DOI: 10.1126/science.1131262. Human Catechol-<i>O</i>-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure

Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure

10.1126/science.1131262

Crossref journal-article

American Association for the Advancement of Science (AAAS)

Science (221)

Abstract

Catechol-O-methyltransferase (COMT) is a key regulator of pain perception, cognitive function, and affective mood. Three common haplotypes of the humanCOMTgene, 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 majorCOMThaplotypes 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.

Bibliography

Nackley, A. G., Shabalina, S. A., Tchivileva, I. E., Satterfield, K., Korchynskyi, O., Makarov, S. S., Maixner, W., & Diatchenko, L. (2006). Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure. Science, 314(5807), 1930â1933.

Authors 8

A. G. Nackley (first)
S. A. Shabalina (additional)
I. E. Tchivileva (additional)
K. Satterfield (additional)
O. Korchynskyi (additional)
S. S. Makarov (additional)
W. Maixner (additional)
L. Diatchenko (additional)

References 23 Referenced 719

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L. Diatchenko et al., Hum. Mol. Genet.14, 135 (2005). (10.1093/hmg/ddi013) / Hum. Mol. Genet. (2005)
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10.1126/science.1078546
G. Winterer, D. Goldman, Brain Res. Brain Res. Rev.43, 134 (2003). (10.1016/S0165-0173(03)00205-4) / Brain Res. Brain Res. Rev. (2003)
B. Funke et al., Behav. Brain Funct.1, 19 (2005). (10.1186/1744-9081-1-19) / Behav. Brain Funct. (2005)
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Materials and methods are available as supporting material on Science Online.
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Sequence accession numbers: S-COMT clones BG290167 CA489448 and BF037202 represent LPS APS and HPS haplotypes respectively. Clones corresponding to all three haplotypes and including the transcriptional start site were constructed by use of the unique restriction enzyme Bsp MI. The gene coding region containing all three SNPs was cut and inserted into the plasmids through use of the S-COMT (BG290167) and MB-COMT (BI835796) clones containing the entire COMT 5â² and 3â² ends as a backbone vector.
S. A. Shabalina, A. Y. Ogurtsov, N. A. Spiridonov, Nucleic Acids Res.34, 2428 (2006). (10.1093/nar/gkl287) / Nucleic Acids Res. (2006)
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.

Dates

Type	When
Created	18 years, 8 months ago (Dec. 21, 2006, 4:48 p.m.)
Deposited	7 months, 2 weeks ago (Jan. 12, 2025, 1 p.m.)
Indexed	1 week ago (Aug. 24, 2025, 7:07 p.m.)
Issued	18 years, 8 months ago (Dec. 22, 2006)
Published	18 years, 8 months ago (Dec. 22, 2006)
Published Print	18 years, 8 months ago (Dec. 22, 2006)

Funders 0

None

BibTeX

@article{Nackley_2006, title={Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure}, volume={314}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.1131262}, DOI={10.1126/science.1131262}, number={5807}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Nackley, A. G. and Shabalina, S. A. and Tchivileva, I. E. and Satterfield, K. and Korchynskyi, O. and Makarov, S. S. and Maixner, W. and Diatchenko, L.}, year={2006}, month=dec, pages={1930–1933} }

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