A Novel Point Mutation in the Ligand-Binding Domain of the Human Glucocorticoid Receptor Causing Generalized Glucocorticoid Resistance: The Importance of the C Terminus in Conferring Transactivational Activity

The document reports on a study that discovered a novel point mutation in the ligand-binding domain (LBD) of the human glucocorticoid receptor (hGR), which led to generalized glucocorticoid resistance in a patient. The mutation, a T→C substitution at nucleotide position 2318, caused a leucine to proline substitution at amino acid position 773 (L773P). This mutation resulted in a 2-fold reduction in the receptor's ability to activate a glucocorticoid-inducible promoter, a 2.6-fold reduction in ligand affinity, delayed nuclear translocation, and abnormal interaction with the coactivator GRIP1. The study emphasizes the importance of the C terminus of the hGR LBD in receptor function and suggests that mutations in this region can significantly impair the receptor's multiple functions, leading to symptoms of glucocorticoid resistance. The patient's condition improved with high-dose dexamethasone treatment. The study did not specify the number of participants or samples used.