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Gene that keeps nerve endings from ‘blossoming’ linked to schizophrenia
By Nancy Touchette

A novel approach to studying the genetic underpinnings of schizophrenia has yielded an unexpected player in this complex disorder. Schizophrenia, depicted recently in the film A Beautiful Mind, is thought to result from a complex mixture of genetic and environmental factors.

The new gene candidate was discovered by researchers who used postmortem tissue to compare the activity of genes in the brains of schizophrenia patients and individuals without the disease. Several other potential susceptibility genes have been identified through studies of families with a high incidence of schizophrenia. This is the first study to propose a schizophrenia gene based on gene activity.

Researchers at the University of Toronto identified nine genes that were more active in the frontal cortex region of affected brains compared to normal brains, and nine genes that were less active. One of these genes, called Nogo, codes for a protein that suppresses the growth of nerve endings.

"One theory of schizophrenia is that nerve terminals may not blossom," says Philip Seeman, who led the study. The researchers found that Nogo was 50 to 100 percent more active in the brains of schizophrenia patients compared to controls. "This was enough to make us really curious," Seeman says.

The researchers sequenced the gene using DNA from 81 patients with schizophrenia and 61 individuals with no history of the disease. Among those with schizophrenia, 17 had inherited an uncommon variant of the Nogo gene from both parents; only two normal individuals had such a variant.

The researchers found that the variant had a DNA 'insert' containing three base pairs, designated 'CAA', in both copies of the Nogo gene in 21 percent of patients. In addition, a second sequence in the gene, designated TATC, was deleted in these same patients.

"This is a solid piece of work," says Kenneth Kendler of the Virginia Commonwealth University in Richmond. "This is the first study to identify a schizophrenia gene based on gene expression in postmortem tissue. I predict we will see more of these studies in the future."

Kendler adds that the results are preliminary and need to be reproduced by other groups using larger study populations before Nogo can be considered a factor in schizophrenia.

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Novak, G. et al. Schizophrenia and Nogo: elevated mRNA in cortex, and high prevalence of a homozygous CAA insert. Mol Brain Res 107, 183-189 (2002).

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