Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure
Abstract
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.
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We are grateful to the National Institute of Child Health and Human Development, National Institute of Neurological Disorders and Stroke, and National Institute of Dental and Craniofacial Research at the NIH for financial support of this work. This research was also supported by the Intramural Research Program of the NIH, National Center for Biotechnology Information.
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Published In
Science
Volume 314 | Issue 5807
22 December 2006
22 December 2006
Copyright
American Association for the Advancement of Science.
Submission history
Received: 13 June 2006
Accepted: 16 November 2006
Published in print: 22 December 2006
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www.sciencemag.org/cgi/content/full/314/5807/1930/DC1
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Figs. S1 to S6
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