Biochemistry: Distinct Brain Disorders Biologically Linked

08/05/2013
Photo: Genes

The team found that a disruption of the gene TOP3B is fairly common in a uniquely genetically distinct founder population from North-eastern Finland; © Georg Stoll/University of Würzburg

A team of researchers have shown that schizophrenia and a disorder associated with autism and learning difficulties share a common biological pathway. This is one of the first times that researchers have uncovered genetic evidence for the underlying causes of schizophrenia.

The team found that a disruption of the gene TOP3B, an exceedingly rare occurrence in most parts of the world, is fairly common in a uniquely genetically distinct founder population from North-eastern Finland. In this population, which has grown in relative isolation for several centuries, the disruption of TOP3B is associated with an increased risk of schizophrenia as well as with impairment in intellectual function and learning.

Furthermore, the biochemical investigation of the protein encoded by the TOP3B gene allowed the researchers to gain first insight into the cellular processes that might be disturbed in the affected individuals.

Although the past two decades have revealed a wealth of information about the genetics of disease, we still know little about the biology behind schizophrenia. Many associations between schizophrenia and genetic risk factors have been reported, but only a very few can be considered schizophrenia susceptibility genes. This study uncovers an important biological pathway that appears to underlie schizophrenia and could contribute to the cognitive impairment that is an important component of this disorder.

"This is a tremendous discovery for our team; not only have we uncovered vital information about the biology behind schizophrenia, but we have also linked this same biological process to a disorder associated with learning difficulties," says Doctor Aarno Palotie, lead author from the Wellcome Trust Sanger Institute and the Institute for Molecular Medicine Finland. "Our findings offer great hope for future studies into the genetic basis of schizophrenia and other brain disorders, potentially finding new drug targets against them."

The North-eastern population of Finland has three times the frequency of schizophrenia compared to the national average in Finland, as well as a higher rate of intellectual impairment and learning difficulties. The team used data collected from this unique population to sift through genomic data for genetic deletions that may influence people's susceptibility to schizophrenia.

The team identified a rare genetic deletion affecting TOP3B in the North-eastern Finnish population that increases a person's susceptibility to schizophrenia two-fold and that also is associated with an increased frequency of other disorders of brain development such as intellectual impairment. They speculate that this deletion directly disrupts the TOP3B gene to cause its effects on the brain.

Having identified the link between TOP3B and schizophrenia, the researchers sought to understand why disrupting this gene might increase susceptibility to disease, and for this purpose they investigated the function of the protein that it encodes.

"Such an approach is only possible when researchers from different disciplines – in our case geneticists and biochemists team up," says Professor Utz Fischer, author from the University of Wurzburg. "Luckily, when we teamed up with the genetic team we had already worked on the TOP3B gene product for more than ten years and hence had a good idea what this protein is doing".

MEDICA.de; Source: Wellcome Trust Sanger Institute