Hopkins researchers have pinpointed a genetic mutation that appears to underlie many symptoms associated with schizophrenia, according to a report published last week in Molecular Psychiatry. The affected gene, disrupted-in-schizophrenia 1 (DISC1), has long been implicated as one of several possible genetic components of the disease.
The DISC1 mutation is what is called a balanced translocation, a process in which genetic material from one chromosome is abnormally swapped with an equal amount of material from another chromosome. In schizophrenic patients, the DISC1 gene is translocated from chromosome 1 to chromosome 11.
According to the National Institute of Mental Health, schizophrenia affects about 1.1 percent of the adult U.S. population in any given year. While the illness' cause is thought to involve many factors, studies have shown that genetic predisposition plays an important role.
Analyses of large families, including the Scottish family in which the DISC1 mutation was first uncovered, have shown that certain genetic abnormalities leave family members susceptible to psychiatric illnesses.
The Hopkins group, led by Mikhail V. Pletnikov at the School of Medicine, succeeded in producing a line of transgenic mice that express the mutant human DISC1 gene under certain conditions.
DISC1 is expressed in many brain areas, including the hippocampus, the cerebral cortex, the hypothalamus and the amygdala. Critically the researchers limited the mutant gene's expression to neurons in the forebrain, the area where most schizophrenia-related functional differences in brain activity are thought to exist.
Additionally they were able to artificially induce the gene's expression by linking it to a specific promoter of gene transcription. As a result of these limits and controls, the transgenic mice functioned as relatively accurate models of human schizophrenia.
Pletnikov and his team tested the mice across several domains and with several hypotheses in mind.
Though normal DISC1 has been implicated in the brain's development, especially that of the cerebral cortex, brain size was not significantly affected in the mutant mice and no substantial developmental defects were observed.
Cognitive tests, however, revealed spontaneous hyperactivity in male mice and severe deficits in spatial cognition in female mice, symptoms similar to those seen in human cases of schizophrenia.
Interestingly the specificity of the spatial deficits to females may be related to the effect of mutated DISC1 on estrogen, a molecule involved in the development and proper functioning of the hippocampus, the center of memory formation. In humans, sex differences in age of onset of the disease are well documented; males usually develop symptoms in their late teens to early twenties, while females generally do not show symptoms until their 20s or 30s.
Additionally researchers observed a decrease in certain proteins usually located at synapses, the areas at which neurons send signals to each other and to other parts of the body. These data support other findings that indicate fewer synaptic proteins in schizophrenic patients.
The DISC1 mutation, then, appears to be at least partially dominant-negative.
That humans are diploid - possessing two versions of the each gene that are not necessarily identical - is critical to understanding this mechanism. With dominant-negative mutations, a single copy of the mutated gene adversely affects the other, normal version within the same cell to produce changes in behavior and cognition as observed in the transgenic mice.
Nonetheless several uncertainties remain. For example it is unclear whether the dominant-negative mechanism exists in humans. An alternative hypothesis involves haploinsufficiency, the result of an organism's possessing only one of two copies of a gene. Human schizophrenia could arise simply from the lack of one copy of the DISC1 gene, even if the remaining copy is not mutated. Data showing decreased presence of DISC1-derived protein in schizophrenic patients supports this idea. Even so Pletnikov and his colleagues noted that both mechanisms could function simultaneously in human cases.
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