Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Chin Med J (Engl). 2011 Feb;124(4):551-5.
Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. This syndrome is partially caused by mutations in the human glucocorticoid receptor (hGR) gene. The clinical spectrum of generalized glucocorticoid resistance is broad, ranging from fatigue or no symptoms to severe hypertension with hypokalemic alkalosis. The purpose of this study was to explore the genetic disorder of glucocorticoid resistance syndrome.
We identified a 56-year-old male patient diagnosed with generalized glucocorticoid resistance syndrome accompanied with an adrenocortical adenoma. This asymptomatic patient referred to Peking Union Medical College Hospital for treatment of his adrenal incidentaloma. Endocrinological evaluation consistently revealed his elevated serum cortisol level. Total RNA was extracted from the patient's peripheral blood mononuclear leukocytes (PBMLs) and entire coding region of hGR alpha was amplified by reverse transcription (RT)-PCR. To confirm the possible mutation identified by sequencing RT-PCR products, genomic DNA sequence of hGR gene from the patient and 50 healthy controls was analyzed by PCR and directly sequencing.
A heterozygotic (C→T) substitution at nucleotide position of 1667 (exon 5) in GR alpha gene was found in this patient by sequencing of RT-PCR products of hGR gene. This substitution was also identified at genomic DNA level and it was absent in 100 chromosomes from 50 unrelated health controls. This substitution resulted in a threonine to isoleucine substitution (ACT→ATT) at amino acid 556 in the ligand-binding domain of GR alpha.
Generalized glucocorticoid resistance in this patient might be caused by a novel heterozygotic mutation in the ligand-binding domain of the GR alpha.
全身性糖皮质激素抵抗综合征是一种罕见的家族性或散发性疾病，其特征为全身性、部分性、靶组织对糖皮质激素不敏感。该综合征部分由人糖皮质激素受体（hGR）基因突变引起。全身性糖皮质激素抵抗的临床谱广泛，从疲劳或无症状到严重高血压伴低钾性碱中毒不等。本研究旨在探讨糖皮质激素抵抗综合征的遗传紊乱。
我们鉴定了一名 56 岁男性患者，该患者被诊断为全身性糖皮质激素抵抗综合征伴肾上腺皮质腺瘤。这名无症状患者因肾上腺意外瘤就诊于北京协和医院。内分泌评估始终显示血清皮质醇水平升高。从患者外周血单核白细胞（PBML）中提取总 RNA，并通过逆转录（RT）-PCR 扩增 hGRα的整个编码区。为了确认通过测序 RT-PCR 产物鉴定出的可能突变，使用 PCR 和直接测序分析了患者和 50 名健康对照者的 hGR 基因的基因组 DNA 序列。
通过对 hGR 基因的 RT-PCR 产物进行测序，发现该患者在 GRα基因的核苷酸位置 1667（外显子 5）处存在杂合性（C→T）取代。该取代也在基因组 DNA 水平上得到确认，并且在 50 名无关健康对照者的 100 条染色体中均不存在。该取代导致 GRα的配体结合域中第 556 位的苏氨酸变为异亮氨酸（ACT→ATT）。
该患者的全身性糖皮质激素抵抗可能是由 GRα配体结合域中的新型杂合突变引起的。
