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Published in the June 16, 2003 issue of the journal Molecular Psychiatry, the findings indicate that a mutation in a gene that regulates sensitivity to brain neurotransmitters such as dopamine, causes bipolar disorder in as many as 10 percent of bipolar cases. The mutation in this gene, G protein receptorkinase 3 (GRK3), occurs in a portion of the gene called the promoter, that regulates when the gene is turned on.
The research team hypothesizes that this mutation causes the individual to become hypersensitive to dopamine, leading to the mood extremes that characterize biopolar disorder.
A complex and variable illness, bipolar disorder is thought to be caused by multiple genes. Although previous research has suggested candidate genes or general DNA regions where faulty genes may reside, the UCSD study is the first to pinpoint a precise gene involved in the disease.
Also known as manic depression, bipolar disorder is characterized by extreme mood states alternating between euphoric peaks and terrible depression. Current treatments help many who suffer from bipolar disorder, but physicians estimate that one-third to one-half of the 1 million bipolar patients worldwide receive little benefit from existing therapies.
“One of the major limitations in bipolar treatment is the lack of new molecular targets for drugs,” said John Kelsoe, M.D., UCSD professor of psychiatry, a psychiatrist at the San Diego VA Healthcare System, and senior author of the study. “Our hope is that discovery of genetic defects that cause bipolar disorder will lead to new drugs that can be directed to those specific genes.”
During a year of screening DNA samples from more than 400 families with bipolar disorder, the study’s first author, Thomas B. Barrett, M.D., Ph.D., assistant professor of psychiatry, UCSD and psychiatrist, San Diego VA Healthcare System, determined that there were six mutations in the promoter region of the GRK3 gene. One of these mutations, P-5, occurred three times more frequently in manic-depression patients than in non-afflicted individuals.
“P-5 is in the region of GRK3 that controls when the gene turns on and off,” Barrett said. “A defect in P-5 affects regulation of the gene. It may be turning on inappropriately, or turning off when it shouldn’t.”
He added that the location of the variant within the gene made it very likely to impact the function of the GRK3 gene.
The current study arose from ongoing work in the Kelsoe lab that used sophisticated gene linkage studies and micro array gene-chip analysis to determine both the positional and functional roles of GRK3.
Research in recent years has pointed to several chromosomes – the hreadlike strands that carry genetic information – as sites for the multiple genes that cause bipolar disorder. In 1997, the Kelsoe team first reported evidence for bipolar candidate genes on Chromosome 22. Utilizing “linkage studies,” which compare the inheritance patterns in families with bipolar disease, they noticed marked similarities, or “peaks” in two regions of Chromosome 22, which they suspected contained genes contributing to the disease.
“When the entire human genome was published, we learned that the gene GRK3 was right on top of one of these two peaks,” Kelsoe said. “Tom Barrett then had the difficult task of screening the gene for mutations.”
In a parallel study, Kelsoe and collaborators Bob Niculescu, David Segal and Ron Kuczenski, used DNA micro arrays, also called gene chips, to look at 8,000 genes from rats treated with amphetamine so as to mimic the mania of bipolar disorder. This relatively new technology allows scientists to track the expression – the turning on and off – of thousands of genes in a single, high-speed test.
“GRK3 had the largest change in levels of expression, indicating that it played a substantial role in the brain’s response to dopamine and possibly other neurotransmitters,” Kelsoe said. He added that “this was one of the most exhilarating moments for all of us involved. We had the positional piece from the linkage studies, and then the expression data which identified the same gene. We call this convergent functional genomics – identifying a gene based on both its position on a chromosome and on its function.”
Once GRK3 was identified, Barrett screened DNA samples from two independent sets of families at UCSD and the National Institutes of Mental Health, to look for mutations. A third set of DNA samples were obtained from Canadian bipolar patients. Barrett noted that the findings of the third group replicated the results from the first two samples.
The researchers hypothesize that
GRK3’s role may be to turn down the level of response to neurotransmitters
such as dopamine. “We believe that a
In addition to Kelsoe and Barrett, additional authors are Richard Hauger, M.D., and Meghan Alexander, B.A., UCSD and VA Departments of Psychiatry; James L. Kennedy, M.D., University of Toronto, Canada; A. Dessa Sadovnick, Ph.D., University of British Columbia, Vancouver; Ronald A. Remick, M.D., St. Paul’s Hospital, Vancouver; Paul E. Keck, M.D. and Susan L. McElroy, M.D., University of Cincinnati; and Sarah H. Shaw, Ph.D., UCSD Department of Psychiatry.
Funding was provided by Novartis
Pharma AG, the Department of Veterans Affairs and the National Institute
of Mental Health.
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