PT  - JOURNAL ARTICLE
AU  - Torsten Schöneberg
AU  - Ines Liebscher
ED  - Insel, Paul
TI  - Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches
AID  - 10.1124/pharmrev.120.000011
DP  - 2021 Jan 01
TA  - Pharmacological Reviews
PG  - 89--119
VI  - 73
IP  - 1
4099  - http://pharmrev.aspetjournals.org/content/73/1/89.short
4100  - http://pharmrev.aspetjournals.org/content/73/1/89.full
SO  - Pharmacol Rev2021 Jan 01; 73
AB  - 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.