Background
22q11.2 deletion syndrome (22q11.2DS) is the most common genetic syndrome associated
with schizophrenia. The catechol-O-methyltransferase (COMT) gene is located in the obligatory deletion region, and possible associations between
COMT variants and neuropsychiatric manifestations in 22q11.2DS have been reported. The
purpose of the current study was to evaluate the effect of COMT hemizygosity and molecular haplotypes on gene expression and enzyme activity and
its association with psychotic symptoms in 22q11.2DS.
Methods
Lymphoblast samples were drawn from 53 individuals with 22q11.2DS and 16 typically
developing control subjects. We measured COMT messenger (m)RNA and protein expression
and enzyme activity using standard procedures. The presence of a psychotic disorder
and cognitive deficits were also evaluated using structured testing.
Results
There was an approximately 50% reduction in COMT mRNA, protein, and enzyme activity
levels in 22q11.2DS samples. Haplotype analysis revealed clear phenotypic differences
between various Val-containing haplotypes on COMT-3′ untranslated region extended mRNA, soluble COMT and membrane-bound proteins, and
enzyme activity. The G variant of rs165599, a 3′ untranslated region single nucleotide
polymorphism, was associated with low levels of COMT expression and with the presence
of psychosis and lower performance IQ scores in our 22q11.2DS sample. Finally, we
demonstrate that the COMT rs74745580 “T” mutation is associated with absent soluble COMT expression and very
low COMT activity in two 22q11.2DS individuals.
Conclusions
Our findings confirm a robust effect of COMT hemizygosity on COMT activity and show complex interactions of variants within the
COMT gene that influence COMT biology and confound conclusions based on associations with
the Val158Met genotype alone.
Key Words
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Article info
Publication history
Published online: August 29, 2013
Accepted:
July 22,
2013
Received in revised form:
July 22,
2013
Received:
March 25,
2013
Footnotes
Authors DG and AJL contributed equally to the work.
Identification
Copyright
© 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Catechol-O-Methyltransferase and Genetic Variation Under HemizygosityBiological PsychiatryVol. 75Issue 5
- PreviewLess than a decade after Julius Axelrod initially described catechol-O-methyltransferase (COMT) (1), an enzyme he had isolated from rat liver to elaborate epinephrine metabolism, Angelo DiGeorge first hinted at a congenital clinical syndrome of hypoparathyroidism and absence of the thymus (2). There is no reason to suspect that these contemporaries, ensconced in entirely different fields and approaches, would have made particular note of each other’s work, much less anticipated that their respective discoveries might inextricably converge half a century later in the modern era of psychiatric genetics.
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