This work investigates how mutant gonadotropin‑releasing hormone receptors (GnRHRs) contribute to disease by altering receptor trafficking and function. Epitope tagging was shown to artificially increase cell surface expression of mutant receptors, leading to earlier misinterpretations. In reality, mutant GnRHRs are retained in the endoplasmic reticulum (ER), where they also trap wild‑type receptors, causing a dominant‑negative effect. Pharmacological chaperones can restore proper folding and membrane localization. The ER chaperone calnexin plays a key role in regulating GnRHR trafficking, highlighting pharmacoperones as potential therapies for diseases caused by ER‑retained proteins.
