Variation, linked to the disease, is part of the promoter region of the sequence encoding Neuregulin 1 type 4.

NIH researchers have found how a genetic variation linked to schizophrenia causes a gene to be overexpressed in the human brain. 

“These variations are not simple to understand because they don’t directly disturb the function of proteins,” according to Amanda J. Law, Ph.D., associate professor at the University of Oxford and visiting scientist at the NIH. “In our study, we identified some clues as to what goes wrong with one of these DNA variations.” 

Investigators 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. In 2006, Dr. Law’s team found that one of these mutations was associated with increased expression of Neuregulin 1 type 4 in the brains of patients with schizophrenia.

In the current study, the scientists showed that Neuregulin 1 type 4 is specifically expressed in the brain, unlike the other types of Neuregulin 1, and that it is 3.5 times more abundant in fetal than adult brains.

The team also discovered that the genetic change that causes overproduction of Neuregulin 1 type 4 is part of a DNA sequence called a promoter. The team demonstrated that alteration of this promoter resulted in increased expression 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,” Dr. 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 study will be published in the August 17 issue of the Journal of Biological Chemistry.

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