COMT (Val158Met) Mutation

COMT is the gene’s official symbol for the gene “catechol-O-methyltransferase”. The COMT gene provides instructions for making an enzyme called catechol-O-methyltransferase. Two versions of this enzyme are made from the gene. The longer form, called membrane-bound catechol-O-methyltransferase (MB-COMT), is chiefly produced by nerve cells in the brain. Other tissues, including the liver, kidneys, and blood, produce a shorter form of the enzyme called soluble catechol-O-methyltransferase (S-COMT). This form of the enzyme helps control the levels of certain hormones. In the brain, catechol-O-methyltransferase helps break down chemical messengers called neurotransmitters which are responsible for conducting signals from one nerve cell to another. Catechol-O-methyltransferase is particularly important in an area at the front of the brain called the prefrontal cortex, which organizes and coordinates information from other parts of the brain. This region is involved with personality, planning, inhibition of behaviors, abstract thinking, emotion, and working (short-term) memory. To function efficiently, the prefrontal cortex requires signaling by neurotransmitters such as dopamine and norepinephrine. Catechol-O-methyltransferase helps maintain appropriate levels of these neurotransmitters in this part of the brain.

COMT and Estrogen

COMT has also been demonstrated to play a role in estrogen metabolism through inactivation of the catecholestrogens. Catecholestrogens are formed during the metabolism of estrogens such as estradiol. Catecholestrogen inactivation decreases the cancer-causing potential of these metabolites, while simultaneously increasing the amount of 2-methoxyestradiol, a metabolite that has been shown to inhibit the growth of breast cancer cells. Additionally, COMT polymorphisms have been shown to influence estradiol levels. As Met/Met allele carriers exhibit a 2-3 fold decrease in their ability to degrade catecholestrogens, this results in higher estradiol levels than Val/Val allele carriers. Estradiol clearance is also diminished in both the Met/Met and Met/Val genotypes as opposed to Val/Val genotypes, however there is no significant difference in estrone levels.

Clinical Utility

The Val108/158Met polymorphism has been associated with other disorders that affect thought (cognition) and emotion. For example, researchers have studied this variation as a possible risk factor for bipolar disorder, panic disorder, anxiety, obsessive-compulsive disorder (OCD), eating disorders, and attention deficit hyperactivity disorder (ADHD). Studies suggest that these conditions may be related to inefficient processing of information in the prefrontal cortex. There are however, many factors play a part in determining the risk of developing these complex disorders. Researchers have looked extensively at the potential connection between changes in the COMT gene and the risk of developing schizophrenia. Most studies have focused on the effects of a particular common variation (polymorphism) in catechol-O-methyltransferase. This variation alters a single amino acid in the enzyme, replacing the amino acid valine with the amino acid methionine. In the longer form of the enzyme, this variation occurs at position 158 (written as Val158Met). In the shorter form of the enzyme, it occurs at position 108 (written as Val108Met). Researchers often shorten this notation to Val108/158Met. The change affects the stability and activity of catechol-O-methyltransferase, which alters the enzyme’s ability to break down neurotransmitters in the prefrontal cortex. Having valine at this position is associated with differences in thought processes that are common in people with schizophrenia, including problems with working memory, inhibition of behavior, and attention. Other changes in the COMT gene may also contribute to these differences. Studies of the Val108/158Met polymorphism in people with schizophrenia have had mixed results. While most studies report no evidence of heightened risk with either methionine or valine at this position, some studies have found a slightly increased risk of schizophrenia in people with valine at position 108/158. A large number of genetic and lifestyle factors, most of which remain unknown, likely determine the risk of developing this condition.