Loss-of-function mutations in the human luteinizing hormone receptor predominantly cause intracellular retention

Abstract

Mutations in G protein-coupled receptors (GPCRs) have been identified for many endocrine hormonesignaling deficiencies. Inactivating mutations can impair ligand binding, receptor activation/ coupling to signaling pathways, or can cause receptor misfolding and consequent impaired expression at the cell membrane. Here we examine the cell surface expression, ligand binding, and signaling of a range of mutant human luteinizing hormone receptors (LHRs) identified as causing reproductive dysfunction inhumanpatients. The data obtained revealhowmutations in GPCRs can have diverse and severely deleterious effects on receptor function. Furthermore, it was found that impaired functionality of the majority of the mutant LHRs was due to reduced expression at the cell surface (14/20) while only two mutations caused impaired binding affinity and two impaired in signaling.Anadditionaltwomutationswerefound to causenoimpairment of receptor function. These data demonstrate that the majority of LHR mutations lead to intracellular retention and highlight the potential for novel pharmacological chaperone therapeutics that can "rescue" expression/ function of retained mutant GPCRs.