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 Research & Giving News Article  Rare mutations disrupt genes in pathways of neuronal development and regulation Among those leading the team of investigators, which involved scientists at nine institutions, were Mary-Claire King, M.D., a NARSAD 2006 Distinguished Investigator at the University of Washington, and a member of her lab, Tom Walsh, Ph.D., a NARSAD 2007 Young Investigator. The team screened for novel deletions and duplications in the genome -- what are called gene copy-number variations, or CNVs. They found that deletions, disruptions, and duplications of normal genes, most of them rare, were three to four times more frequent in people with schizophrenia than in healthy people. “This is an important new finding in the genetics of schizophrenia,” said NIMH Director Thomas R. Insel, M.D. “Identifying genes prone to harboring these mutations in brain development pathways holds promise for treatment and prevention of schizophrenia, as well as a wide range of other neurodevelopmental brain disorders.” A New Method of Finding Candidate Genes The researchers used a novel method to study their sample, which included 418 individuals, 150 of whom had schizophrenia or schizoaffective disorder. Instead of trying to show a statistical correspondence between a large group of people with schizophrenia and irregularities in common versions of genes, the team began by looking, in every test subject, for “glitches” or changes in DNA, that are likely to disrupt gene function. Then they compared which genes -- with what kinds of functions -- were impaired, both in the healthy subjects and those with schizophrenia. The results were striking. Rare mutations showed up in only 5 percent of the healthy controls versus 15 percent of those with schizophrenia. The rate of rare mutation was higher still – 20 percent -- among an “early-onset” subset of patients, who had developed schizophrenia before age 19. The results were replicated by a second research team at the National Institute of Mental Health, led by NARSAD Scientific Council member Judith Rapoport, M.D., which found a higher rate of rare duplications or deletions patients whose schizophrenia began before age 12 years, a very rare and severe form of the disorder. “This part of our findings indicates something we didn’t know before: that rare structural mutations in genes, while present in both healthy people and people with schizophrenia, are much more likely to occur among people with the illness. This suggests a previously unknown role for rare mutations in the causation of schizophrenia,” said Jonathan Sebat, Ph.D., who directed the team at Cold Spring Harbor Laboratory in New York, which also collaborated in the study. Rare Mutations and What They Do The second part of the research aimed to answer a key question about the genes discovered to be irregular: What were their functions? Were their functions similar or different in healthy people versus those with schizophrenia? Here, too, the results were striking. In people with schizophrenia, almost half the time, the disrupted genes were involved in pathways important in brain development. By contrast, when the scientists looked at the set of genes that were disrupted in healthy people, they found that they were not overrepresented in any particular pathway. In a paper that first appeared March 27 in the online edition of Science, the team notes that of 24 rare mutations seen in the schizophrenia group, 11, or 45 percent, affect cellular signaling pathways critical to neuronal cell growth, migration, proliferation, differentiation, apoptosis, and synapse formation. Some of the affected pathways have turned up in past studies of schizophrenia, notably those involving signaling in neuregulin, a growth factor, and glutamate, a neurotransmitter. Implications and Future Studies While the study, as the scientists directly concede in their paper, “does not prove the involvement with the illness of any specific variant, or even the involvement of any specific gene,” it does, however, indicate a role for rare mutations that disrupt genes in pathways of neuronal development and regulation. The results are powerful because they link specific structural variation in genes with specific functions known to be important in the early years of life during which schizophrenia develops in many patients. This important result leads the scientists to advocate broad use of the method they employed in the study. Gene discovery in complex psychiatric illnesses “should focus on methods that allow detection of structural mutations” across the genome in affected individuals, the team urges. The prevailing genetic model of schizophrenia implicates common variants of certain suspect candidate genes, each exerting modest effects, in interaction with each other and environmental factors. This hypothesis holds that risk stems from common variations in the sequence of the genetic code that result in altered protein products. About a year ago, Dr. Sebat and colleagues reported evidence strengthening the case for a different kind of genetic risk. Many people with autism were found to have different, spontaneous and individually rare structural variations -- variations in the number of copies of genes. These copy number variations were scattered throughout the genome, suggesting that many different genes could be involved in autism spectrum disorders, and that often they were not inherited from an individual’s parents, but rather, the result of spontaneous mutation. The new findings in schizophrenia echo those in autism, in that a number of spontaneous mutations were found in the sample of schizophrenia patients; but conclusions about the importance of spontaneous mutations were not possible in the schizophrenia study because the sample did not include a sufficient number of family “sets” -- patients and both of their parents. Dr. Sebat’s lab is currently assembling such a sample for study of the role of spontaneous mutation in schizophrenia. What was important about the study just published, the team writes in their paper, is the fact that “although each mutation discovered may be individually rare, collectively the total number of disease-causing variants in a gene [found to be] relevant to the disorder may explain a substantial number of cases.” Other NARSAD-affiliated scientists contributing to the study are Robert L. Findling, M.D., of Case Medical Center in Cleveland, who was a 1993 Young Investigator; Stanley F. Nelson, M.D., of UCLA, a 1994 Young Investigator; and Linmarie Sikich, M.D., of the University of North Carolina, who received Young Investigator awards in 1998 and 2000. |
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