Proline affects brain function in 22q11DS children with the low activity COMT 158 allele

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). COMT(158) genotype and plasma proline levels were determined in the 22q11DS children. We hypothesized an interaction between the COMT(158) genotype and proline, predicting the strongest negative effect of high proline on brain function to occur in 22q11DS children who are carriers of the COMT(met) 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 COMT(158) genotype and proline level with significantly decreased SPEM performance in children with high plasma proline levels and the low activity COMT(met) 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.

Figure 1

The association between proline and SPEM is moderated by the COMT¹⁵⁸ genotype. Only in the COMT^met subgroup a decreased SPEM performance was associated with high plasma proline levels in 22q11DS individuals (p = 0.028), whereas in the COMT^val group no significant difference was revealed between the high/low proline subgroups (p = 0.827). Proline levels were not available in seven subjects; therefore the sample size in this analysis is 49.

Figure 2

Schematic representation of the hypothesized model. High proline levels induce glutamatergic signaling in the hippocampus. Increased glutamatergic tone causes a release of DA in the PFC. In 22q11DS subjects hemizygous for COMT^met (in blue), the inefficiency in catabolizing DA leads to a large shift to the right (dotted line). This, in combination with a starting position somewhat right of the curve’s optimum, leads to a decrease in PFC function. In those hemizygous for COMT^val (in red), excess DA can be more adequately catabolized; the resulting shift, if any, on the hypothetical model of the inverted U-shaped curve is more moderate and does not result in a substantial change in PFC function (inverted U-shape curve adapted from Mattay et al, 2003).