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One of medicine’s more inscrutable mysteries - why the brains of some individuals malfunction so badly they develop serious mental illnesses - may be one step closer to being solved with the announcement that researchers believe that they have identified a gene linked to an increased risk of developing schizophrenia.
George Chandy, Jay Gargus, and George Gutman, geneticists at the University of California, Irvine, School of Medicine, and colleagues from the University of Pittsburgh’s Western Psychiatric Institute, the University of Frieburg in Germany, and the Centre Hospital in Rouffach, France, presented their findings at the annual conference of the American Society of Human Genetics in Baltimore on October 31.
While enthusiastic about their finding, the Irvine researchers noted that other purported discoveries of genes linked to serious mental illnesses have failed to hold up during replication studies. They acknowledged that additional studies are required to verify just what role the newly identified gene plays in increasing schizophrenia risk.
The gene they are linking to the disease encodes a protein known as a potassium ion channel and controls electrical activity in nerves. The protein dampens electrical activity in the brain, essentially operating as an "off switch." The researchers suggest that a malfunction of this gene could alter brain behavior.
This ion channel protein, the researchers explained, can shut off signals triggered through the NMDA receptor found in nerves. They pointed out that some illicit drugs such as PCP block NMDA neuroreceptors, resulting in a syndrome that resembles schizophrenia. Certain antipsychotic medications, in contrast, bring about symptom improvement by activating this type of receptor.
Because the location of genes that encode NMDA receptors differs from that usually associated with mental disorders, previous genetic tests have dismissed the notion that such genes are linked with these illnesses, according to the researchers.
"The newly discovered ion channel gene, however, is found at the right place on the chromosome in a region called 22q," the researchers report in the paper presented at the conference. "Previous studies by a large number of investigators, especially those in the international consortia studying schizophrenia and bipolar disorder, have identified the 22q region as containing genes that enhance risk of mental illness."
Despite extensive efforts, "attempts to identify a specific gene out of the thousands of genes present have so far proven unsuccessful," but the ion channel gene may turn out to be the critical gene in this chromosome region, Gutman said at the Baltimore meeting.
Chandy indicated that the newly discovered gene is unlikely to be necessary or sufficient for schizophrenia to develop and probably works to increase risk when an abnormality appears in combination with other genetic risk factors and environmental influences.
The irregularity they identified in the suspect gene involves a DNA sequence that encodes abnormally long stretches of the repetitive sequence known as CAG, which is the genetic code for the amino acid glutamine. Long sequences of CAG’s produce a protein sequence called polyglut-amine, the researchers explained, which has been linked to neurodegenerative diseases such as Huntington’s chorea.
They investigated repeats of the CAG sequence in the newly discovered gene in 150 schizophrenia patients and a matched sample of healthy adults in the U.S. and Europe. The study uncovered an excess of genes containing longer CAG repeats in the schizophrenia sample. They found some evidence, though not nearly as strong, linking this trend toward longer polyglutamine stretches in bipolar patients as well.
Gargus said that the discovery "is a significant step toward understanding the origins of mental illness" and, if confirmed by additional studies, "could lead to the development of new tests to identify those at risk for these diseases and possibly to a new generation of highly targeted drugs with which to treat them."
"With a more precise understanding of how this molecular difference contributes to mental illness, we may be able to develop genetic screening tools as well as more effective therapies," Gargus said.
Another piece in the complicated neurobiological puzzle of schizophrenia may have been identified earlier this year when psychiatrist Robert Freedman, M.D., and colleagues at the University of Colorado published a study pointing to a gene on chromosome 15. When defective, this chromosome appears to cause a sensory-processing deficit that leads to auditory hallucinations, a symptom that plagues many schizophrenia sufferers (Psychiatric News, March 21, 1997). As did the University of California researchers, Freedman cautioned that more substantial proof of the suspected link to schizophrenia that his group found also will depend on replication by future investigations.