。对肾上腺偶发瘤的调查发现了一个家族（跨越三代的八个受影响的个体），易于皮质醇抵抗、双侧肾上腺增生、动脉高血压和低钾血症。这种表型随着时间的推移而加剧，与迄今为止报道的GR的第一个杂合无义突变p.R469[R，X]共分离，在受体的DNA结合结构域的第二锌指的氨基酸469处，精氨酸（CGA）被终止（TGA）取代。在体外，这种突变导致截短的50-kDa GR缺乏激素和DNA结合能力，缺乏依赖性的核转位和反式激活特性。在先证者的成纤维细胞中，我们提供了体内缺乏缺陷等位基因表达的证据。可检测的突变GR mRNA的缺失伴随着野生型GR转录物和蛋白质的50%减少。这种GR表达的降低导致成纤维细胞中糖皮质激素诱导的靶基因FKBP 5的诱导显著低于正常水平。我们证明了糖皮质激素信号传导功能障碍的分子机制涉及GR单倍不足，这是由于突变的GR转录物通过无义介导的mRNA衰变的选择性降解，这在依米丁处理的先证者的成纤维细胞上得到了实验验证。GR单倍不足导致高血压是由于皮质醇升高非法占据肾盐皮质激素受体，而不是原发性糖皮质激素抵抗中报告的盐皮质激素产生增加。事实上，受影响患者尿四氢可的松-四氢皮质醇比值降低证明了明显的盐皮质激素过量，表明11β-羟类固醇脱氢酶2型（GR调节基因）的肾活性降低了糖皮质激素降解。因此，我们建议GR单倍不足损害糖皮质激素的敏感性，并可能代表一种新的遗传原因的亚临床皮质醇增多症，偶然发现双侧肾上腺皮质增生和盐皮质激素非依赖性高血压。
Primary glucocorticoid resistance (OMIM 138040) is a rare hereditary disease that causes a generalized partial insensitivity to glucocorticoid action, due to genetic alterations of the glucocorticoid receptor (GR). Investigation of adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to cortisol resistance, bilateral adrenal hyperplasia, arterial hypertension and hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous nonsense mutation p.R469[R,X] reported to date for the GR, replacing an arginine (CGA) by a stop (TGA) at amino-acid 469 in the second zinc finger of the DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking hormone and DNA binding capacity, devoid of hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR mRNA was accompanied by a 50% reduction in wild type GR transcript and protein. This reduced GR expression leads to a significantly below-normal induction of glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to hypertension due to illicit occupation of renal mineralocorticoid receptor by elevated cortisol rather than to increased mineralocorticoid production reported in primary glucocorticoid resistance. Indeed, apparent mineralocorticoid excess was demonstrated by a decrease in urinary tetrahydrocortisone-tetrahydrocortisol ratio in affected patients, revealing reduced glucocorticoid degradation by renal activity of the 11β-hydroxysteroid dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises glucocorticoid sensitivity and may represent a novel genetic cause of subclinical hypercortisolism, incidentally revealed bilateral adrenal hyperplasia and mineralocorticoid-independent hypertension.
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