Generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene

Background Generalized glucocorticoid resistance syndrome is a rare familial or sporadic condition characterized bygeneralized,partial,target-tissue insensitivity to glucocorticoids.This syndrome is partially caused by mutations in thehuman 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 toexplore the genetic disorder of glucocorticoid resistance syndrome.Methods We identified a 56-year-old male patient diagnosed with generalized glucocorticoid resistance syndromeaccompanied with an adrenocortical adenoma.This asymptomatic patient referred to Peking Union Medical CollegeHospital for treatment of his adrenal incidentaloma.Endocrinological evaluation consistently revealed his elevated serumCortisol level.Total RNA was extracted from the patient’s peripheral blood mononuclear leukocytes (PBMLs) and entirecoding region of hGR alpha was amplified by reverse transcription (RT)-PCR.To confirm the possible mutation identifiedby sequencing RT-PCR products,genomic DNA sequence of hGR gene from the patient and 50 healthy controls wasanalyzed 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 thispatient by sequencing of RT-PCR products of hGR gene.This substitution was also identified at genomic DNA level and itwas absent in 100 chromosomes from 50 unrelated health controls.This substitution resulted in a threonine to isoleucinesubstitution (ACT->ATT) at amino acid 556 in the ligand-binding domain of GR alpha.Conclusion Generalized glucocorticoid resistance in this patient might be caused by a novel heterozygotic mutation inthe ligand-binding domain of the GR alpha.