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Catechol-O-methyl transferase

About: Catechol-O-methyl transferase is a research topic. Over the lifetime, 1646 publications have been published within this topic receiving 87360 citations.


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Journal ArticleDOI
TL;DR: Testing for linkage in ADHD families using the functional polymorphism at codon 158 that determines COMT activity and analyzed the data with the transmission disequilibrium test (TDT) finds no evidence for linkage.
Abstract: Attention-deficit hyperactivity disorder is the most common child psychiatric disorder with a prevalence rate in an Ontario study of 9% in boys and 3% in girls [Szatmari et al., 1989]. This disorder is characterized by problems in the areas of attention, overactivity, impulse control, and distractibility. Strong evidence for a genetic component has been provided from twin, family, and adoption studies [for review see Levy et al., 1998] and molecular genetic studies are in progress by several groups worldwide. The Catechol-O-Methyltransferase (COMT) gene is an interesting candidate for ADHD as it is involved in the breakdown of dopamine and norepinephrine, neurotransmitters strongly implicated in the etiology of ADHD. In addition, children with velo-cardio-facial syndrome, a deletion syndrome of the chromosomal region 22q11 where the COMT gene has been localized, often have symptoms of ADHD suggesting this gene may have an etiological role in ADHD. In this study, we have tested for linkage in ADHD families using the functional polymorphism at codon 158 that determines COMT activity [Lachman et al., 1996] and analyzed the data with the transmission disequilibrium test (TDT). A total of 77 nuclear families collected from Toronto were genotyped. We find no evidence for linkage of this polymorphism and ADHD in our sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:710-713, 1999.

101 citations

Journal ArticleDOI
TL;DR: Preliminary evidence for a role of the functional val158met COMT polymorphism in amygdala and prefrontal activation in response to emotional faces in panic disorder is provided.
Abstract: Panic disorder is an anxiety disorder with an estimated heritability of up to 48%. The functional val158met polymorphism in the catechol-O-methyltransferase (COMT) gene has been found to be associated with panic disorder and to influence limbic and prefrontal brain activation in response to unpleasant stimuli. In the present study, neuronal activation following emotional stimulation was used as an endophenotype and investigated for association with the COMT val158met polymorphism in panic disorder. Twenty patients with panic disorder were scanned by means of functional magnetic resonance imaging at 3 Tesla under visual presentation of emotional faces and genotyped for the COMT val158met polymorphism. In response to fearful faces, increased activation in the right amygdala was observed in patients carrying at least one 158val allele. Increased activation or less deactivation associated with the 158val allele was seen upon presentation of fearful, angry and happy faces in the orbitofrontal and ventromedial prefrontal cortex, respectively. Our data provide preliminary evidence for a role of the functional val158met COMT polymorphism in amygdala and prefrontal activation in response to emotional faces in panic disorder. This COMT variant might increase the vulnerability to panic disorder by modulating dopaminergic tonus in relevant brain regions and thus altering neuronal processing of anxiety-related emotional cues.

101 citations

Journal ArticleDOI
TL;DR: In this paper, a specific COMT antibody was used in immunohistochemical and confocal co-localization studies to explore the distribution of COMT in general in normal mice and MB-COMT in particular, in an SCOMT deficient mouse line.
Abstract: Catechol-O-methyltransferase (COMT) has both soluble (S-COMT) and membrane-bound (MB-COMT) isoforms. A specific COMT antibody was used in immunohistochemical and confocal co-localization studies to explore the distribution of COMT in general in normal mice and MB-COMT in particular, in an S-COMT deficient mouse line. In the peripheral tissues, high COMT protein and activity levels were observed in liver and kidney, whereas in the brain, COMT expression and activity were much lower. MB-COMT was widely distributed throughout all tissues, and overall, the MB-COMT distribution mimicked the distribution of S-COMT. MB-COMT displayed some preference for brain tissue, notably in the hippocampus. MB-COMT related enzymatic activity was also pronounced in the cerebral cortical areas and hypothalamus. MB-COMT, like S-COMT, was found to be an intracellular enzyme but it was not associated with plasma membranes in the brain. Both COMT forms were abundantly found in microglial cells and intestinal macrophages, but also in astroglial cells. COMT was also present in some neuronal cells, like pyramidal neurons, cerebellar Purkinje and granular cells and striatal spiny neurons, but not in major long projection neurons. Finally, it seemed that nuclear COMT is not visible in S-COMT deficient mice.

101 citations

Journal ArticleDOI
TL;DR: Results confirm that membrane‐bound COMT is an integral membrane protein that may be structurally distinct from soluble COMT.
Abstract: Catechol-O-methyltransferase (COMT; E.C. 2.1.1.6) from human frontal cortex occurs in both a soluble and membrane-bound form. Attempts to solubilize the membrane-bound transferase by repeated washing or by extraction into solutions of high ionic strength were unsuccessful. The finding that Triton X-100 was capable of solubilizing membrane-bound COMT suggested that the membrane-bound transferase is an integral membrane protein. The membrane-bound and soluble enzymes did not differ in their requirements for magnesium ions or in their pH-activity profiles; both enzymes showed an optimum near pH 8.0 when assayed in phosphate buffer. In addition, the two enzymes did not differ in the degree of inhibition caused by CaCl2, both enzymes displaying 65% inhibition at 2.5 mM CaCl2. The competitive inhibitors tropolone and nordihydroguaiaretic acid displayed Ki values for the membrane-bound transferase five- to 10-fold lower than those observed for the soluble transferase. Solubilization of membrane-bound COMT in Triton X-100 resulted in an increase in the apparent Km value of the membrane-bound transferase for dopamine. The increase in Km appeared to be due to apparent competitive inhibition by Triton X-100 and reached a limiting value of approximately 80 microM. These results confirm that membrane-bound COMT is an integral membrane protein that may be structurally distinct from soluble COMT.

98 citations

Journal ArticleDOI
TL;DR: It is found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS− (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes, and multiple differential mechanisms for regulating COMT function are associated with impaired fear inhibition in PTSD.
Abstract: The catechol-O-methyltransferase (COMT) enzyme is critical for the catabolic regulation of synaptic dopamine, resulting in altered cortical functioning. The COMT Val158Met polymorphism has been implicated in human mental illness, with Met/Met homozygotes associated with increased susceptibility to posttraumatic stress disorder (PTSD). Our primary objective was to examine the intermediate phenotype of fear inhibition in PTSD stratified by COMT genotype (Met/Met, Val/Met, and Val/Val) and differential gene regulation via methylation status at CpG sites in the COMT promoter region. More specifically, we examined the potential interaction of COMT genotype and PTSD diagnosis on fear-potentiated startle during fear conditioning and extinction and COMT DNA methylation levels (as determined using genomic DNA isolated from whole blood) . Participants were recruited from medical and gynecological clinics of an urban hospital in Atlanta, Georgia. We found that individuals with the Met/Met genotype demonstrated higher fear-potentiated startle to the CS- (safety signal) and during extinction of the CS+ (danger signal) compared to Val/Met and Val/Val genotypes. The PTSD+ Met/Met genotype group had the greatest impairment in fear inhibition to the CS- (p=.006), compared to Val carriers. In addition, the Met/Met genotype was associated with DNA methylation at 4 CpG sites, 2 of which were associated with impaired fear inhibition to the safety signal. These results suggest that multiple differential mechanisms for regulating COMT function – at the level of protein structure via the Val158Met genotype and at the level of gene regulation via differential methylation - are associated with impaired fear inhibition in PTSD.

97 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202338
202265
202129
202032
201931
201834