Gene and Protein Domain-Specific Patterns of Genetic Variability Within the G-Protein Coupled Receptor Superfamily
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Am J Pharmacogenomics 2003; 3 (1): 65-71 1175-2203/03/0001-0065/$30.00/0 © Adis International Limited. All rights reserved.
Gene and Protein Domain-Specific Patterns of Genetic Variability Within the G-Protein Coupled Receptor Superfamily Kersten M. Small,1 Debra A. Tanguay,2 Krishnan Nandabalan,2 Ping Zhan,2 J. Claiborne Stephens2 and Stephen B. Liggett1 1 Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA 2 Genaissance Pharmaceuticals Inc., New Haven, Connecticut, USA
Abstract
Introduction: Guanine nucleotide binding proteins (G-proteins) represent the targets for >50% of all therapeutics. There is substantial interindividual variation in response to agonists and antagonists directed to these receptors, which may, in part, be due to genetic polymorphisms. As a class, the sequence variability of G-protein-coupled receptor (GPCR) genes has not been characterized. Study design: This variability was investigated by sequencing promoter, 5′- and 3′-UTR, coding blocks, and intron-exon boundaries, of 64 GPCR genes in an ethnically diverse group of 82 individuals. Results: Of the 675 single-nucleotide variations found, 61% occurred in ≥1% of the population sample and the nature of these 412 single nucleotide polymorphisms (SNPs) was assessed. 5′-UTR (p = 0.002) and coding (p = 0.006) SNPs were observed more often in GPCR genes, compared with 309 non-GPCR genes similarly interrogated. The prevalence of non-synonymous coding SNPs was unexpectedly high, with 65% of GPCR genes having at least one. Intron-containing genes had half as many non-synonymous coding SNPs compared with intronless genes (p = 0.0009), suggesting that when introns are not available coding regions provide sites for variation. A distinct relationship between the prevalence of non-synonymous SNPs and receptor structural domains was evident (p = 0.0006 by ANOVA), with variability being most prominent in the transmembrane spanning domains (38%) and the intracellular loops (24%). Phosphoregulatory domains, particularly the carboxy terminus, often the site for agonist-promoted phosphorylation by G-protein coupled receptor kinases, were the least polymorphic (8%). Conclusions: There is substantial genetic variability in potentially pharmacologically relevant coding and noncoding regions of GPCRs. Such variability should be considered in the development of new agents, or optimization of existing agents, targeted to these receptors.
Receptors which couple to guanine nucleotide binding proteins (G-proteins) represent one of the largest families of proteins in the genome.[1-3] G-protein-coupled receptors (GPCRs) subserve a broad range of signaling which involves neurotransmission, autocrine, paracrine, and hormonal signaling. All cell types express many GPCRs, and every organ system is dependent upon these receptors for functional integration into the body, where signaling is necessary for the maintenance of homeostasis and response to disease. Both GPCR agonists and antagonists are utilized therapeutically for a wide ra
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