Human Molecular Genetics Advance Access originally published online on December 22, 2008
Human Molecular Genetics 2009 18(6):1037-1051; doi:10.1093/hmg/ddn439
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Expansion of the human µ-opioid receptor gene architecture: novel functional variants
1 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA 2 National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA 3 Center for Neurosensory Disorders, School of Dentistry, University of North Carolina at Chapel Hill, CB 7455, Chapel Hill, NC 27599, USA 4 Department of Health and Human Services, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA 5 Laboratory of Neurogenetics, Department of Health and Human Services, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Room 3S-32, Rockville, MD 20852, USA 6 Department of Anesthesiology, University of Pittsburgh, Pittsburgh, PA 15261, USA 7 Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, 1329 SW 16th Street, Gainesville, FL 32608, USA 8 University of Florida College of Dentistry, Community Dentistry and Behavioral Science, 1329 SW 16th Street, Gainesville, FL 32608, USA 9 Division of Therapeutic Proteins, Center for Drug Evaluation and Research, US Food and Drug Administration, Bethesda, MD 20892, USA
* To whom correspondence should be addressed. Tel: +1 3015945693; Fax: +1 3014802290; Email: shabalin{at}ncbi.nlm.nih.gov (S.A.S.) and lbdiatch{at}email.unc.edu (L.D.)
Received September 18, 2008; Accepted December 18, 2008
The µ-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.
We would like to dedicate the work presented in this manuscript to the memory of our dear friend and colleague Dr Mitchell B. Max whose untimely passing has created a loss to our scientific community and a void in our hearts.