Researchers identify specific genetic mutations that contribute to disorders of brain development

A collaborative team of researchers including 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 TOP3B was associated with an increased risk of schizophrenia as well as impairment in intellectual function, the researchers said, and TOP3B's interaction with a protein called FMRP was found to be responsible for Fragile X syndrome.

The findings, published Aug. 4 in the online edition of the journal Nature Neuroscience, suggest a previously unsuspected link between the two disorders.

Although the past two decades have revealed a wealth of information about the genetics of disease, little is known about the biology behind schizophrenia, said Dr. Nelson Freimer, a UCLA professor of psychiatry 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 said.

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 of 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 TOP3B 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 TOP3B and schizophrenia, the researchers sought to understand why disrupting this gene might increase susceptibility to disease. For this, they investigated the function of the protein that TOP3B encodes. They found that the protein encoded by TOP3B 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 TOP3B 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," said Freimer, who directs the UCLA Center for Neurobehavioral Genetics. "So it is not unexpected that they could share some of the same biological processes.

"What is interesting about this study 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. Potentially, this may someday lead to new drug targets against these disorders."

SOURCE University of California, Los Angeles