G Protein-Coupled Receptor Mutations and Human Genetic Disease

Abstract

Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common pharmacogenetic variants.

Illuminating the Onco-GPCRome: Novel G protein–coupled receptor-driven oncocrine networks and targets for cancer immunotherapy

“…As a result of the use of alignment tools and gene ontology, 342 functional nonolfactory human GPCRs (1) have been documented and further classified into major receptor families based on sequence similarity and function (27,28) (http:// gpcrdb.org/). To date, over 600 inactivating and almost 100 activating mutations in GPCRs have been identified, which are responsible for more than 30 different human diseases (29). Consequently, GPCRs have remained a long-standing interest as pharmacological targets.…”

A disease-associated mutation in the adhesion GPCR BAI2 (ADGRB2) increases receptor signaling activity

“…For example, missense mutations in the retinal‐binding lysine‐296 of rhodopsin can result in a constitutively active receptor and lead to the deterioration of rod cells in retinitis pigmentosa (Robinson, Cohen, Zhukovsky, & Oprian, ), and the substitution of aspartate for glycine at residue 578 in the luteinizing hormone receptor imparts constitutive activity, which can induce precocious puberty (Shenker et al., ). Thus, the investigation of GPCR‐activating mutations is important for understanding human disease as well as for shedding light on basic receptor biology (Thompson, Hendy, Percy, Bichet, & Cole, ).…”

Effects of Di-(2-ethylhexyl) Phthalate on the Hypothalamus–Uterus in Pubertal Female Rats

“…However, basic research on GnRH and GnRHR in recent years shows that GnRHR also exists in other organs, including the ovaries, testes, uteruses, etc. [41,42,43,44]. In addition, tissues of malignant tumors, such as breast cancer, ovarian cancer and endometrial cancer, experience high affinity of GnRHR expression as well [56,57,58].…”

“…GnRH influences the reproductive processes mainly by regulating pituitary gonadotropin synthesis and release, which, in turn, modulate steroid genesis and gametogenesis [39,40]. Even if the hypothalamus is the principal source of GnRH, and the pituitary is the target site for it, several studies have reported that GnRH receptor (GnRHR) will be in many other tissues including reproductive organs, such as testes, prostates, ovaries, and uteruses [41,42,43,44]. …”