Functional Analysis of Genetic Variation in Catechol-O-Methyltransferase (COMT): Effects on mRNA, Protein, and Enzyme Activity in Postmortem Human Brain
Jingshan Chen,Barbara K. Lipska,Nader D. Halim,Quang D. Ma,Mitsuyuki Matsumoto,Samer Melhem,Bhaskar Kolachana,Thomas M. Hyde,Mary M. Herman,Jose A. Apud,Michael F. Egan,Joel E. Kleinman,Daniel R. Weinberger +12 more
TLDR
Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.Abstract:
Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3′ flanking region (rs165599)—both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val—had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3′ SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.read more
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References
More filters
Book
Psychopharmacology: The Fourth Generation of Progress
Floyd E. Bloom,David J. Kupfer +1 more
TL;DR: Part 1 Preclinical section: critical analysis of methods transmitter systems - amino acids, amines, peptides, new transmitterscritical analysis of integrative concepts.
Journal ArticleDOI
Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia.
Michael F. Egan,Terry E. Goldberg,Bhaskar Kolachana,Joseph H. Callicott,C.M. Mazzanti,Richard E. Straub,David Goldman,Daniel R. Weinberger +7 more
TL;DR: The data suggest that the COMT Val allele, because it increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology, and by this mechanism slightly increases risk for schizophrenia.
Journal ArticleDOI
Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence.
TL;DR: This review critically summarizes the neuropathology and genetics of schizophrenia, the relationship between them, and speculates on their functional convergence via an influence upon synaptic plasticity and the development and stabilization of cortical microcircuitry.
Journal ArticleDOI
Enzymatic O-methylation of epinephrine and other catechols.
Julius Axelrod,Robert Tomchick +1 more
TL;DR: The properties of an enzyme that transfers the methyl group of S-adenosylmethionine to the hydroxyl group in position 3 of epinephrine and other catechols are described.
Journal ArticleDOI
Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme.
Timo Lotta,Jukka Vidgren,Carola Tilgmann,I. Ulmanen,Krister Melén,Ilkka Julkunen,Jyrki Taskinen +6 more
TL;DR: Comparison of velocity parameters, substrate selectivity, and regioselectivity of the methylation of both enzyme forms, and a revised mechanism for the reaction cycle are discussed.