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4 November 2005. There is now overwhelming evidence that genetic inheritance plays a major role in susceptibility to schizophrenia. And though no schizophrenia genes have yet been confirmed, there are plenty of candidates. Multiple lines of evidence, for example, suggest that a region in the small arm of chromosome 22 (22q11.2) might confer susceptibility to the disease. Two recent Nature Neuroscience papers bolster that connection.
The link between schizophrenia and chromosome 22q11.2 is particularly interesting because that segment of DNA harbors genes for two enzymes that can influence neurotransmission—catechol-O-methyltransferase (COMT) and proline dehydrogenase (PRODH). COMT, of course, is crucial for dopamine metabolism, so any genetic variance that alters the activity of this enzyme could tip the balance toward too much, or too little, of this neurotransmitter. The PRODH link is less obvious, but again, loss or reduction of PRODH activity could lead to an increase in the level of proline, and it was recently shown that this amino acid accumulates in glutamatergic synapses where it probably modulates glutamate transmission (see, for example, Renick et al., 1999). Now, together, the two papers add weight to the COMT/PRODH link.
Allan Reiss and colleagues at Stanford University, California, together with collaborators at Tel Aviv University, Israel; the University of Geneva, Switzerland; and the University of Washington, Seattle, report on a study of adolescents with 22q11.2 deletion syndrome. The disorder is often referred to as velocardiofacial syndrome (VCFS), a term that encompasses some of the most common early childhood manifestations such as cleft palate, heart defects, characteristic facial appearance, minor learning problems, and speech and feeding problems. The constellation of some 30 different identifying features, not all of which appear in any given child, are traceable to the deletion of that region of chromosome 22. About one third of all babies born with these deletions will go on to later develop schizophrenia (see, for example, Murphy et al., 1999).
First author Doron Gothelf and colleagues considered whether polymorphisms, or variations, in the undeleted copy of COMT may help to explain why some with the 22q11.2 deletion will develop schizophrenia, while others do not. They followed patients known to have the deletion, correlating the emergence of the disease with a known single nucleotide polymorphism—one that results in a methionine amino acid instead of a valine at position 158 and that ablates about one third of the enzyme’s activity.
Gothelf and colleagues tested 24 patients with 22q11.2 deletion syndrome. During childhood, none showed evidence of a psychotic disorder, but in early adulthood, seven did. The authors found that the COMT variant with low enzyme activity (COMTL) correlated with lower verbal IQ and language skills and lower prefrontal cortex volume in these seven adolescents. The results suggest that “extreme deficiency in COMT activity, as present in the COMTL subjects with 22q11.2DS, is an important neurodevelopmental risk factor for decline in PFC [prefrontal cortex] volume and cognition and for the emergence of psychotic symptoms during adolescence,” write the authors.
In the second paper, Maria Karayiorgou's group at Rockefeller University, New York, and Joseph Gogos's group at Columbia University, New York, collaborated to model the effect of altering the expression of PRODH. First author Marta Paterlini and colleagues found that in mice, loss of the enzyme leads to increases in neuronal proline and that this, in turn, increases the probability that glutamate will be released into synapses in the hippocampus. In addition, the authors discovered that synaptic plasticity, as defined by the ability of neurons to modulate their activity in response to the activity of other nearby neurons, is compromised. They found, for example, that both paired-pulse facilitation and long-term potentiation, two commonly used measures of plasticity, were inhibited. The authors also found that loss of PRODH and increases in proline were accompanied by behavioral changes—the mice were generally less active, exploring about 25 percent less than normal mice, and they reacted less frequently in conditioned responses to stimuli such as mild shock. The animals also had a poorer response to psychotomimetic drugs, such as MK801, which increase glutamate release (this could be because the PRODH-deficiency already causes more release of glutamate than normal), but when given amphetamine, locomotor activity increased almost twofold more than in normal animals. “This is reminiscent of the increased susceptibility to the disorganizing effects of D-amphetamine observed in individuals with schizophrenia,” note the authors.
Gothelf and colleagues, in their 22q11.2 deletion paper, emphasize that many other genes in the vicinity of COMT and PRODH should be evaluated, and Paterlini and colleagues do just this, using a transcriptional profiling method to evaluate what genes may be turned on or off by the loss of PRODH in their animal model. And one of the genes that interacts most strongly with PRODH was none other than COMT, which was upregulated in the prefrontal cortex of the PRODH-deficient animals. This not only buttresses the argument for COMT and PRODH as key risk factors for schizophrenia, but also suggests that the two genes may interact.—Tom Fagan.
References:
Paterlini M, Zakharenko SS, Lai W-S, Qin J, Zhang H, Mukai J, Westphal KGC, Olivier B, Sulzer D, Pavlidis P, Siegelbaum SA, Karayiorgou M, Gogos JA. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci. 2005 Nov;8(11):1586-1594. Epub 2005 Oct 23.
Abstract
Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Einstein C, Kwon H, Jin S, Jo B, Antonarakis SE, Morris MA, Reiss AI. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci. 2005 Nov;8(11):1500-2. Epub 2005 Oct 23.
Abstract
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