title: Genotype-phenotype correlation in a family with primary cortisol resistance: possible modulating effect of the ER22/23EK polymorphism.
abstract: OBJECTIVE
  Glucocorticoid resistance is a rare sporadic or familial condition that is characterized by generalized, partial resistance to glucocorticoids. It is caused by a mutation in the glucocorticoid receptor-alpha (GR-alpha) gene. We aimed to understand the reasons for different phenotypes (severe to asymptomatic) observed in a family with primary cortisol resistance.
  
  
  METHODS
  The genotype leading to cortisol resistance in the family members was investigated and correlated to the clinical phenotype.
  
  
  METHODS
  Three siblings were presented with clinical cortisol resistance, featuring severe hypertension, hypokalemia and hyperandrogenism. Three other siblings and both parents were asymptomatic. Genomic DNA from peripheral lymphocytes was isolated from family members. The entire GR-alpha coding sequence (exons 2-9) was amplified by PCR and sequenced.
  
  
  RESULTS
  A homozygous G679S mutation was present in the three clinically affected subjects. Heterozygous G66A (E22E) and G68A (R23K) polymorphisms and G2035A (G679S) mutation were found in the father and two siblings. Mother and one sibling had only heterozygous G679S mutation. The clinically unaffected subjects showed two different responses to dexamethason. Those with heterozygous G679S mutation and ER22/23EK polymorphism had normal cortisol suppression, whereas those with only heterozygous G679S mutation failed to suppress normally.
  
  
  CONCLUSIONS
  A homozygous G679S mutation of the GR-alpha gene is associated with severe cortisol resistance, whereas a heterozygous mutation of the same gene can lead to subclinical cortisol resistance. The effect of the heterozygous mutation was abolished in subjects carrying the ER22/23EK polymorphism.
authors: Departments of Medicine Genetics, King Faisal Specialist Hospital and Research Centre, PO Box 3354, Riyadh 11211, Saudi Arabia. hraef@kfshrc.edu.sa
authors: Hussein
authors: H
authors: Raef
authors: Essa Y
authors: EY
authors: Baitei
authors: Minjing
authors: M
authors: Zou
authors: Yufei
authors: Y
authors: Shi
mesh_terms: D000307:Adrenal Gland Diseases / Q000235:genetics*; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D001120:Arginine / Q000235:genetics; D005190:Family; D030342:Genetic Diseases, Inborn / Q000235:genetics; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D008239:Lysine / Q000235:genetics; D008297:Male; D010641:Phenotype; D011110:Polymorphism, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics*
chemical_list: D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D018698:Glutamic Acid; D001120:Arginine; D008239:Lysine; D006854:Hydrocortisone