Despite advances in genetic research, the development of schizophrenia remains a puzzle.
New research has discovered a common biological pathway between schizophrenia and Fragile X syndrome, a disorder associated with autism and learning difficulties.
This is one of the few times researchers have uncovered genetic evidence for the underlying causes of schizophrenia. Many associations between schizophrenia and genetic risk factors have been reported, but only a very few can be considered schizophrenia susceptibility genes.
Investigators found that a disruption of the gene TOP3B, an exceedingly rare occurrence in most parts of the world, is fairly common in a genetically unique population from northeastern Finland.
The region 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 population to sift through genomic data for genetic deletions that may influence people’s susceptibility to schizophrenia.
In this population, which has existed in relative isolation for several centuries, the disruption of TOP3B is associated with a twofold greater 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.
The new 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,” said molecular geneticist Dr. Aarno Palotie, lead author.
“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.”
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, 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 10 years and hence had a good idea what this protein is doing.”
TOP3B encodes a type of protein that typically helps the cell to unwind and wind DNA helices – essential to normal cell function. Quite unexpectedly for an enzyme of this class, however, TOP3B was found to act on messenger-RNA rather than DNA.
As they probed TOP3B further, the team found that the TOP3B protein interacts with a protein known as FMRP. The deactivation or disruption of this protein is responsible for Fragile X syndrome, a disorder associated with autism and learning difficulties, primarily in men.
Within the northern Finnish population, the team identified four people who did not have a functioning copy of the TOP3B gene.
These four people were either diagnosed as having learning difficulties or as having schizophrenia, solidifying the evidence that this gene is important in these brain disorders and that they are biologically linked.
“These two disorders, schizophrenia and Fragile X syndrome, although they may seem drastically different, share key features, particularly the cognitive impairment that is frequently associated with both conditions,” said co-author Dr, Nelson Freimer, director of the Center for Neurobehavioral Genetics and professor of psychiatry at UCLA. “So, it is not unexpected that they could share some of the same biological processes.
“What is fantastic about this study,” he said, “is that through investigations in an isolated corner of Finland we are contributing to concerted international efforts that are beginning to unravel the genetic root of schizophrenia, a debilitating disorder that affects so many people throughout the world.”
Source: Wellcome Trust Sanger Institute