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-a (GR-a) gene. We aimed to understand the reasons for different phenotypes (severe to asymptomatic) observed in a family with primary cortisol resistance. Design: The genotype leading to cortisol resistance in the family members was investigated and correlated to the clinical phenotype. Method: 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-a 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-a 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.

Investigation of glucocorticoid receptor polymorphisms in relation to metabolic parameters in Addison's disease

“…LDL increases with age, and a higher baseline LDL may be modified to a greater degree by the ER22/23EK polymorphism (45). Beneficial effects on LDLC are not universal and one study confirmed benefit by trend, but failed to reach statistical significance (21,44,46,47). The ER22/23EK polymorphism was rare and it is important to recall that we present only descriptive statistics.…”

Generalized glucocorticoid resistance caused by a novel two-nucleotide deletion in the hormone-binding domain of the glucocorticoid receptor gene NR3C1

“…Phenotypes may vary even among patients and relatives with the same disease-causing mutation (18,20,26). The characteristically low plasma renin and aldosterone levels in glucocorticoid resistance have been ascribed to the high cortisol level.…”

“…In glucocorticoid resistance, inappropriate binding of cortisol to the mineralocorticoid receptor causes increased sodium reabsorption and extracellular volume expansion, resulting in low renin and aldosterone levels and contributing to the elevated blood pressure. At least 14 mutations in NR3C1 in regions that encode the DNA-or hormone-binding domain of hGRa have been previously reported in patients with generalized glucocorticoid resistance (1,2,6,7,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26). Eleven of these mutations represent amino acid substituting point mutations in exons 4, 5, 7, 8, and 9a (6, 7, 12, 13, 14, 15, 16, 17, 18, 19).…”

“…Today, at least 14 mutations that impair or eliminate the intrinsic activity of hGRa have been identified in NR3C1 of patients with generalized glucocorticoid resistance (1,2,6,7,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26). Eleven of these mutations represent point mutations that substitute amino acids in the DNA-or hormone-binding domain of the hGRa (6,7,12,13,14,15,16,17,18,19).…”

Vulnerability to stroke: implications of perinatal programming of the Hypothalamic-Pituitary-Adrenal axis

“…There are significant differences in how individuals perceive and interpret stressors, and the encoding of memories of past stressful events influences one's response to future stressors (Buchanan and Lovallo, 2001; Marti et al, 2001; Wolf, 2003). Genetic factors also can contribute to individual differences in HPA function and stress responsivity (Kuningas et al, 2007; Ising et al, 2008; Peeters et al, 2008; Raef et al, 2008; Duan et al, 2009). Recognizing the potential for an interaction between glucocorticoid gene polymorphisms and environment in influencing physiological and behavioral phenotypes is also important (Bet et al, 2008).…”