Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets

Abstract

By virtue of their large number, widespread distribution and important roles in cell physiology and biochemistry, G-protein-coupled receptors (GPCR) play multiple important roles in clinical medicine. Here, we focus on 3 areas that subsume much of the recent work in this aspect of GPCR biology: (1) monogenic diseases of GPCR; (2) genetic variants of GPCR; and (3) clinically useful pharmacological agonists and antagonists of GPCR. Diseases involving mutations of GPCR are rare, occurring in <1/1000 people, but disorders in which antibodies are directed against GPCR are more common. Genetic variants, especially single nucleotide polymorphisms (SNPs), show substantial heterogeneity in frequency among different GPCRs but have not been evaluated for some GPCR. Many therapeutic agonists and antagonists target GPCR and show inter-subject variability in terms of efficacy and toxicity. For most of those agents, it remains an open question whether genetic variation in primary sequence of the GPCR is an important contributor to such inter-subject variability, although this is an active area of investigation.

Figure 1

Schematic structure of rhodopsin. Each amino acid residue is shown as a green dot; amino acid residues that are mutated in patients with retinitis pigmentosa are shown as red dots. Seven transmembrane domains are boxed. Mutations are collected from the Human Gene Mutation Database (www.hgmd.org), the Retinal Information Network (www.sph.uth.tmc.edu/RetNet/sym-dis.htm), and the Retina International Mutation Database (www.retina-international.com/sci-news/rhomut.htm) and references [88] and [89].

Figure 2

Schematic structure of the vasopressin V₂ receptor (AVPR2). Each amino acid residue is shown as a green dot; amino acid residues that are mutated in patients with nephrogenic diabetes insipidus are shown as red dots. Seven transmembrane domains are boxed. Mutations found in the AVPR2 gene were collected from the Human Gene Mutation Database (www.hgmd.org) and the Diabetes Insipidus Mutation Database (www.medicine.mcgill.ca/nephros).