Irvine, Calif. -- UC Irvine researchers and their collaborators at the University of Pittsburgh and in Europe have identified a gene they believe is responsible for increasing the risk of schizophrenia, a psychiatric disorder that afflicts 60 million people worldwide, including three million in the United States. This gene also may enhance risk for manic-depressive illness (also called bipolar disorder), which affects 60 million to 100 million people worldwide.
The findings are being presented Friday, Oct. 31, at the 47th annual conference of the American Society of Human Genetics in Baltimore, and will appear in the January 1998 issue of Molecular Psychiatry.
George Chandy and Jay Gargus, professors of physiology and biophysics and human genetics, at the UC Irvine College of Medicine, and George Gutman, a UCI college of Medicine professor of microbiology and molecular genetics, said they may have isolated one of a series of elusive genes that scientists believe may increase susceptibility for these mental illnesses. However, they cautioned that many previous reports by other investigators had turned out to be false leads. "Additional studies involving greater numbers of patients are needed to verify what role the new gene may play in mental illness," Chandy said.
"We located the candidate gene in a region of a chromosome long thought to be associated with these diseases, and the job this protein normally carries out makes it reasonable that it could contribute to such disorders," Gargus explained.
Specifically, the gene the team identified encodes a protein, called a potassium ion channel, that controls electrical activity in nerves. Alterations in its function could change brain behavior. "This is a significant step toward understanding the origins of mental illnesses. If our results are confirmed by further studies, this discovery 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," Gargus said.
Research material from U.S. patients and ethnically matched control subjects were provided by Drs. Vishwajeet Nimgaonkar and Rohan Ganguli from the Western Psychiatric Institute at the University of Pittsburgh. Studies were independently performed on European patients with this gene by Drs. Deborah Morris-Rosendahl, Oliver Wittekindt (both from the University of Freiburg, Germany) and Marc-Antoine Crocq (Centre Hospital, Rouffach, France). Other scientists at UCI involved in the study were Emmanuelle Fantino, Katalin Kalman, Lili Tong and Than-Hien Ho, all in the department of physiology and biophysics.
The new ion channel protein works as an "off-switch," dampening electrical activity in the brain. For example, this channel shuts off signals triggered through the NMDA receptor in nerves. Toxic "street" drugs (e.g. PCP) that have long been recognized to cause a schizophrenia-like syndrome block the NMDA neuroreceptor, while therapeutic anti-psychotic drugs activate it. Psychiatrists have therefore begun to consider schizophrenia a disease caused by too little activity of this receptor. Genetic tests, however, have shown that the genes encoding NMDA-receptors are very unlikely to cause mental illness. These genes have not been found in those places on human chromosomes that have been associated with mental disorders.
The newly discovered ion channel gene is found at the right place on the chromosome in a region called 22q. 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. "Attempts to identify a specific gene out of the thousands of genes present have so far proven unsuccessful," Gutman said. This ion channel gene may represent the critical gene in this region.
"Excessive activity of the ion channel could indirectly cause an effect like PCP, that is by shutting down NMDA receptors and thereby increasing risk for schizophrenia," Chandy explained.
The suspect gene identified by these researchers contains another remarkable feature, a tell-tale unstable DNA sequence that encodes abnormally long stretches of the repetitive sequence, technically known as CAG. The CAG sequence is the genetic code for an amino acid (a unit of a protein) called glutamine. Many CAGs in a row produce a simple protein sequence called polyglutamine. Long stretches of polyglutamines in a number of different proteins cause neurodegenerative diseases, including Huntington's disease and imbalance-disorders called ataxias. Studies by several researchers have implicated polyglutamine-containing proteins in mental illnesses, although the specific protein(s) have yet to be discovered.
The newly discovered ion channel has the tell-tale polyglutamine-stretch, and may be the elusive protein that scientists have been seeking. "Many neurodegenerative disorders, including Huntington's disease, get progressively more severe from one generation to the next, with the illness beginning earlier and earlier in life in successive generations," Chandy said. This phenomenon is called "anticipation." A similar worsening of mental illness from one generation to the next also has been recognized. Anticipation is caused by progressive lengthening of polyglutamine repeat sequences in proteins from one generation to the next. The presence of the polyglutamine stretch in the newly discovered ion channel might therefore help explain anticipation in mental illness.
The UCI researchers and their collaborators studied the CAG repeats in the new gene, hSKCa3, in 150 patients with schizophrenia from Europe and the United States, and a similar number of carefully matched unaffected adults. They found a significant excess of genes containing longer CAG repeats in patients. Therefore, the channel proteins in these patients would contain longer polyglutamine-stretches, possibly contributing to the molecular origins of this illness.
Studies with a smaller number of patients with bipolar disorder also show the same trend toward longer polyglutamine stretches in patients. "With a more precise understanding of how this molecular difference contributes to mental illness, we may be able to develop genetic screening tools and more effective therapies," Gutman said.
The UCI group plans to use the cloned gene to take the first steps in that direction. "By expressing this gene in cultured cells, we plan to determine the effect of longer polyglutamine repeats on the channel's function", Gargus said.
"Modern techniques available in the laboratory now allow the identification of subtle differences caused by longer polyglutamine repeats, even at the level of single molecules," Chandy said.
In collaboration with other scientists at UCI, these investigators plan to determine the precise areas of the brain that express this channel, and whether there exist differences in these areas between the brains of schizophrenia patients and unaffected donors.
Finally, these investigators are planning to extend their analysis by studying more patients and their families.
Journal
Molecular Psychiatry