Catechol-O-Methyltransferase

Description

Catechol-O-methyltransferase (COMT; EC 2.1.1.6) is one of the major mammalian enzymes involved in the metabolic degradation of catecholamines (summary by Gogos et al., 1998). COMT catalyzes the transfer of a methyl group from S-adenosyl-methionine (SAM) to a hydroxyl group on a catechol nucleus (e.g., dopamine, norepinephrine, or catechol estrogen) (summary by Chen et al., 2004).

Cloning and Expression

Lundstrom et al. (1991) isolated cDNA clones for COMT from a human placenta cDNA library using synthetic oligonucleotides as probes. The clones contained an open reading frame that potentially coded for a 24.4-kD polypeptide, presumably corresponding to the cytoplasmic form of COMT. DNA analysis suggested that the human, as well as the rat, dog, and monkey, has 1 gene for COMT.

Mapping

Wilson et al. (1984) excluded tight and close linkage of COMT with 21 and 15 loci, respectively. A lod score of 1.27 at theta = 0.1 was found between COMT and phosphogluconate dehydrogenase (PGD; 172200), which is on chromosome 1.

In studies of mouse-human cell hybrids with a method permitting direct detection of COMT isozymes in autoradiozymograms, Brahe et al. (1986) located the COMT gene on human chromosome 22. By study of DNAs from a panel of human-hamster somatic cell hybrid lines, Grossman et al. (1991, 1992) mapped COMT to 22q11.1-q11.2. Winqvist et al. (1991) assigned COMT to 22q11.2 by means of Southern blot analysis of somatic cell hybrids and chromosomal in situ hybridization. They concluded that COMT is located proximal to the breakpoint cluster region (BCR) involved in chronic myeloid leukemia (151410). Bucan et al. (1993) mapped the homologous murine gene to chromosome 16, where, as in the human, it is closely linked to the lambda light chain genes.

During experiments aimed at building a contiguous group of YACs spanning 22q11, Dunham et al. (1992) found that the HP500 sequence often deleted in the velocardiofacial syndrome (VCFS; 192430) was located within the same 450-kb YAC as the COMT gene. They raised the question of whether low COMT might be responsible for psychotic illness, which is a feature of the VCF syndrome in adolescents and adults (Shprintzen et al., 1992).

Biochemical Features

Gustavson et al. (1973, 1982) reported that COMT activity was about 40% higher in Down syndrome children than in normal controls. They attributed this to dosage effect owing to a presumed location of the COMT gene on chromosome 21. Brahe et al. (1986) studied the expression of human COMT in interspecies somatic cell hybrids and found 27% discordance between human chromosome 21 and human COMT, suggesting that an assignment of the human COMT gene to chromosome 21 was very unlikely.

Molecular Genetics

COMT Activity Polymorphism

Catechol-O-methyltransferase catalyzes the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine. This O-methylation results in one of the major degradative pathways of the catecholamine transmitters. In addition to its role in the metabolism of endogenous substances, COMT is important in the metabolism of catechol drugs used in the treatment of hypertension, asthma, and Parkinson disease. In blood COMT is found mainly in erythrocytes; in leukocytes it exhibits low activity. Weinshilboum and Raymond (1977) found bimodality for red cell catechol-O-methyltransferase activity. Of a randomly selected population, 23% had low activity. Segregation analysis of family data suggested that low activity is recessive. Scanlon et al. (1979) found that homozygotes have a thermolabile enzyme. Thus, the site of the low COMT mutation is presumably the structural locus. Levitt and Baron (1981) confirmed the bimodality of human erythrocyte COMT. They further showed thermolability of the enzyme in 'low COMT' samples, suggesting a structural alteration in the enzyme. Autosomal codominant inheritance of the gene coding for erythrocyte COMT activity was adduced by Floderus and Wetterberg (1981) and by Weinshilboum and Dunnette (1981). Gershon and Goldin (1981) concluded that codominant inheritance was consistent with the family data. Spielman and Weinshilboum (1981) suggested that the inheritance of red cell COMT is intermediate, or codominant, there being 3 phenotypes corresponding to the 3 genotypes in a 2-allele system. The COMT of persons with low enzyme activity is more thermolabile than that of persons with high activity.

Susceptibility to Obsessive-Compulsive Disorder

Karayiorgou et al. (1997, 1999) found an association between obsessive-compulsive disorder (OCD; 164230) and COMT; the homozygous low activity genotype of the COMT gene was associated with risk for OCD in males. Alsobrook et al. (2002) used a family-based genetic design in haplotype relative risk (HRR) and transmission disequilibrium test (TDT) analyses of the association between OCD and COMT. Fifty-six OCD probands and their parents were genotyped for the COMT locus. Analysis of allele and genotype frequencies between the proband genotypes and the control (parental nontransmitted) genotypes failed to replicate the previous finding of gender divergence and gave no evidence of overall association; furthermore, no linkage was detected by TDT. However, further analysis of the COMT allele frequencies by proband gender gave evidence of a mildly significant association with the low activity COMT allele in female probands (P = 0.049), but not in male probands.

Susceptibility to Schizophrenia

The COMT gene is a strong candidate for schizophrenia susceptibility (see 181500), owing to the role of COMT in dopamine metabolism and the location of the gene within the deleted region in VCFS, a disorder associated with high rates of schizophrenia. Shifman et al. (2002) found a highly significant association between schizophrenia and a COMT haplotype in a large case-control sample in Ashkenazi Jews. In addition to the functional val158-to-met polymorphism (116790.0001; rs4680), this haplotype included 2 noncoding SNPs at either end of the COMT gene (rs737865 and rs165599). With this background information, Bray et al. (2003) postulated that the COMT susceptibility haplotype is associated with low COMT expression. To test their hypothesis, they applied quantitative measures of allele-specific expression using mRNA from human brain. They demonstrated that COMT is subject to allelic differences in expression in human brain and that the COMT haplotype implicated in schizophrenia by Shifman et al. (2002) is associated with lower expression of COMT mRNA. They also showed that the 3-prime flanking region SNP that in the study of Shifman et al. (2002) gave greatest evidence for association with schizophrenia is transcribed in human brain and exhibits significant differences in allelic expression, with lower relative expression of the associated allele. They concluded that the haplotype implicated in schizophrenia susceptibility is likely to exert its effect, directly or indirectly, by downregulating COMT expression.

In 38 populations representing all major regions of the world, Palmatier et al. (2004) studied the frequency of the schizophrenia-associated COMT haplotype reported by Shifman et al. (2002) as well as a 7-site COMT haplotype. Their results supported the relevance of the COMT P2 promoter to schizophrenia. The population data showed that the schizophrenia-associated haplotype varies significantly in frequency around the world and has significant heterogeneity when other markers in COMT are also considered.

Lee et al. (2005) screened for 17 known polymorphisms in the COMT gene in 320 Korean patients with schizophrenia and 379 controls. They identified a positive association of schizophrenia with a nonsynonymous SNP (rs6267) at codon 72/22 (membrane/soluble-bound form) causing an ala-to-ser substitution (A72S; 116790.0002). Lee et al. (2005) showed that the A72S substitution was correlated with reduced COMT enzyme activity, and their results supported previous reports that the COMT haplotypes implicated in schizophrenia are associated with low COMT expression.

Susceptibility to Anorexia Nervosa

Frisch et al. (2001) found an association between anorexia nervosa (AN; 606788) and the COMT val158 allele (V158M; 116790.0001) in a family-based study of 51 Israeli-Jewish AN trios. Gabrovsek et al. (2004) could not replicate this finding in a combined sample of 372 European AN families, suggesting that the findings of Frisch et al. (2001) were specific to a particular population and that val158 is in linkage disequilibrium with other molecular variations in the COMT gene, or its vicinity, which were the direct cause of genetic susceptibility to anorexia nervosa. Michaelovsky et al. (2005) studied 85 Israeli-Jewish AN trios, including the original sample of Frisch et al. (2001), comprising 66 anorexia nervosa restricting (AN-R) and 19 binge-eating/purging patients. They performed a family-based TDT analysis for 7 SNPs in the COMT-ARVCF (602269) region including the V158M polymorphism. TDT analysis of 5-SNP haplotypes in the AN-R group revealed overall statistically significant transmission disequilibrium for 'haplotype B' (COMT 186C, 408G, 472G [val158] and ARVCF 659C[pro220] and 524T[val175]) (P less than 0.001), while 'haplotype A' (COMT 186T, 408C, 472A[met158] and ARVCF 659T[leu220] and 524C[ala175]) was preferentially not transmitted (P = 0.01). Haplotype B was associated with increased risk (RR of 3.38), while haplotype A exhibited a protective effect (RR of 0.40) for AN-R. Preferential transmission of the risk alleles and haplotypes from parents was mostly contributed by fathers.

Associations Pending Confirmation

Sweet et al. (2005) conducted a study to determine if COMT genetic variation was associated with a risk of psychosis in Alzheimer disease (AD; see 114300). The study included a case-control sample of 373 individuals diagnosed with AD with or without psychosis. Subjects were characterized for alleles at 3 loci previously associated with schizophrenia, rs737865, rs4680, and rs165599, and for a C/T transition adjacent to an estrogen response element (ERE6) in the COMT P2 promoter region. Single-locus and haplotype tests of association were conducted. Logit models were used to examine independent and interacting effects of alleles at the associated loci and all analyses were stratified by sex. In female subjects, rs4680 demonstrated a modest association with AD plus psychosis; rs737865 demonstrated a trend towards an association. There was a highly significant association of AD plus psychosis with a 4-locus haplotype, which resulted from additive effects of alleles at rs4680 and ERE6/rs737865 (the latter were in linkage disequilibrium). In male subjects, no single-locus test was significant, although a strong association between AD with psychosis and the 4-locus haplotype was observed. That association appeared to result from interaction of the ERE6/rs737865, rs4680, rs165599 loci. Genetic variation in COMT was associated with AD plus psychosis and thus appears to contribute to psychosis risk across disorders.

Three common haplotypes of the human COMT gene are divergent at 2 synonymous and 1 nonsynonymous position (Diatchenko et al., 2005). One is rs4633, which is either a C or T, but both code for a histidine at amino acid 62; the other is rs4818, which can be a G or C, but both code for a leucine at nucleotide 136; the nonsynonymous haplotype is represented by rs4680, a met158-to-val change change (116790.0001). Nackley et al. (2006) noted that the 3 common haplotypes 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 major COMT haplotypes varied with respect to mRNA 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. Nackley et al. (2006) concluded that their data highlighted the functional significance of synonymous variations and suggested the importance of haplotypes over SNPs for analysis of genetic variations.

Animal Model

Gogos et al. (1998) generated mice deficient for COMT. They measured the basal concentrations of brain catecholamines in the striatum, frontal cortex, and hypothalamus of adult male and female mutants and analyzed locomotor activity, anxiety-like behaviors, sensorimotor gating, and aggressive behavior. Mutant mice demonstrated sexually dimorphic and region-specific changes of dopamine levels, notably in the frontal cortex. Homozygous COMT-deficient female (but not male) mice displayed impairment in emotional reactivity in the dark/light exploratory model of anxiety. Furthermore, heterozygous COMT-deficient male mice exhibited increased aggressive behavior. Gogos et al. (1998) concluded that their results provided conclusive evidence for an important sex- and region-specific contribution of COMT in the maintenance of steady-state levels of catecholamines in the brain and suggested a role for COMT in some aspects of emotional and social behavior in mice.

Kanasaki et al. (2008) showed that pregnant mice deficient in COMT showed a preeclampsia-like phenotype resulting from absence of 2-methoxyestradiol (2-ME), a natural metabolite of estradiol that is elevated during the third trimester of normal human pregnancy. Administration of 2-ME ameliorated all preeclampsia-like features without toxicity in Comt -/- pregnant mice and suppressed placental hypoxia, Hif1a (603348) expression, and soluble Flt1 (165070) elevation. The levels of COMT and 2-ME were significantly lower in women with severe preeclampsia. Kanasaki et al. (2008) suggested that Comt-null mice may provide a model for preeclampsia and that 2-ME may serve as a diagnostic marker as well as a therapeutic agent for preeclampsia.

Duplications of human chromosome 22q11.2 (608363) are associated with elevated rates of mental retardation, autism, and many other behavioral phenotypes. Suzuki et al. (2009) determined the developmental impact of overexpression of an approximately 190-kb segment of human 22q11.2, which includes the genes TXNRD2 (606448), COMT, and ARVCF (602269), on behaviors in bacterial artificial chromosome (BAC) transgenic mice. BAC transgenic mice and wildtype mice were tested for their cognitive capacities, affect- and stress-related behaviors, and motor activity at 1 and 2 months of age. BAC transgenic mice approached a rewarded goal faster (i.e., incentive learning), but were impaired in delayed rewarded alternation during development. In contrast, BAC transgenic and wildtype mice were indistinguishable in rewarded alternation without delays, spontaneous alternation, prepulse inhibition, social interaction, anxiety-, stress-, and fear-related behaviors, and motor activity. Compared with wildtype mice, BAC transgenic mice had a 2-fold higher level of COMT activity in the prefrontal cortex, striatum, and hippocampus. Suzuki et al. (2009) suggested that overexpression of this 22q11.2 segment may enhance incentive learning and impair the prolonged maintenance of working memory, but has no apparent affect on working memory per se, affect- and stress-related behaviors, or motor capacity. High copy numbers of this 22q11.2 segment may contribute to a highly selective set of phenotypes in learning and cognition during development.