Description of Invention:
Abnormalities of prefrontal cortical function are prominent features of schizophrenia and have been associated with genetic risk, suggesting that susceptibility genes for schizophrenia may impact on the molecular mechanisms of prefrontal function. A potential susceptibility mechanism involves regulation of prefrontal dopamine, which modulates the response of prefrontal neurons during working memory. The Catechol-o-methyltranferase (COMT) gene contains a G to A mutation which causes a substitution of methionine for valine at codon 158. The met allele has a four fold reduction in enzyme activity which leads to an increase in prefrontal cortical dopamine levels. NIH investigators observed that the functional polymorphism in the gene encoding COMT is associated with variations in executive function and efficiency of working memory in normal controls and schizophrenic patients.
The invention provides a method of detecting impaired prefrontal cognitive function in a subject individual comprising determining the individual's COMT genotype and associating a high activity val allele with impaired prefrontal cognitive function and a low activity met allele with enhanced prefrontal cognitive function. The COMT genotype can be determined using a relatively simple restriction fragment length polymorphism analysis after PCR amplification of the polymorphic region of exon four since the met substitution introduces an NlaIII restriction site into the allele. Clinical medical tests to determine prognosis in schizophrenia and other conditions associated with the polymorphism would thus be possible. The invention also provides for treating patients with COMT inhibitors after tests that predict the response of a patient with schizophrenia, other neurological disorders or aging related declines in cognition to administration of a COMT inhibitor.
Inventors:
Daniel R. Weinberger (NIMH) Michael F. Egan (NIMH) Terry E. Goldberg (NIMH) David Goldman (NIAAA) Joseph H. Callicott (NIMH)
Patent Status:
DHHS Reference No. E-174-2000/0 --
U.S. Provisional Application No. 60/290,565 filed 11 May 2001
U.S. Patent Application No. 10/144,000 filed 10 May 2002
U.S. Patent Application No. 11/395,043 filed 31 Mar 2006
Portfolios: Central Nervous System
Central Nervous System -Therapeutics Central Nervous System -Diagnostics
For Additional Information Please Contact: Norbert J. Pontzer PhD JD
NIH Office of Technology Transfer
6011 Executive Blvd, Suite 325
Rockville, MD 20852-3804
Phone: (301) 435-5502
Email: pontzern@mail.nih.gov
Fax: (301) 402-0220
