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

Abstract

Objective: Generalized glucocorticoid resistance is characterized by impaired cortisol signaling, resulting from mutations of the glucocorticoid receptor (GR) gene NR3C1. The objective of our study was to identify the causative mutation in a patient with clinical manifestations compatible with generalized glucocorticoid resistance and to determine the functional consequences of the mutation. The possible occurrence of NR3C1 mutations in a selected group of hypertensive subjects with low plasma renin and aldosterone levels was also explored. Patients: The proband, a male athlete, was diagnosed with hypertension associated with low plasma renin activity and low serum aldosterone concentration at the age of 27 years. Liddle's syndrome was suspected and the patient was treated with amiloride with initial success. Subsequent examinations revealed elevated serum cortisol and ACTH levels, with resistance to suppression with low doses of dexamethasone. After identification of an NR3C1 mutation in the proband, the available family members and 51 nonrelated hypertensive subjects with low plasma renin and aldosterone concentrations were also studied. Results: A two-nucleotide deletion in exon 9a, predicted to cause a frameshift mutation (p.L773VfsX25) in the hormone-binding domain of the GR, was identified in the patient in a heterozygous form. Affected brother and father died of premature coronary heart disease. Functional studies in COS-1 cells showed that this mutation eliminates both ligand-binding and transactivation ability of the receptor. No pathogenic NR3C1 mutations were identified in 51 unrelated hypertensive patients with low plasma renin and aldosterone levels. Conclusion: We identified a novel frameshift mutation in NR3C1 as the cause of glucocorticoid resistance. The mutation eliminates the functional activity of the GR, as studied by in vitro experiments. Mutations in NR3C1 do not seem to be common causes for hypertension with low renin and aldosterone levels.

A secretagogin locus of the mammalian hypothalamus controls stress hormone release

“…Nr3c1 can both function as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription or act as a regulator of other transcription factors. Nr3c1 mutations manifest as generalized glucocorticoid resistance (Donner et al , ), characterized by the insensitivity of target tissues to glucocorticoids, resulting in the compensatory activation of the HPA axis and CRH hypersecretion into the systemic circulation. Thus, secretagogin may be the first molecular hinge linking Nr3c1‐mediated feedback to CRH release from parvocellular neurons.…”

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes

“…Cereblon (CRBN) was recently identified as being essential for the anti-MM activity of IMiDs. [11][12][13][14][15][16][17][18] To date, the reported incidence of mutations in proteasome subunits, the CRBN pathway, or the steroid receptor is low, and mutations in these genes, except in single case studies 19,20 or in vitro cell line analyses, 20,21 have not yet been identified as a major source of primary or acquired drug resistance in larger MM data sets.…”

Complex karyotype with cryptic FUS gene rearrangement and deletion of NR3C1 and VPREB1 genes in childhood B‑cell acute lymphoblastic leukemia: A case report

“…Interestingly, loss of NR3C1 gene is associated with glucocorticoid resistance, which is a key component of childhood ALL therapy. Besides, deletion of NR3C1 gene is rare in B-ALL and significantly associated with clinical high risk of relapse and an inferior outcome, where it correlated to high rate of induction failure and death (2,7,29).…”