A NOVEL GLUCOCORTICOID RECEPTOR MUTATION IN PRIMARY GENERALIZED GLUCOCORTICOID RESISTANCE DISEASE

Objective: Primary generalized glucocorticoid resistance (PGGR) is a rare hereditary disease characterized by generalized partial target-tissue insensitivity to glucocorticoids. To date, few cases have been reported, and more cases, especially involving other races, are needed to fully understand this disease. Methods: This study presented a novel glucocorticoid receptor mutation in a PGGR pedigree. The index patient was a 14-year-old male with fatigue, hypokalemia, hypertension, and polyuria. Eleven family members were available for the genetic screen. Next-generation sequencing and Sanger sequencing were used to identify the mutation. We systematically investigated the molecular mechanism through which the mutation impaired glucocorticoid signal transduction in COS-7 cells. Results: The index patient carried a de novo homozygous mutation within exon 6 (c.1652C>A, p.551S>Y), whereas eight family members carrying a heterozygous mutation were all phenotypically silent. The affinity of the human glucocorticoid receptor (hGR) for the ligand was 1.97-fold lower in the patient than in the family members. Mutant hGR alpha (551Y) displayed a 3.2-fold reduction in its ability to transactivate glucocorticoid-responsive genes. When exposed to the same concentration of dexamethasone, hGR alpha (551Y) displayed a reduced ability to translocate into the nucleus and decreased levels of hGR dimer formation and could not effectively induce the glucocorticoid response element to regulate the transcription of related genes. After 2 years of dexamethasone treatment, the volume of the left and right adrenal glands of the index subject decreased by 55.6% and 32.4%, respectively. The pituitary volume decreased by 18.9%. During the 2-year follow-up, none of the heterozygous carriers developed hypertension or hypokalemia. Conclusion: We described a novel homozygous glucocorticoid receptor mutation causing PGGR. This homozygous mutation leads to hypertension and hypokalemia, but its heterozygous mutation has no relevant clinical symptoms.