Abstract
Mutant gonadotropin-releasing hormone (GnRH) receptors isolated from patients with GnRH-resistant hypogonadotropic hypogonadism are frequently proteins that are misrouted in the cell. Such mutant receptors are retained in the endoplasmic reticulum and can be rescued by pharmacological chaperones. This understanding contrasts with the view that these mutant receptors lose the ability to bind ligand or effect signal transduction. Pharmacological chaperones, or “pharmacoperones,” bind specifically to GnRH receptors and allow them to escape retention by the cellular quality control systems and route to the plasma membrane, where they function normally. This observation suggests that pharmacoperones have the potential to be used to treat a number of human diseases characterized by misrouted proteins, among these, hypogonadotropic hypogonadism, cystic fibrosis and nephrogenic diabetes insipidus.