A collaborative team of researchers, including scientists from UCLA, has uncovered evidence for a genetic alteration that appears to contribute to disorders of brain development, including schizophrenia. The study also establishes a genetic link between two unrelated mental disorders, schizophrenia and Fragile X syndrome, a disorder associated with both intellectual impairment and autism. The discovery might lead to new therapies to treat mental disorders. It was published in the August 4 online edition of the journal Nature Neuroscience.
The researchers discovered that a disruption of a gene called TOP3B is associated with an increased risk of schizophrenia, as well as impairment in intellectual function. In addition, they found that the TOP3B protein also interacts with another protein called FMRP. The disruption of this protein is responsible for Fragile X. These findings suggest a previously unsuspected link between the two disorders.
A wealth of information about genetic factors involved in disease; however, little is known about the biology behind schizophrenia, noted senior author Nelson Freimer, a UCLA professor of psychiatry. He said, “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.”
For the study, the researchers drew from a database that facilitates research in 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 compared to the national average in Finland; it also has a higher rate of intellectual impairment. The researchers accessed the genomic data from the database and looked for genetic deletions or mutations that are relatively common in this region although rare elsewhere in the world. They discovered a rare genetic deletion affecting TOP3B that increases a person’s susceptibility to schizophrenia as well as other disorders of brain development, including intellectual impairment. They theorized that this deletion directly disrupts the TOP3B gene to cause its effects on the brain.
After identifying the link between TOP3B and schizophrenia, the researchers attempted to determine why disrupting this gene might increase susceptibility to disease. For this, they investigated the function of the protein TOP3B encodes. They found that the TOP3B protein interacts with another protein known as FMRP. The deactivation or disruption of FMRP 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. 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.
Dr. Freimer explained, “Although schizophrenia and Fragile X may seem drastically different, cognitive impairment is frequently associated with both conditions. 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.”