Expansion of the human mu-opioid receptor gene architecture: novel functional variants.
The mu-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5'-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.
Shabalina
Svetlana A
SA
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
Zaykin
Dmitri V
DV
Gris
Pavel
P
Ogurtsov
Aleksey Y
AY
Gauthier
Josee
J
Shibata
Kyoko
K
Tchivileva
Inna E
IE
Belfer
Inna
I
Mishra
Bikashkumar
B
Kiselycznyk
Carly
C
Wallace
Margaret R
MR
Staud
Roland
R
Spiridonov
Nikolay A
NA
Max
Mitchell B
MB
Goldman
David
D
Fillingim
Roger B
RB
Maixner
William
W
Diatchenko
Luda
L
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D001483:Base Sequence; D015331:Cohort Studies; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010146:Pain / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*
C485764:OPRM1 protein, human; D020033:Protein Isoforms; D017450:Receptors, Opioid, mu