Repeating DNA linked to schizophrenia.

A genetic stutter already convicted of causing Huntington's disease and several other neurodegenerative disorders is now under suspicion as an accomplice in the triggering of mental illnesses such as schizophrenia.

Investigators have found that in a group of people with schizophrenia, this unusual stutter, known as a CAG repeat, tends to be significantly longer than normal in a gene that helps control the flow of potassium ions into brain cells.

This unexpected finding is bolstered by earlier research suggesting that a schizophrenia-related gene exists in the region of chromosome 22 where the new-found gene resides, notes J. Jay Gargus of the University of California, Irvine, who presented the work last week at the American Society of Human Genetics meeting in Baltimore.

In light of previous failures to replicate studies linking a gene to mental disorders, Gargus and other scientists caution that the new finding must be confirmed by studying many more people with schizophrenia.

"This is an interesting candidate and it should be tested, but it shouldn't be considered a gene that contributes to schizophrenia at this point," says CAG repeat researcher Christopher A. Ross of Johns Hopkins University Medical Institutions in Baltimore.

"Stories of these genes have been wrong in the past and will be wrong in the future. Only time will tell," agrees Michael J. Owen of the University of Wales College of Medicine in Cardiff.

Gargus and his colleagues normally study ion channels, complexes in cell membranes that govern ion movement into and out of cells. After finding a rat gene that encodes a potassium channel, they unearthed the human version and noticed it had CAG repeats.

This feature--a repetition of the nucleotide sequence cytosine, adenosine, and guanine--has become a theme in genes underlying neurological illnesses (SN: 6/10/95, p. 360). The repeats apparently trigger problems by adding extra copies of the amino acid glutamine to the protein normally encoded by a gene.

Gargus and his colleagues therefore wondered if their gene, with its CAG r repeats, might cause some illness. "We wanted a nice, rare neurodegenerative disease," he recalls.

The scientists mapped the gene to the chromosome 22 region deleted in velocardio-facial syndrome, an inherited developmental disorder marked by an increased incidence of manic depression and schizophrenia (SN: 1/4/97, p. 7).

Working with scientists at the University of Pittsburgh and in Europe, they determined the number of the gene's CAG repeats in about 150 people with schizophrenia and about 150 without the disorder. Although the number of repeats ranged from 10 to 28 in both groups, statistical tests showed that, on average, people w6 schizophrenia had significantly more repeats.

Since the number of CAG repeats may vary less among related people, some scientists suggest that the gene's link to schizophrenia would have been more compelling if the researchers had compared CAG repeat numbers between people with the mental illness and their unaffected, close relatives.

It's unclear how CAG repeats in the newly identified gene could increase susceptibility to schizophrenia. Gargus and his colleagues speculate that extra repeats lead to abnormally active potassium channels, which suppress proteins called NMDA receptors. Drugs that inhibit this receptor, such as PCP, induce schizophrenialike symptoms, and some antipsychotic drugs activate the receptor, says Gargus.

As they seek to confirm their gene's link to schizophrenia, as well as determine its role in other mental disorders, such as manic depression, the investigators plan to examine where in the brain the gene is active. In the hope of developing new drugs for schizophrenia, they will also search for compounds that block the channel.