Scientists have provided new insight into how a genetic variation is linked to schizophrenia.
The study may provide a new way to design better drugs to treat schizophrenia.
Amanda J. Law, Medical Research Council Fellow and Associate Professor at the University of Oxford, United Kingdom, and Visiting Scientist at the National Institutes of Health (NIH), along with colleagues at NIH describe for the first time a genetic variation that causes a gene to be over expressed in the human brain.
"Although the exact causes of schizophrenia are yet to be determined, scientists agree that the disease is in part due to genetic variations," Law said.
"These variations are not simple to understand because they don't directly disturb the function of proteins. In our study, we identified some clues as to what goes wrong with one of these DNA variations,' Law added.
Scientists originally found in an Icelandic population that genetic variations in a DNA sequence close to a gene that produces a protein called Neuregulin 1 were associated with schizophrenia, but how the Neuregulin 1 gene was affected remained unknown.
In 2006, Law and colleagues found that one of these DNA variations is associated with increased expression of a novel type of Neuregulin 1 called type 4 - one of the six known types of Neuregulin 1 proteins - in the brains of patients with schizophrenia.
The role of this protein in the brain is not completely understood but the other types of Neuregulin 1 proteins are involved in controlling how the brain develops and works in adults. In this study, Law and colleagues showed that Neuregulin 1 type 4 is specifically expressed in the brain - unlike the other types of Neuregulin 1. Also, the scientists showed that this protein is 3.5 times more abundant in foetal than adult brains, supporting the protein's important role in the developing brain.
"Since the Neuregulin 1 protein plays a key role in brain development and is more abundant in foetal brains, DNA changes that alter the expression of this protein may contribute to schizophrenia by modifying the development and wiring of the brain. By understanding how this novel protein works in the brain, we may be able to target it in people with the disease," Law said.
The researchers showed that the genetic change that causes overproduction of Neuregulin 1 type 4 is part of a DNA sequence called a promoter, which enables genes to be coded for proteins. A protein called a transcription factor binds to the promoter and helps other proteins to express the gene. When the promoter is altered, the transcription factor may not bind properly and impair genetic expression. Law and colleagues showed that alteration of the promoter in the genetic sequence linked to schizophrenia resulted in altered amounts of Neuregulin 1 type 4.
"For the first time, we have identified a promoter for the Neuregulin 1 gene and showed that the activity of that gene is altered by a single genetic variation in this promoter. These results will probably help us understand how DNA variations affect the function of this gene and lead to symptoms of schizophrenia," Law said.
The researchers are now planning to investigate further the role of Neuregulin 1 type 4 in brain development and behaviour and determine how various alterations of the Neuregulin 1 gene lead to schizophrenia.
"By better understanding the genetic causes of schizophrenia, we can start to make sense of the underlying biology of the disease and develop improved therapies based on people's genes. The insight gained on the Neuregulin 1 gene is, I hope, bringing us closer to that goal," Law said.
The study is published in the August 17 issue of the Journal of Biological Chemistry.