School of Medicine, University of Manchester, Manchester Academic Health Sciences Centre, Oxford Road, Manchester M13 9PT, United Kingdom.
J Clin Endocrinol Metab. 2010 Dec;95(12):E490-9. doi: 10.1210/jc.2010-0705. Epub 2010 Sep 22.
Familial glucocorticoid resistance is a rare condition with a typical presentation of women with hirsutism and hypertension, with or without hypokalemia.
The aim was to determine the cause of apparent glucocorticoid resistance in a young woman.
We studied a family with a novel glucocorticoid receptor (GR) mutation and a surprisingly mild phenotype. Their discovery resulted from serendipitous measurement of serum cortisol with little biochemical or clinical evidence for either hyperandrogenism or mineralocorticoid excess.
The causative mutation was identified as a frameshift mutation in exon 6. Transformed peripheral blood lymphocytes were generated to analyze GR expression in vitro. Carriers of the mutation had less full-length GR, but the predicted mutant GR protein was not detected. However, this does not exclude expression in vivo, and so the mutant GR (Δ612GR) was expressed in vitro. Simple reporter gene assays suggested that Δ612GR has dominant negative activity. Δ612GR was not subject to ligand-dependent Ser211 phosphorylation or to ligand-dependent degradation. A fluorophore-tagged construct showed that Δ612GR did not translocate to the nucleus in response to ligand and retarded translocation of the wild-type GR. These data suggest that Δ612GR is not capable of binding ligand and exerts dominant negative activity through heterodimerization with wild-type GR.
Therefore, we describe a novel, naturally occurring GR mutation that results in familial glucocorticoid resistance. The mutant GR protein, if expressed in vivo, is predicted to exert dominant negative activity by impairing wild-type GR nuclear translocation.
家族性糖皮质激素抵抗是一种罕见的疾病，其典型表现为女性出现多毛症和高血压，伴或不伴低钾血症。
确定一位年轻女性出现明显糖皮质激素抵抗的原因。
我们研究了一个携带有新型糖皮质激素受体（GR）突变的家族，其表型出奇地轻微。他们的发现源于偶然测量血清皮质醇，当时几乎没有生化或临床证据表明存在高雄激素血症或盐皮质激素过多。
确定了导致该疾病的突变是外显子 6 中的移码突变。生成转化的外周血淋巴细胞，以体外分析 GR 表达。突变携带者的全长 GR 较少，但未检测到预测的突变 GR 蛋白。然而，这并不能排除体内的表达，因此体外表达了突变的 GR（Δ612GR）。简单的报告基因检测表明，Δ612GR 具有显性负性活性。Δ612GR 不受配体依赖性 Ser211 磷酸化或配体依赖性降解的影响。荧光标记的构建体表明，Δ612GR 不能响应配体而向核内易位，并且延迟野生型 GR 的易位。这些数据表明，Δ612GR 不能结合配体，并且通过与野生型 GR 形成异二聚体发挥显性负性活性。
因此，我们描述了一种新型的、天然发生的 GR 突变，导致家族性糖皮质激素抵抗。如果突变的 GR 蛋白在体内表达，则预计通过损害野生型 GR 核易位而发挥显性负性活性。
