Back to Search Start Over

COMT gene locus: new functional variants.

Authors :
Meloto, Carolina B.
Segall, Samantha K.
Smith, Shad
Parisien, Marc
Shabalina, Svetlana A.
Rizzatti-Barbosa, Célia M.
Gauthier, Josée
Tsao, Douglas
Convertino, Marino
Piltonen, Marjo H.
Slade, Gary Dmitri
Fillingim, Roger B.
Greenspan, Joel D.
Ohrbach, Richard
Knott, Charles
Maixner, William
Zaykin, Dmitri
Dokholyan, Nikolay V.
Reenilä, Ilkka
Männistö, Pekka T.
Source :
PAIN. Oct2015, Vol. 156 Issue 10, p2072-2083. 12p.
Publication Year :
2015

Abstract

Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3' untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
03043959
Volume :
156
Issue :
10
Database :
Academic Search Index
Journal :
PAIN
Publication Type :
Academic Journal
Accession number :
111919302
Full Text :
https://doi.org/10.1097/j.pain.0000000000000273