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Science 22 December 2006:
Vol. 314. no. 5807, pp. 1930 - 1933
DOI: 10.1126/science.1131262
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Reports
Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure
A. G. Nackley,1
S. A. Shabalina,2
I. E. Tchivileva,1
K. Satterfield,1
O. Korchynskyi,3
S. S. Makarov,4
W. Maixner,1
L. Diatchenko1*
Catechol-O-methyltransferase (COMT) is a key regulator of pain perception, cognitive function, and affective mood. Three common haplotypes of the human COMT gene, divergent in two synonymous and one nonsynonymous position, code for differences in COMT enzymatic activity and are associated with pain sensitivity. Haplotypes divergent in synonymous changes exhibited the largest difference in COMT enzymatic activity, due to a reduced amount of translated protein. The major COMT haplotypes varied with respect to messenger RNA local stem-loop structures, such that the most stable structure was associated with the lowest protein levels and enzymatic activity. Site-directed mutagenesis that eliminated the stable structure restored the amount of translated protein. These data highlight the functional significance of synonymous variations and suggest the importance of haplotypes over single-nucleotide polymorphisms for analysis of genetic variations.
1 Center for Neurosensory Disorders, University of North Carolina, Chapel Hill, NC 27599, USA.
2 National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20894, USA.
3 Thurston Arthritis Center, University of North Carolina, Chapel Hill, NC 27599, USA.
4 Attagene, Inc., 7030 Kit Creek Road, Research Triangle Park, NC 27560, USA.
* To whom correspondence should be addressed. E-mail: lbdiatch{at}email.unc.edu
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