Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

Abstract

There are approximately 800 annotated G protein-coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain-and loss-of-function variants, other aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches. Significance Statement-With the advent of new transgenic and sequencing technologies, the number of monogenic diseases related to G protein-coupled receptor (GPCR) mutants has significantly increased, and our understanding of the functional impact of certain kinds of mutations has substantially improved. Besides the classical gain-and loss-of-function alterations, additional aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, uniparental disomy, pseudogenes, gene fusion, and gene dosage, need to be elaborated in light of GPCR dysfunctions and possible therapeutic strategies.

Mutational Landscape of the Proglucagon-Derived Peptides

“…The allele frequency spectrum represents both low-frequent variants such as singletons only found in single samples and variants with higher frequency such as I158V 13 found in 1 in 492 individuals (mean AF across cohorts: 0.27%). Furthermore, the GLP-1 variant K117N 26 and the glucagon variant R70H Glucagon,18 are among the most frequent, respectively occurring 1 in 33,282 and 1 in 23,951 individuals.…”

“…GPCRs mediate the therapeutic effect of approximately 34% of drugs on the market (24). Recent studies have shown extensive variability in GPCRs, and mutations within the coding region can lead to several monogenic diseases or to altered drug responses (25,26). Therefore, missense variants in GCG, coding for the hormones may play a role in metabolic diseases or affect the treatment of these.…”

Allosteric communication regulates ligand‐specific GPCR activity

“…Knowledge of the residues involved in allosteric communication will also allow us to engineer GPCR mutants that would bias the receptor toward one signaling pathway over the other. In the same vein, many disease‐associated mutations are located in GPCRs [7,8] and these mutations can lead to gain or loss of function of the receptors. Identifying the residues involved in allosteric communication and their overlap with disease‐associated mutations would allow us to annotate the functional role of these mutations at a protein level and open up therapeutic opportunities.…”

Insights into Nuclear G-Protein-Coupled Receptors as Therapeutic Targets in Non-Communicable Diseases

“…Therefore, the GPCRs localized in the nuclear membrane may also be influenced by these phenomena and be involved in the pathophysiology and development of non-communicable diseases [ 60 , 61 ]. Moreover, scientific data also indicate the occurrence of constitutively active mutations in GPCRs that have been associated with diseases [ 62 , 63 ], which can also have a role in the pathophysiological processes.…”