In a study published in the August 17 issue of the Journal of Biological Chemistry, Amanda J. Law, Associate Professor at the University of Oxford and colleagues at NIH describe for the first time a genetic variation that causes a gene to be overexpressed in the human brain. These results may provide a new way to design better drugs to treat schizophrenia.

“Although the exact causes of schizophrenia are yet to be determined, scientists agree that the disease is in part due to genetic variations,” Law says. “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.”

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 fetal 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 fetal brains, DNA changes that alter the expression of this protein may contribute to schizophrenia by modifying the development and wiring of the brain,” Law says. “By understanding how this novel protein works in the brain, we may be able to target it in people with the disease.”

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,” Law says. “These results will probably help us understand how DNA variations affect the function of this gene and lead to symptoms of schizophrenia.”

The researchers are now planning to investigate further the role of Neuregulin 1 type 4 in brain development and behavior 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,” Law says. “The insight gained on the Neuregulin 1 gene is, I hope, bringing us closer to that goal.”

ARTICLE: “Molecular Cloning of a Brain-specific, Developmentally Regulated Neuregulin 1 (NRG1) Isoform and Identification of a Functional Promoter Variant Associated with Schizophrenia,” by Wei Tan, Yanhong Wang, Bert Gold, Jingshan Chen, Michael Dean, Paul J. Harrison, Daniel R. Weinberger, and Amanda J. Law