Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Nackley, AG; Shabalina, SA; Tchivileva, IE; Satterfield, K; Korchynskyi, O; Makarov, SS; Maixner, W; Diatchenko, L

Published Date

  • December 22, 2006

Published In

Volume / Issue

  • 314 / 5807

Start / End Page

  • 1930 - 1933

PubMed ID

  • 17185601

Pubmed Central ID

  • 17185601

Electronic International Standard Serial Number (EISSN)

  • 1095-9203

Digital Object Identifier (DOI)

  • 10.1126/science.1131262

Language

  • eng

Conference Location

  • United States