Genetic variation in
G protein-coupled receptors (GPCRs) results in the disruption of GPCR function in a wide variety of human
genetic diseases. In vitro strategies have been used to elucidate the molecular pathologies that underlie naturally occurring GPCR mutations. Various degrees of inactive, overactive, or constitutively active receptors have been identified. These mutations often alter
ligand binding,
G protein coupling, receptor desensitization, and receptor recycling. The role of inactivating and activating
calcium-sensing receptor (CASR) mutations is discussed with respect to familial hypocalciuric hypercalemia (FHH) and autosomal dominant hypocalemia (ADH). Among ADH mutations, those associated with
tonic-clonic seizures are discussed. Other receptors discussed include
rhodopsin,
thyrotropin,
parathyroid hormone,
melanocortin,
follicle-stimulating hormone,
luteinizing hormone,
gonadotropin-releasing hormone (GnRHR),
adrenocorticotropic hormone,
vasopressin,
endothelin-beta, purinergic, and the
G protein associated with
asthma (GPRA). Diseases caused by mutations that disrupt GPCR function are significant because they might be selectively targeted by drugs that rescue altered receptors. Examples of
drug development based on targeting GPCRs mutated in disease include the calcimimetics used to compensate for some CASR mutations,
obesity therapeutics targeting
melanocortin receptors, interventions that alter GnRHR loss from the cell surface in
idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor in a rare
bleeding disorder. The discovery of GPRA suggests that
drug screens against variant GPCRs may identify novel drugs. This review of the variety of GPCRs that are disrupted in monogenic disease provides the basis for examining the significance of common pharmacogenetic variants.