title: Generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Generalized glucocorticoid resistance in this patient might be caused by a novel heterozygotic mutation in the ligand-binding domain of the GR alpha.
authors.affiliation: 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.
authors.forename: Hui-juan
authors.initials: HJ
authors.lastname: Zhu
authors.forename: Yu-fei
authors.initials: YF
authors.lastname: Dai
authors.forename: Ou
authors.initials: O
authors.lastname: Wang
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.forename: Wei-gang
authors.initials: WG
authors.lastname: Zhao
authors.forename: Xiao-ping
authors.initials: XP
authors.lastname: Xing
authors.forename: Hui
authors.initials: H
authors.lastname: Pan
authors.forename: Nai-shi
authors.initials: NS
authors.lastname: Li
authors.forename: Feng-ying
authors.initials: FY
authors.lastname: Gong
mesh_terms: D018246:Adrenocortical Adenoma / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics; D004700:Endocrine System Diseases / Q000235:genetics; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid