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Chromosome 22 Link to Schizophrenia Strengthened

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.

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

Comments on News and Primary Papers
Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 5 November 2005 Posted 5 November 2005

The fact that the PRODH alteration studied in Gogos et al....  Read more

View all comments by Anthony Grace

Comment by:  Caterina Merendino
Submitted 5 November 2005 Posted 5 November 2005
  I recommend the Primary Papers

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

Comment by:  Jeffrey Lieberman, SRF Advisor
Submitted 6 November 2005 Posted 6 November 2005
  I recommend this paper

Isn't the association of the low-activity COMT allele with...  Read more

View all comments by Jeffrey Lieberman

Comment by:  Leboyer Marion
Submitted 6 November 2005 Posted 6 November 2005
  I recommend the Primary Papers

Comment by:  Anne Bassett
Submitted 7 November 2005 Posted 7 November 2005
  I recommend the Primary Papers

I echo Jeff Lieberman's comment regarding previous reports...  Read more

View all comments by Anne Bassett

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 14 November 2005 Posted 14 November 2005

Drs. Lieberman and Basset raise an important question...  Read more

View all comments by Daniel Weinberger

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

Comment by:  Doron GothelfAllan Reiss
Submitted 18 November 2005 Posted 18 November 2005

Reply to comments by Lieberman and Bassett

I...  Read more

View all comments by Doron Gothelf
View all comments by Allan Reiss

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

Comment by:  Carrie Bearden
Submitted 21 November 2005 Posted 21 November 2005
  I recommend this paper

Gothelf and colleagues present a novel study (the first...  Read more

View all comments by Carrie Bearden

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

Comment by:  Patricia Estani
Submitted 23 November 2005 Posted 23 November 2005
  I recommend this paper

I agree with the comments of Dr. Weinberger about the COMT...  Read more

View all comments by Patricia Estani

Primary Papers: COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome.

Comment by:  William Carpenter, SRF Advisor (Disclosure)
Submitted 27 December 2005 Posted 27 December 2005
  I recommend this paper
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