HUMAN CATECHOL-O-METHYLTRANSFERASE PHARMACOGENETICS - DESCRIPTION OF A FUNCTIONAL POLYMORPHISM AND ITS POTENTIAL APPLICATION TO NEUROPSYCHIATRIC DISORDERS

Catechol-O-methyltransferase (COMT) inactivates catecholamines and cat echol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-ford variation in COMT enzyme activit y and is also associated with individual variation in COMT thermal ins tability, We now show that this is due to G-->A transition at codon 15 8 of the COMT gene that results in a valine to methionine substitution , The two alleles can be identified with a PCR-based restriction fragm ent length polymorphism analysis using the restriction enzyme N1a III. The identification of a gentic marker associated with significant alt erations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnorm alities in catecholamine neurotransmission are believed to occur, incl uding mood disorders, schizophrenia, obsessive compulsive disorder, al cohol and substance abuse, and attention deficit hyperactivity disorde r, In addition, this polymorphism may have pharmacogentic significance in that it will help make it possible to identify patients who displa y altered metabolism of catechol drugs.