Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploin-sufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methyltransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine-->methionine substitution at amino acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158met leads to a 3-4-fold reduction in enzymatic activity, compared with homozygotes for COMT158val. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158met, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form.

Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome

Catechol-O-Methyltransferase (COMT): A Gene Contributing to Sex Differences in Brain Function, and to Sexual Dimorphism in the Predisposition to Psychiatric Disorders

Human catechol-O-methyltransferase down-regulation by estradiol.

We have recently characterized a functional polymorphism in the catechol-O-methyltransferase (COMT) gene that is responsible for substantial variability in COMT enzymatic activity found in humans A common low-activity variant of the enzyme contains a methionine residue at amino acid 158 of membrane-bound COMT whereas the common high activity variant has a valine at this site Considering the role of COMT in dopamine metabolism and the involvement of dopaminergic pathways in the pathogenesis of schizophrenia and violence, we screened 37 patients with schizophrenia to determine whether or not a behavioral association with the COMT polymorphism exists Patients were assessed for dangerousness on the basis of a history of violent and threatening behavior, crime, cocaine and alcohol abuse, and other antisocial behaviors We found that schizophrenic patients who were homozygous for the low activity allele were judged by their psychiatrists to be at higher risk for aggressive and dangerous behavior than those who were homozygous for the high activity allele (Kruskal-Wallis statistic = 1043; P = 0003)

Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior

Cloning, expression and structure of catechol-O-methyltransferase

A significant decrease in catechol-O-methyltransferase (COMT) activity of erythrocytes was found in both male and female schizophrenic patients, as well as in male patients with schizophreniform psychosis. Among control subjects, a sex difference in COMT activity of erythrocytes was found, with males showing significantly higher activity than females. It is suggested that a genetically determined deficiency of catecholamine degradative enzymes in the central nervous system or, alternatively, influences of nongenetic hormonal factors could be implicated in the findings of altered erythrocyte COMT activity reported.

Otto Schrappe

Papers

Catechol-O-methyltransferase of erythrocytes in patients with endogenous psychoses.