A new studio has identified a direct link between gene SUV39H2 and the ASD. This was declared by a research team from RIKEN Center for Brain Science (CBS) in Japan which highlighted a deficiency in histone methylation could lead to the development of autism spectrum disorders (ASD). (1)
The study was published in the scientific journal Molecular Psychiatry.
SUV39H2: that’s what its function is
Genes are turned on and off throughout our development. But Genetic variation means that what is turned off in some people stays on in others. This is why, for example, some adults can digest dairy products and others are lactose intolerant; the gene for the production of the lactase enzyme is deactivated when some people become adults, but not others.
One way genes can be turned on and off is through a process called histone methylation in which special enzymes transfer methyl groups to histone proteins that are wrapped around DNA.
Changes in methylation-related genes during brain development can lead to serious problems. One of these variations occurs in a rare disease called Kleefstra syndrome, in which a mutation prevents the methylation of H3K9, a specific location on histone H3. Because Kleefstra syndrome somewhat resembles autism, RIKEN CBS researchers led by Takeo Yoshikawa looked for autism-specific variations in genes that can modify H3K9.
Among nine of these genes, they found a variant in a methyltransferase gene H3K9 — SUV39H2—which was present in autism, and the mutated SUV39H2 prevented methylation when tested in the laboratory. Similar loss-of-function results were found for the mouse version of the variant. (2)
The next step was to see what happens in the mice lacking the Suv39h2 gene. Behaviorally, the researchers found that the mice could learn a simple cognitive task, but had difficulty when the task required cognitive flexibility. In the simple task, the mice learned how to get a reward by opening a door at the alternating diagonal corners of a cage. After they got it right, the possible reward positions moved to the other two diagonal corners.
Genetically modified mice did this exercise, as did wild-type mice. In another task, after learning to alternate between the two diagonal corners, only the position of a reward was changed. When the mice were challenged to randomly alternate between these two tasks, the wild-type mice could adapt quickly, but the Suv39h2-deficient mice took much longer.
“This serial reverse learning task was essential“, Explained the first author Shabeesh Balan. “Cognitive inflexibility is a key symptom of ASD and our new task was able to address this behavioral trait in ways that previous mouse studies could not. “
Once the researchers looked at what happened in the mouse brain when H3K9 methylation did not occur, they found that important genes were activated in the experimental mice that are usually silenced in the early stages of development. “Suv39h2 is known to be expressed early in neurodevelopment and to methylate H3K9“Explains Yoshikawa. “This keeps a check on the genes that should be turned off. But without it, the genes in the protocaderin cluster were abnormally expressed at high levels in mice embryonic “. So long as the protocaderins are fundamental for the formation of neural circuits, the researchers believe they have found an important biological pathway that could be central to several developmental disorders neurological.
The experts years old then verified the importance of SUV39H2 in human ASD and found that its expression was lower in the post-mortem brain of people with ASD compared to controls.
“What started with a loss-of-function mutation in one person with ASD “, says Yoshikawa, “Led to a general causal landscape for ASD culminating in the brain circuit abnormality.”
Protocaderins have already been proposed to be related to a wide range of mental disorders. This study shows that SUV39H2 gene activation is a potential therapy for mental disorders, including ASD, which should be investigated more fully in future studies.