COMT gene locus

New functional variants

Carolina B. Meloto, Samantha K. Segall, Shad Smith, Marc Parisien, Svetlana A. Shabalina, Celia M. Rizzatti-Barbosa, Josee Gauthier, Douglas Tsao, Marino Convertino, Marjo H. Piltonen, Gary Dmitri Slade, Roger B. Fillingim, Joel D. Greenspan, Richard Ohrbach, Charles Knott, William Maixner, Dmitri Zaykin, Nikolay Dokholyan, Ilkka Reenila, Pekka T. Mannisto & 1 others Luda Diatchenko

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 39 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 painprotective 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.

Original languageEnglish (US)
Pages (from-to)2072-2083
Number of pages12
JournalPain
Volume156
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Catechol O-Methyltransferase
Genes
Pain
Protein Isoforms
Adrenergic Agents
Untranslated Regions
Phenotype
High-Throughput Nucleotide Sequencing
Nociception
Brain
Substrate Specificity
Computer Simulation
Cognition
Primates
Epinephrine
Neurotransmitter Agents
Dopamine
Catalytic Domain

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

Cite this

Meloto, C. B., Segall, S. K., Smith, S., Parisien, M., Shabalina, S. A., Rizzatti-Barbosa, C. M., ... Diatchenko, L. (2015). COMT gene locus: New functional variants. Pain, 156(10), 2072-2083. https://doi.org/10.1097/j.pain.0000000000000273
Meloto, Carolina B. ; Segall, Samantha K. ; Smith, Shad ; Parisien, Marc ; Shabalina, Svetlana A. ; Rizzatti-Barbosa, Celia M. ; Gauthier, Josee ; 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 ; Reenila, Ilkka ; Mannisto, Pekka T. ; Diatchenko, Luda. / COMT gene locus : New functional variants. In: Pain. 2015 ; Vol. 156, No. 10. pp. 2072-2083.
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Meloto, CB, Segall, SK, Smith, S, Parisien, M, Shabalina, SA, Rizzatti-Barbosa, CM, Gauthier, J, Tsao, D, Convertino, M, Piltonen, MH, Slade, GD, Fillingim, RB, Greenspan, JD, Ohrbach, R, Knott, C, Maixner, W, Zaykin, D, Dokholyan, N, Reenila, I, Mannisto, PT & Diatchenko, L 2015, 'COMT gene locus: New functional variants', Pain, vol. 156, no. 10, pp. 2072-2083. https://doi.org/10.1097/j.pain.0000000000000273

COMT gene locus : New functional variants. / Meloto, Carolina B.; Segall, Samantha K.; Smith, Shad; Parisien, Marc; Shabalina, Svetlana A.; Rizzatti-Barbosa, Celia M.; Gauthier, Josee; 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; Reenila, Ilkka; Mannisto, Pekka T.; Diatchenko, Luda.

In: Pain, Vol. 156, No. 10, 01.10.2015, p. 2072-2083.

Research output: Contribution to journalArticle

TY - JOUR

T1 - COMT gene locus

T2 - New functional variants

AU - Meloto, Carolina B.

AU - Segall, Samantha K.

AU - Smith, Shad

AU - Parisien, Marc

AU - Shabalina, Svetlana A.

AU - Rizzatti-Barbosa, Celia M.

AU - Gauthier, Josee

AU - Tsao, Douglas

AU - Convertino, Marino

AU - Piltonen, Marjo H.

AU - Slade, Gary Dmitri

AU - Fillingim, Roger B.

AU - Greenspan, Joel D.

AU - Ohrbach, Richard

AU - Knott, Charles

AU - Maixner, William

AU - Zaykin, Dmitri

AU - Dokholyan, Nikolay

AU - Reenila, Ilkka

AU - Mannisto, Pekka T.

AU - Diatchenko, Luda

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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 39 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 painprotective 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.

AB - 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 39 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 painprotective 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.

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Meloto CB, Segall SK, Smith S, Parisien M, Shabalina SA, Rizzatti-Barbosa CM et al. COMT gene locus: New functional variants. Pain. 2015 Oct 1;156(10):2072-2083. https://doi.org/10.1097/j.pain.0000000000000273