Novel mutations in the glucocorticoid receptor gene: from familial bilateral adrenal hyperplasia to glucocorticoid receptor haploinsufficiency
Jacques Young1,3, Severine Trabado1,3, Jerome Bouligand1,3, Larbi Amazit1, Say Viengchareun1, Anne Guiochon-Mantel1,3, Brigitte Delemer2 & Marc Lombes1,3
Glucocorticoid receptor (GR or NR3C1) is a ligand-dependent transcription factor that plays an essential role in differentiation, development, inflammatory responses and energy balance and is implicated in several human diseases. Eleven germinal GR mutations have been described so far, responsible for glucocorticoid resistance with variable clinical presentation.
We report original heterozygous GR mutations in three independent patients, which have been incidentally discovered in the context of bilateral adrenal hyperplasia and subclinical hypercorticism.
Investigation of adrenal incidentaloma leads to the discovery of a family (eight affected individuals spanning three generation) carrying the first nonsense GR mutation. This stop mutation (R469X) results in a non-functional 50-kDa truncated GR, lacking hormone and DNA binding capacity and devoid of hormone-dependent nuclear translocation and transactivation properties in vitro. We further provide evidence for an in vivo mechanism of a nonsense-mediated mRNA decay, which accounts for the lack of expression of the defective allele and GR hapoinsufficiency. In this kindred, we describe the natural history of the disease, as demonstrated by the degree of adrenal hyperplasia, the severity of the hypertension and the intensity of the apparent mineralocorticoid excess (urinary THE/THF) which exacerbated over time.
Two missense GR mutations (one in the N terminal domain, the other in the hinge region) did not lead to major functional alterations in terms of hormone binding, subcellular trafficking or transactivation. We exclude rare polymorphisms and are currently exploring transdominant negative effect and modification in coragulator recruitment.
Altogether, our results indicate that alteration of GR signaling may constitute an underestimated cause of bilateral adrenal hyperplasia and suggest a prominent role of intra-adrenal GR impacting adrenal cortical cell proliferation and function. Thus, we propose that GR genetic defects should be sought in patients with adrenal incidentalomas and subclinical hypercorticolism without signs of Cushing, especially when associated with hypertension and hypokalemia.