A novel point mutation in the ligand-binding domain of the human glucocorticoid receptor (hGR) in a patient with glucocorticoid resistance.

Abstract: The aim of this study is to evaluate the genetic abnormalities that led to a diagnosis of glucocorticoid resistance syndrome (GRS) in a young woman presenting with hirsutism and irregular menstrual cycles. A 16-yr-old girl presented with acne and hirsutism since menarche and recent secondary amenorrhea. The patient had borderline hypertension, but with no signs of hypercortisolism. She had an intact circadian rhythm of circulating ACTH and cortisol. Higher than normal oral doses of dexamethasone were required to decrease her serum cortisol significantly. We performed single-strand conformation polymorphism (SSCP) analysis to screen the gene encoding the isoform a of glucocorticoid receptor (GRa). Amplicons displaying abnormal migration pattern were subjected to direct sequencing. We found the patient heterozygous for a novel point mutation of GRa in exon 6 (Leu595Val), which yielded molecular structure, with functional consequences based on comparative molecular modeling of the ligand binding domain (LBD) of the wild-type and mutant GRa. She was also heterozygous for a silent mutation in exon 9 (Asn766Asn). We demonstrated that GRS was associated with a novel point mutation in the LBD of GRa gene that apparently modifies the binding to dexamethasone, in a young woman.