Mighell, T.; Lehner, B.

Reduced protein stability is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating destabilizing variants is pharmacological chaperones (PCs, also known as correctors or stabilizers), small molecules that bind to and stabilize target proteins. PCs have been approved as clinical treatments for specific variants, but protein energetics suggest their effects might be much more general. Here, we test this hypothesis for the first time by comprehensively quantifying PC efficacy for all missense variants in a human disease gene, the vasopressin 2 receptor (V2R), a G-protein coupled receptor in which loss-of-function variants cause nephrogenic diabetes insipidus (NDI). Strikingly, treatment with a PC rescues the expression of nearly all destabilized variants, with non-rescued variants identifying the drug\'s binding site. Our results provide proof-of-principle that a single small molecule can rescue destabilizing variants throughout a protein\'s structure. The application of this principle to other proteins should allow the development of effective therapies for many genetic diseases.