According to a study by Johns Hopkins investigators published in the Nov. 16 issue of Neuron, the risk of developing schizophrenia may be increased by carrying single DNA letter changes from two different genes.
Researchers have found identifying the causes for psychiatric diseases like autism and schizophrenia difficult as they might be activated by several small genetic alterations. Individually these small genetic alterations may be insufficient to cause any change, but in the right combination may cause psychiatric disease.
Schizophrenia, as well as other major mental disorders, is known to be caused by extreme DNA alterations in the genetic letters of the DISC1 gene. These drastic alterations are rare and do not apply to most of individuals with schizophrenia. DISC1 is considered a starting point for investigating the cause of schizophrenia. Defects in DISC1 together with defects in other genes might contribute to disease.
Guo-li Ming, M.D., Ph.D., professor of neurology and neuroscience and member of the Johns Hopkins Institute for Cell Engineering, explained:
“We studied the function of two proteins known to interact, FEZ1 and DISC1, in cells and animal models, which suggested that these proteins work together in adult brain development. When we looked at the human genetic sequences of DISC1 and FEZ1, we found that a combination of small DNA changes raises risk for schizophrenia.”
The team used molecular biology methods to lower the amount of FEZ1 in the new neurons in the adult mouse hippocampus, the researchers then analyzed the cells under a microscope in order to find out if DISC1 and FEZ1 collaborate in adult brain development. The neurons with less FEZ1 were bigger and had longer feelers and looked similar to cells with less DISC1. Neurons use feelers to find and communicate with other nearby neurons. According to the investigators these proteins may be collaborating in neurons in order to control feeler length and cell size. Disruption of this process may cause psychiatric diseases.
In order to see if combinations of single-letter DNA alterations in FEZ1 and DISC1 made individuals more susceptible to schizophrenia, the researchers examined existing cases of the disease and analyzed a large patient database, the Genetic Association Information Network, produced by the National Institutes of Health to identify genome associated diseases. They used statistical methods to analyze 4 different single-letter DNA alterations in the FEZ1 sequence from 1,378 healthy individuals and 1,351 individuals with schizophrenia.
Individually, single-letter DNA alterations in FEZ1 did not contribute to the risk of developing the disease. Although, when they examined these 4 different FEZ1 DNA letter alterations together with a DISC1 single DNA letter alteration already known to slightly increase the risk of schizophrenia, they discovered that one particular FEZ1 DNA alteration combined with the DISC1 alteration dramatically increased the risk of developing the disease by two and half times.
Hongjun Song, Ph.D., professor of neurology and director of the Stem Cell Program at the Institute for Cell Engineering, explained:
“By continuing to examine interactions of key genes involved with disease in cells and correlating the results with patient databases, we can begin to unravel the genetic contributions of psychiatric disorders that previously were a mystery to us,Finding sets of proteins, like FEZ1 and DISC1, that synergistically work together to cause disease will also give us new drug targets to develop new therapies.”
Written by Grace Rattue