INT101121

Context Info Confidence 0.53 First Reported 2002 Last Reported 2010 Negated 1 Speculated 1 Reported most in Body Documents 19 Total Number 21 Disease Relevance 10.66 Pain Relevance 7.22

mitochondrion (Comt) methyltransferase activity (Comt) plasma membrane (Comt)

Anatomy Link Frequency brain 2 tail 1 proximal 1 prefrontal 1 Comt (Mus musculus)

Pain Link Frequency Relevance Heat Catechol-O-methyltransferase 420 100.00 Glutamate receptor 28 99.96 Lasting pain 46 99.48 Dopamine 343 99.04 Pain 207 97.48 tail-flick 4 97.36 Catecholamine 52 94.80 Opioid 62 93.00 analgesia 25 92.08 Hippocampus 92 91.76

Disease Link Frequency Relevance Heat Pain 263 99.48 Disease 48 99.46 Nociception 17 99.40 Targeted Disruption 38 99.16 Attention Deficit Hyperactivity Disorder 39 98.40 Schizophrenia 23 98.32 Cognitive Disorder 70 98.28 Sprains And Strains 822 97.76 Urological Neuroanatomy 21 97.68 Anxiety Disorder 231 96.96

Sentences Mentioned In

Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

To rule out the possibility that other sequence variants regulate Comt we queried genomic sequence data from seventeen inbred strains available from the Sanger Institute.

Spec (possibility) Regulation (regulate) of Comt associated with sprains and strains

1) Confidence 0.53 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0.49 Pain Relevance 0

Despite the differences in the genetic regulation of Comt between mouse and human, manipulations point to very similar roles in cognition and behavior.

Regulation (regulation) of Comt associated with cognitive disorder

2) Confidence 0.53 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0.58 Pain Relevance 0.55

This profile of brain region specific regulation of COMT by estrogen in ArKO mice is not in accord with CSTC circuit dysfunction in OCD.

Regulation (regulation) of COMT in brain associated with catechol-o-methyltransferase and anxiety disorder

3) Confidence 0.46 Published 2008 Journal Current Chemical Genomics Section Body Doc Link PMC2746669 Disease Relevance 0.67 Pain Relevance 0.41

Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine.

Regulation (responsible) of Catechol-O-methyltransferase associated with catechol-o-methyltransferase and dopamine

4) Confidence 0.45 Published 2010 Journal PLoS ONE Section Abstract Doc Link PMC2923157 Disease Relevance 0.25 Pain Relevance 0.20

As mentioned above, results of the microarray experiment for the Atp1a2 and Comt transcripts were not consistent.

Regulation (results) of Comt associated with catechol-o-methyltransferase

5) Confidence 0.44 Published 2006 Journal BMC Genomics Section Body Doc Link PMC1553451 Disease Relevance 0.16 Pain Relevance 0.13

Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes.

Regulation (contribution) of COMT associated with catechol-o-methyltransferase and disease

6) Confidence 0.40 Published 2002 Journal Eur. J. Neurosci. Section Abstract Doc Link 11849292 Disease Relevance 0.16 Pain Relevance 0.59

Here, we used old male Comt gene knock-out mice as an animal model to study the effects of COMT deficiency on nociception that was assessed by the hot plate and tail flick tests.

Regulation (effects) of COMT in tail associated with nociception, targeted disruption, catechol-o-methyltransferase and tail-flick

7) Confidence 0.40 Published 2008 Journal Basic Clin. Pharmacol. Toxicol. Section Abstract Doc Link 18834357 Disease Relevance 0.57 Pain Relevance 1.61

This mutation has effects on COMT activity and is clearly linked to downstream variation in expression of many other genes, dopamine tone, and behavior.

Regulation (effects) of COMT associated with catechol-o-methyltransferase and dopamine

8) Confidence 0.39 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0.84 Pain Relevance 0.10

This demonstrates that sequence variants in or around the Comt gene control its expression.

Regulation (control) of Comt

9) Confidence 0.27 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0.25 Pain Relevance 0.03

In addition, we validated alterations in the enzyme activity of one mRNA product, catechol-O-methyltransferase (Comt).

Regulation (alterations) of catechol-O-methyltransferase associated with catechol-o-methyltransferase

10) Confidence 0.26 Published 2007 Journal BMC Genomics Section Abstract Doc Link PMC1851712 Disease Relevance 0.60 Pain Relevance 0.42

The val158met polymorphism alters the in-vivo activity of the COMT enzyme; Val/Val homozygotes have higher levels of the COMT enzyme and correspondingly lower levels of D2 receptor neurotransmission leading to a higher level of activation of the µ-opioid system [11], [12].

Regulation (alters) of COMT enzyme associated with opioid

11) Confidence 0.23 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2964315 Disease Relevance 0.46 Pain Relevance 0.72

primers specifically targeting Comt 3?

Regulation (targeting) of Comt

12) Confidence 0.23 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0.36 Pain Relevance 0

The cause of this Comt cis-regulation is the insertion of a strong and premature polyadenylation signal in the proximal 3?

Regulation (regulation) of Comt in proximal

13) Confidence 0.23 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0.86 Pain Relevance 0.12

Downstream targets of Comt participate in cytoskeletal regulation (Cmip, Etnk1, and Ptprd), intracellular signaling (Cdc42, Araf, Hipk2, Cmip, Etnk1, Ptprd, and Rasgrp1), transport (Stau1, Adam10, Dnajc10, Mcoln1, Golga3, Arl7, Spo, Pitpnb, Ddx47, Capns1, and Kif5a), receptor/channel trafficking (Palm, Akap9, Sqstm1, Cntn2, Nsg1, and Dlgap1), synaptic maintenance and plasticity (Apba1, Tle3, Slit3, Slc12a6, Elavl4, and Syt1), transcriptional regulation (Nipbl, Myt1l, Ncor1, Jundm2, and Tef), and catecholamine metabolism (Maoa).

Regulation (targets) of Comt associated with catecholamine

14) Confidence 0.23 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0 Pain Relevance 0.27

Variation in Comt mRNA expression and cis-regulation in CNS and peripheral tissues

Regulation (regulation) of Comt

15) Confidence 0.23 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2923157 Disease Relevance 0.80 Pain Relevance 0.09

Differences in the signal of four genes (Atp1a2, Kcnj9, Grm7, Comt) selected for further investigation were found to be regulated by strong cis-acting elements.

Regulation (regulated) of Comt associated with catechol-o-methyltransferase and glutamate receptor

16) Confidence 0.23 Published 2006 Journal BMC Genomics Section Body Doc Link PMC1553451 Disease Relevance 0.27 Pain Relevance 0.16

While the Kerns study did not identify changes in Comt, our analysis of an independent dataset supported our results.

Neg (not) Regulation (changes) of Comt associated with catechol-o-methyltransferase

17) Confidence 0.23 Published 2007 Journal BMC Genomics Section Body Doc Link PMC1851712 Disease Relevance 0.29 Pain Relevance 0.24

Variations in COMT gene affecting enzyme activity has been associated with schizophrenia, ADHD, pain sensitivity and several other pathological conditions [6], [55], [56], [58], [59] but the role of this enzyme has been exclusively related to modulation of metabolism of classical catecholamines, such as dopamine and norepinephrine.

Regulation (affecting) of COMT associated with pain, dopamine, catecholamine, attention deficit hyperactivity disorder and schizophrenia

18) Confidence 0.23 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2956650 Disease Relevance 0.87 Pain Relevance 0.32

The realization of the fact that 3-MT has its own neuromodulatory properties suggests that alterations in COMT activity, which serves as the rate limiting enzyme for this putative neuromodulator, could affect brain functions also by altering extracellular 3-MT concentrations.

Regulation (alterations) of COMT in brain

19) Confidence 0.23 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2956650 Disease Relevance 0.94 Pain Relevance 0.24

Thus the results demonstrate that the presence of chronic pain complaints moderates the influence of the COMT and the BDNF polymorphisms on the cortical processing of experimental pain stimuli.

Regulation (influence) of COMT associated with pain and lasting pain

20) Confidence 0.20 Published 2010 Journal PLoS ONE Section Body Doc Link PMC2964315 Disease Relevance 0.74 Pain Relevance 0.82

General Comments

This test has worked.