A gene called DISC1, (for “disrupted in schizophrenia”) has been a leading contender among possible genetic causes since it was implicated in schizophrenia in a large Scottish clan two decades ago. The DISC1 gene codes for a protein important for brain development, as well as for mood and memory – functions that are disturbed in schizophrenia. However, until now there have been few clues as to how DISC1 might increase risk for the chronic mental disorder.
A new study suggests how impaired expression of DISC1 might wreak havoc during early critical periods as the developing brain gets wired up. NIMH researchers have discovered that previously unknown shortened forms of the gene were expressed 2.5 times more in the fetal brain than after birth. By contrast, other forms were expressed more evenly across development. The shortened forms were also over-expressed in brains of adults who had schizophrenia.
“These shortened forms may result in a functionally aberrant and truncated protein that is more highly expressed in the brains of people with schizophrenia” explained NIMH’s Dr. Joel Kleinman, who led the research.
Drs. Kleinman, Barbara Lipska, Kenji Nakata, Daniel Weinberger and colleagues, report on their discoveries in postmortem brain tissue online, during the week of August 24, 2009 in the Proceedings of the National Academy of Science (PNAS).
Background: The new findings may help explain the molecular roots of the illness in the Scottish clan, in which more than half of the members developed schizophrenia or other serious mental disorders. Previous studies had traced their disease, in part, to a different aberration, a mismatch called a translocation, in which a chunk of genetic material from one chromosome gets attached to another chromosome. But this has never been seen in other families. A translocation, like the shorter messenger RNA forms, would result in shortened forms of DISC1 protein. So other affected families and the Scottish clan could in fact share a similar illness process, say the researchers.
Results of This Study: The researchers linked several illness-implicated variations in the DISC1 gene to the shorter forms of DISC1 products, called messenger RNAs, that transform the gene into protein. The results suggest that variations in the DISC1 gene boost risk for schizophrenia by producing shortened messenger RNAs that are predominantly expressed during the formative period when the fetal brain is taking shape.
Significance: “Our results cast a new light on apparent failures to replicate findings that have long plagued psychiatric genetics” said Kleinman. “We discovered that different genetic variations can result in the same or similar messenger RNAs and protein. That means that different studies could turn up different variations and still be pointing to the same underlying disease process. So some findings thought to be non-replications may ultimately prove to be replications.”
Since at least a half-dozen genes implicated in schizophrenia by the NIMH group interact with DISC1, the downstream adverse effects of impaired DISC1 on brain systems are likely considerable, said Kleinman.
What’s Next: One of the suspect gene variants associated with a shortened messenger RNAs is detectable in white blood cells, raising the possibility that it could someday be used as a genetic marker for the illness.
NIMH’s Dr. Joel Kleinman explained how the DISC1 gene may increase risk for schizophrenia at a recent NIMH seminar.
Nakata K, Lipska BL, Hyde TM, Ye T, Fink E, Morita Y, Vakkalanka R, Bareboim M, Sei Y, Weinberger DR, Kleinman JE. DISC1 splice variants are unregulated in schizophrenia and associated with risk polymorphisms. Aug 24, 2009 PNAS.