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A mutant strain of very badly behaved mice has led researchers to an important gene that can increase the risk of bipolar disorder in humans.

The discovery raises the possibility of understanding the biology behind a condition that strikes one in every 100 people, and tailoring specific treatments for it.

Scientists at the University of British Columbia first reported in 2002 that mice missing this gene were prone to kill their mates, beat their siblings and bite the lab hands that feed them.

The unanswered question was whether the gene played a similar role in violent people.

The Vancouver team eventually found the gene is so crucial to brain development that any human missing it completely could not survive. After screening nearly 800 mentally ill patients and 500 control subjects, the researchers learned that people with bipolar disorder, once known as manic depression, tend to carry mutations in this gene.

"The discovery opens up this disorder to treatments we could not otherwise know about," said Elizabeth Simpson, an associate professor at UBC's Centre for Molecular Medicine. "Most of the drugs and treatments we have for mental illness we have discovered by chance, by trial and error."

Dr. Simpson, senior author of the report published today in the American Journal of Medical Genetics, stressed that mental illnesses are a product of multiple genes and environmental triggers. But, she added, understanding even one small piece of a puzzle in a common disorder makes the finding significant.

She said groups with the Pittsburgh School of Medicine and the U.S. National Institutes of Health have also submitted early reports linking the gene to psychosis and bipolar disorder.

The gene, Nuclear Receptor-2E1, seems to regulate the production of stem cells in the forebrain - the region involved in executive functions such as reasoning and decision-making. Stem cells are the blank seed cells that can give rise to various tissues, such as new neurons in the brain.

As a result, Dr. Simpson said, the study's "most immediate impact" is that it bolsters the budding theory that mental illness might be the result of brain stem cells gone awry.

In the so-called "cancer-stem-cell hypothesis," some researchers believe that abnormal stem cells lie behind the runaway growth that spawns tumours. In the mental-health field, some experts suspect the lack of proper stem-cell growth results in "a brittle brain," Dr. Simpson said.

"You're unable to cope or react to certain changes ... there's less plasticity in the brain," she said.

Robert Cooke, a staff psychiatrist at the Mood and Anxiety Clinic at the Centre for Addiction and Mental Health in Toronto, cautioned that "there are genetic associations with bipolar disorders every year or two."

However, he said, "this study began with a reasonable hypothesis, that makes it a better study. ... It was not just a fishing expedition."

After identifying the gene in the "fierce mice," the UBC team proved its function in 2005 by inserting the human form of the gene into the DNA of nasty rodents. The swap transformed the animals into nice, gentle mice.

That same year, a large study from the Harvard School of Public Health concluded that a region of chromosome 6 - where the NR2E1 gene lies - plays a key role in bipolar disorder. The work convinced Dr. Simpson they were onto something.

The UBC study, with contributors in Scotland, England, and the United States, screened the NR2E1 genes of 394 patients with bipolar disorders, 396 with schizophrenia and 496 healthy control subjects. They also ran detailed genetic scans of another 126 patients to home in on the gene mutations.

The researchers concluded that people with a variant form of the gene have a risk 1.3 per cent higher than those who do not carry a variant. Dr. Simpson said the number may seem small, but she noted that even a 1-per-cent increase is a significant gene association for a mental illness with myriad causes.

Researchers found the link to be strongest in Type 1 bipolar disorder, the most severe form, and among women.

"Women get bipolar disorder less than men, but when they do, it's much more severe," Dr. Simpson explained. "This suggests this gene is linked to the most severe forms of bipolar disorder."

Dr. Simpson now plans to test the impact of eight variant forms of the human gene they identified in specially bred mice. Although she fully expects the behavioural effects will be far more subtle than the fierce strain that started it all.

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Mood disorders 101

Bipolar disorders are a category of mood disorders that involve a "cycling" between mania and depression. They strike 1 per cent of the population.

The most severe form of the three subtypes categorized is Type 1 bipolar disorder.

It involves episodes of gloom and extreme euphoria that can require hospitalization.

In the manic phase, says Robert Cooke of Toronto's Centre for Addiction and Mental Health, patients are apt to be highly irritable, argumentative, sexually or financially reckless and a possible danger to themselves. Episodes can last anywhere from a month to six months.

The disorder tends to begin in adolescence and becomes a lifelong condition.

Elizabeth Simpson at the University of British Columbia notes that 60 to 80 per cent of the cause is believed to be rooted in genetics, with environmental factors contributing as well.

Bipolar disorders are usually treated with medications, counselling therapy or both.

Carolyn Abraham