Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders

TLDR

COMT degrades catecholamines and drugs such as L‑DOPA, and a common polymorphism produces a 3–4× variation in enzyme activity and thermal stability. The study aims to use this polymorphic marker to investigate COMT’s role in neuropsychiatric disorders involving catecholamine dysregulation and to guide personalized catechol drug metabolism. The alleles were distinguished by PCR followed by restriction fragment length polymorphism analysis using the NlaIII enzyme. The polymorphism is a G→A transition at codon 158 that substitutes valine with methionine.

Abstract

Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G-->A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogenetic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.