By Lisa Seachrist

Washington Editor

BALTIMORE — The genes that combine to produce the mental distortions of schizophrenia have proved an elusive tangle for researchers searching to unravel its cause and provide relief to the 60 million schizophrenics worldwide.

Repeatedly, genes have risen to the surface as potential causes for the disease only to have the link dissipate upon further analysis. However, researchers have reliably noted that a region of chromosome 22 appears to enhance the risk of developing the disorder.

Scientists from the University of California, Irvine (UCI), told attendees at the 47th annual conference of the American Society of Human Genetics Friday a newly discovered gene encoding a protein that slows the firing of neurons may increase the risk of developing schizophrenia as well as bipolar disorder.

"We located the candidate gene in a region of chromosome 22 long thought to be associated with these diseases," said J. Jay Gargus, a UCI professor of physiology and biophysics. "The normal function of this protein makes it reasonable that it could contribute to the disorders."

The gene, hSKCa3, that Gargus and his colleagues from the University of Pittsburgh, the University of Frieburg, Germany, and the Centre Hospital, in Rouffach, France, identified is a potassium channel. The channel shuts off neuronal firing by turning off signals triggered through the N-methyl-D-aspartate (NMDA) receptor. Street drugs like PCP cause a schizophrenia-like reaction by blocking the NMDA receptor.

"The NMDA receptor, however, has never been genetically linked to mental illness," Gargus said. "So, a protein that affects the activity of the NMDA receptor would be a reasonable candidate."

Because some research has shown that schizophrenia and bipolar disorder worsen with each generation, Gargus and his colleagues decided to search for a cytosine-adenine-guanine (CAG) triplet repeat pattern that has been implicated in other neurodegenerative diseases like Huntington's disease.

Gene Search Targeted More Than 100 Patients

The researchers studied 150 patients with schizophrenia from Europe and the U.S. and a similar number of matched unaffected adults. Using the criteria that 20 or more CAG repeats in the gene constituted an excess number of repeats, the researchers found that 21 percent of the schizophrenic patients harbored 20 or more CAG repeats compared to 12 percent of the controls.

"These repeats appear to cause a graduated rather than a stochastic change in the potassium channel," Gargus said. "That would be in character with the linkage found at chromosome 22 — it is neither necessary nor sufficient to cause disease, but it seems to increase the risk."

Gargus believes that the polyglutamine encoded by the CAG repeats may cause the proteins that make up the channel to stick together, leaving the channel open longer than is normal. An open potassium channel dampens neuronal activity by shutting down the NMDA receptor.

"It is in theory acting like PCP," Gargus said.

Gargus noted that his findings need to be repeated in a larger sample and among families in order to establish the gene's role, if any, in the development of schizophrenia. In addition, he is working on testing how exactly the CAG repeats affect the activity of the potassium channel.

The University of California has patented hSKCa3 and the researchers have been contacted by several companies hoping to develop drugs that turn off the potassium channel. *

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