Catechol Omethyltransferase

COMT is localized to chr22q11 where a microdeletion results in velocardiofacial syndrome (22qDS; DiGeorge or Shprintzen syndrome), a genetic subtype of schizophrenia. The COMT gene exists in two versions: Met158 and Val158, the former coding for a form of COMT that is less thermostable and thus has lower activity than the Val158. COMT is important for regulating DA but not norepinephrine (NE) levels in the prefrontal cortex.28 Val158Met heterozygotic mice which have high COMT activity and, correspondingly, low prefrontal cortex DA levels show greater tyrosine hydroxylase expression in the midbrain, indicative of increased DA synthetic capability. In human Val158 carriers, neuroimaging studies showed greater midbrain F-DOPA uptake than Met158 carriers, consistent with increased DA biosynthesis. DA levels in prefrontal cortex play a key role in cognitive function and high-activity Val158 is associated with poorer performance and 'inefficient' prefrontal cortex function in some but not all studies. Despite several studies, the relationship of COMT dysfunction to schizophrenia is controversial with Val158 being considered a 'weak risk factor for schizophrenia'28 that may reflect COMT variation providing 'a weak general predisposition to neuropsychiatric disease.'29 In addition to the association with schizophrenia, the Val158Met mutation has also been associated with alterations in pain sensation82 and breast cancer risk83 adding further complexity to the psychiatric association. Nonetheless, in normal subjects and in Val158 carriers, COMT inhibitors like tolcapone 14 can improve aspects of working memory and executive function.

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