Endocr Pract. 2020 Jun 2;26(6):651-659. doi: 10.4158/EP-2019-0475. Epub 2020 Feb 11.
Primary generalized glucocorticoid resistance (PGGR) is a rare hereditary disease characterized by generalized partial target-tissue insensitivity to glucocorticoids. To date, few cases have been reported, and more cases, especially involving other races, are needed to fully understand this disease. This study presented a novel glucocorticoid receptor mutation in a PGGR pedigree. The index patient was a 14-year-old male with fatigue, hypokalemia, hypertension, and polyuria. Eleven family members were available for the genetic screen. Next-generation sequencing and Sanger sequencing were used to identify the mutation. We systematically investigated the molecular mechanism through which the mutation impaired glucocorticoid signal transduction in COS-7 cells. The index patient carried a de novo homo-zygous mutation within exon 6 (c.1652C>A, p.551S>Y), whereas eight family members carrying a heterozygous mutation were all phenotypically silent. The affinity of the human glucocorticoid receptor (hGR) for the ligand was 1.97-fold lower in the patient than in the family members. Mutant hGRα (551Y) displayed a 3.2-fold reduction in its ability to transactivate glucocorticoid-responsive genes. When exposed to the same concentration of dexamethasone, hGRα (551Y) displayed a reduced ability to trans-locate into the nucleus and decreased levels of hGR dimer formation and could not effectively induce the glucocorticoid response element to regulate the transcription of related genes. After 2 years of dexamethasone treatment, the volume of the left and right adrenal glands of the index subject decreased by 55.6% and 32.4%, respectively. The pituitary volume decreased by 18.9%. During the 2-year follow-up, none of the heterozygous carriers developed hypertension or hypokalemia. We described a novel homozygous glucocorticoid receptor mutation causing PGGR. This homozygous mutation leads to hypertension and hypokalemia, but its heterozygous mutation has no relevant clinical symptoms. = adrenocorticotropic hormone; = DNA-binding domain; = glucocorticoid receptor; = glucocorticoid response element; = human glucocorticoid receptor; = ligand-binding domain; = primary generalized glucocorticoid resistance.
原发性全身性糖皮质激素抵抗（PGGR）是一种罕见的遗传性疾病，其特征为全身多个靶组织对糖皮质激素的部分敏感性降低。迄今为止，报道的病例较少，需要更多的病例，特别是涉及其他种族的病例，才能充分了解这种疾病。本研究在一个 PGGR 家系中发现了一个新的糖皮质激素受体突变。索引患者是一名 14 岁男性，表现为疲劳、低钾血症、高血压和多尿。有 11 个家族成员可用于基因筛查。下一代测序和 Sanger 测序用于识别突变。我们通过在 COS-7 细胞中系统地研究突变对糖皮质激素信号转导的影响，来探讨分子机制。索引患者携带一个位于外显子 6 中的纯合突变（c.1652C>A，p.551S>Y），而携带杂合突变的 8 个家族成员均表现为表型沉默。与家族成员相比，患者的人糖皮质激素受体（hGR）对配体的亲和力低 1.97 倍。突变型 hGRα（551Y）的糖皮质激素反应基因转录激活能力降低 3.2 倍。当暴露于相同浓度的地塞米松时，hGRα（551Y）的核易位能力降低，hGR 二聚体形成水平降低，不能有效诱导糖皮质激素反应元件调节相关基因的转录。经过 2 年的地塞米松治疗，患者的左右肾上腺体积分别减少了 55.6%和 32.4%，垂体体积减少了 18.9%。在 2 年的随访中，杂合携带者均未出现高血压或低钾血症。我们描述了一种新的导致 PGGR 的糖皮质激素受体纯合突变。这种纯合突变导致高血压和低钾血症，但杂合突变没有相关的临床症状。ACTH = 促肾上腺皮质激素；DNA-binding domain = DNA 结合域；GR = 糖皮质激素受体；GR = 糖皮质激素反应元件；hGR = 人糖皮质激素受体；LBD = 配体结合域；PGGR = 原发性全身性糖皮质激素抵抗。
