Gene Mutation Increases Risk of Schizophrenia, Learning Impairment

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A team of researchers that includes scientists from UCLA has uncovered evidence that a specific genetic alteration appears to contribute to disorders of brain development, including schizophrenia. They also found that schizophrenia shares a common biological pathway with Fragile X mental-retardation syndrome, a disorder associated with both intellectual impairment and autism.

A disruption of the gene known as TOP3ß was associated with an increased risk of schizophrenia as well as impairment in intellectual function, the researchers said, and TOP3ß ‘s interaction with a protein called FMRP was found to be responsible for Fragile X syndrome. The findings suggest a previously unsuspected link between the two disorders.

In Finland, the prevalence of schizophrenia is highest in northeastern regions that were populated in the 16th and 17th centuries and remain genetically isolated.
Intellectual disability shows a similar prevalence pattern to that for schizophrenia. Illustrations: Courtesy of Dr. Nelson Freimer

Although the past two decades have revealed a wealth of information about the genetics of disease, little is known about the biology behind schizophrenia, says Nelson Freimer, MD, professor of psychiatry and biobehavioral sciences and a senior author of the research. “This collaborative effort has uncovered a promising biological pathway that appears to underlie schizophrenia and may contribute to the cognitive impairment that is an important component of the disorder,” he says.

For the study, the researchers drew from a database that facilitates research on the genetically unique population of northeast Finland, where people have lived in relative isolation for several centuries. This population has three times the frequency of schizophrenia as the rest of Finland and a higher rate of intellectual impairment. The team used the database to sift through genomic data for genetic deletions or mutations that are relatively common in this region but are rare elsewhere in the world.

They discovered a rare genetic deletion affecting TOP3ß that increases a person’s susceptibility to schizophrenia. They also found that this deletion was associated with an increased frequency of other disorders of brain development, including intellectual impairment. Having identified a link between TOP3ß and schizophrenia, the researchers sought to understand why disrupting this gene might increase susceptibility to disease. For this research, they investigated the function of the protein that TOP3ß encodes. They found that the protein encoded by TOP3ß interacts with another protein known as FMRP. The deactivation or disruption of FMRP is responsible for Fragile X syndrome, which is 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 TOP3ß gene. All four were diagnosed as having cognitive impairments and/ or schizophrenia, solidifying the evidence that this gene is important in these brain disorders and that they are biologically linked. “Although schizophrenia and Fragile X may seem drastically different, cognitive impairment is frequently associated with both conditions,” says Dr. Freimer, who directs the UCLA Center for Neurobehavioral Genetics in the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA. “So it is not unexpected that they could share some of the same biological processes.”

“Deletion of TOP3ß, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders,” Nature Neuroscience, August 2013