Primary
glucocorticoid resistance (OMIM 138040) is a rare
hereditary disease that causes a generalized partial insensitivity to
glucocorticoid action, due to genetic alterations of the
glucocorticoid receptor (GR). Investigation of
adrenal incidentalomas led to the discovery of a family (eight affected individuals spanning three generations), prone to
cortisol resistance, bilateral adrenal
hyperplasia, arterial
hypertension and
hypokalemia. This phenotype exacerbated over time, cosegregates with the first heterozygous
nonsense mutation p.R469[R,X] reported to date for the GR, replacing an
arginine (CGA) by a stop (TGA) at
amino-acid 469 in the second zinc finger of the
DNA-binding domain of the receptor. In vitro, this mutation leads to a truncated 50-kDa GR lacking
hormone and
DNA binding capacity, devoid of
hormone-dependent nuclear translocation and transactivation properties. In the proband's fibroblasts, we provided evidence for the lack of expression of the defective allele in vivo. The absence of detectable mutated GR
mRNA was accompanied by a 50% reduction in wild type GR transcript and
protein. This reduced GR expression leads to a significantly below-normal induction of
glucocorticoid-induced target genes, FKBP5 in fibroblasts. We demonstrated that the molecular mechanisms of
glucocorticoid signaling dysfunction involved GR haploinsufficiency due to the selective degradation of the mutated GR transcript through a nonsense-mediated mRNA Decay that was experimentally validated on
emetine-treated propositus' fibroblasts. GR haploinsufficiency leads to
hypertension due to illicit occupation of renal
mineralocorticoid receptor by elevated
cortisol rather than to increased
mineralocorticoid production reported in primary
glucocorticoid resistance. Indeed, apparent
mineralocorticoid excess was demonstrated by a decrease in urinary
tetrahydrocortisone-
tetrahydrocortisol ratio in affected patients, revealing reduced
glucocorticoid degradation by renal activity of the 11β-hydroxysteroid
dehydrogenase type 2, a GR regulated gene. We propose thus that GR haploinsufficiency compromises
glucocorticoid sensitivity and may represent a novel genetic cause of subclinical
hypercortisolism, incidentally revealed bilateral adrenal
hyperplasia and
mineralocorticoid-independent
hypertension.