title: Distribution analysis of nonsynonymous polymorphisms within the G-protein-coupled receptor gene family.
abstract: The G-protein-coupled receptor (GPCR) superfamily is one of the largest classes of proteins in mammalian genomes. GPCRs mediate diverse physiological functions and are the targets of >50% of all clinical drugs. The sequencing of the human genome and large-scale polymorphism discovery efforts have established an abundant source of single nucleotide polymorphisms (SNPs), particularly those that result in a change in the encoded amino acids (cSNPs), many are of which in GPCRs. Although the majority of these cSNPs are assumed not to be disease-causing (nDCs), experimental data on their functional impact are lacking. Here, we have computationally analyzed the distribution of 454 cSNPs within the GPCR gene family and have found that disease-causing cSNPs (DCs) are overrepresented, whereas nDCs are underrepresented or neutral in transmembrane and extracellular loop domains, respectively. This finding reflects the relative importance of these domains to GPCR function and implies different biological characteristics for the two sets of human polymorphisms.
authors.affiliation: ACADIA Pharmaceuticals, 3911 Sorrento Valley Blvd., San Diego, CA 92121, USA. alee@acadia-pharm.com
authors.forename: Andria
authors.initials: A
authors.lastname: Lee
authors.forename: B K
authors.initials: BK
authors.lastname: Rana
authors.forename: H H
authors.initials: HH
authors.lastname: Schiffer
authors.forename: N J
authors.initials: NJ
authors.lastname: Schork
authors.forename: M R
authors.initials: MR
authors.lastname: Brann
authors.forename: P A
authors.initials: PA
authors.lastname: Insel
authors.forename: D M
authors.initials: DM
authors.lastname: Weiner
mesh_terms: D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D005810:Multigene Family; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism
chemical_list: D011956:Receptors, Cell Surface; D019204:GTP-Binding Proteins