Proline affects brain function in 22q11DS children with the low activity COMT158 allele

Jacob A.S. Vorstman, Bruce I. Turetsky, Monique E.J. Sijmens-Morcus, Monique G. De Sain, Bert Dorland, Mirjam Sprong, Eric F. Rappaport, Frits A. Beemer, Beverly S. Emanuel, René S. Kahn, Herman Van Engeland, Chantal Kemner

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

The association between the 22q11.2 deletion syndrome (22q11DS) and psychiatric disorders, particularly psychosis, suggests a causal relationship between 22q11DS genes and abnormal brain function. The genes catechol-O-methyl-transferase (COMT) and proline dehydrogenase both reside within the commonly deleted region of 22q11.2. COMT activity and proline levels may therefore be altered in 22q11DS individuals. Associations of both COMT 158 genotype and elevated serum proline levels with abnormal brain function have been reported. Fifty-six 22q11DS children and 75 healthy controls were assessed on physiological measures of brain function, including prepulse inhibition (PPI) of startle, P50 auditory sensory gating and smooth pursuit eye movements (SPEM). COMT158 genotype and plasma proline levels were determined in the 22q11DS children. We hypothesized an interaction between the COMT158 genotype and proline, predicting the strongest negative effect of high proline on brain function to occur in 22q11DS children who are carriers of the COMTmet allele. Of the three physiological measures, only SPEM and PPI were abnormal in the patient sample. With regard to the SPEM performance, there was a significant interaction between the COMT158 genotype and proline level with significantly decreased SPEM performance in children with high plasma proline levels and the low activity COMTmet allele. A similar interaction effect was not observed with regard to PPI. These findings are consistent with a model in which elevated proline negatively affects brain function by an increase in dopamine in the prefrontal cortex. 22q11DS patients with low dopamine catabolic capacity are therefore especially vulnerable to this functional disruption.

Original languageEnglish
Pages (from-to)739-746
Number of pages8
JournalNeuropsychopharmacology
Volume34
Issue number3
DOIs
StatePublished - Feb 2009
Externally publishedYes

Keywords

  • 22q11.2DS
  • Catechol-O-methyl transferase
  • Endophenotype
  • Prepulse inhibition
  • Proline
  • Smooth pursuit

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