Direct genetic link to autism spectrum disorders

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H3K9 cerebellar methylation levels were lower in Suv39h2-deficient mice than in control mice.Credit: RIKEN

A new study from the RIKEN Brain Science Institute (CBS) in Japan shows that the lack of methylation of histones can lead to the development of autism spectrum disorders (ASD). A human variant of the SUV39H2 gene led researchers to study its deficiency in mice. Molecular psychiatryThe study found that in the absence, adult mice exhibited cognitive flexibility similar to that seen in autism, and embryonic mice exhibited spurious expression of genes associated with brain development. The results of these surveys are SUV39H2 Genes and TSA.

Genes are turned on and off throughout our development. Corn Genetic variation This 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 genes that make the lactase enzyme are turned off in some people as they grow older, but not in others. uncomfortable It can be turned on and off through a process called histone methylation. In this process, a special enzyme transfers the methyl group to the histone protein wrapped around DNA.

Mutations in genes associated with methylation during brain development can cause serious problems. One of these mutations occurs in a rare disease called Criefstra syndrome, in which the mutation interferes with the methylation of H3K9, a specific location of the H3 histone. Because Kleefstra syndrome resembles autism in some ways, researchers at RIKEN CBS, led by Takeo Yoshikawa, looked for an autism-specific mutation in a gene that could alter H3K9. Among those nine genes, they found SUV39H2, a variant of the H3K9 methyltransferase gene found in autism, and the mutated SUV39H2 prevented methylation in lab tests. .. Similar loss of function results were seen in the mouse version of the variant.

Behavioral sequence tasks for learning and flexibility at your own pace. Indicates the opposite reward corner where the mouse should move back and forth. In a task, meeting a successful visit rate criterion on a diagonal will alternate the reward corners on the opposite side of the diagonal with the other. For other tasks, only one of the two previously rewarded coins will be reversed. When these two tasks were mixed (continuous inversion learning), mice deficient in Suv39h2 had difficulty adapting to rule changes.Credit: RIKEN

The next step was to see what happens in the mice lacking the Suv39h2 gene. Behaviorally, the researchers found that mice could learn simple cognitive tasks, but were difficult when the tasks required cognitive flexibility. In a simple task, the mouse learned to earn rewards by alternately opening the diagonal corners of the cage and piercing the door. After successfully doing this well, the possible reward slots are moved to the other two diagonal corners. Genetically engineered mice did it the same way as wild type mice. In another task, after learning how to switch between the two diagonal corners, only one reward slot was changed. The wild-type mice were able to adapt quickly when the mice were challenged to alternate randomly between these two tasks, but the Suv39h2-deficient mice took much longer. “This continuous inversion learning task was essential,” says lead author Shabeesh Balan. “Cognitive inflexibility is a central symptom of ASD, and our new task addressed this behavioral characteristic in a way that was not possible in previous mouse studies.”

The researchers looked at what happened in the mouse brain when H3K9 methylation did not occur and found that experimental mice turn on important genes that are usually silent early in development. I discovered. “Suv39h2 is known to be expressed early in neurogenesis and from H3K9 methylate,” Yoshikawa explains. “This allows us to check which genes need to be turned off, but without them the β-cluster genes of Protocadherin would have been abnormally expressed at high levels in the embryo. MouseBecause Protocadherins are important in forming neural circuits, researchers believe they have discovered important biological pathways that may be at the heart of certain neurodevelopmental disorders.

The team then examined the importance of SUV39H2 in human ASDs by finding that expression of SUV39H2 is lower in the postmortem brain of people with ASD than in controls. “What started as a loss-of-function mutation in a single person with ASD has led to a situation that is a common cause of ASD leading to abnormalities in brain circuits,” Yoshikawa explains.

Protocadherin has previously been proposed to be associated with a wide range of psychiatric disorders. This study shows that activation of the SUV39H2 gene is a potential treatment for psychiatric disorders, including ASD, and needs to be further investigated in future studies.


Important brain molecules may play a role in many brain disorders


For more information:
Shabeesh Balan et al, a loss-of-function mutant of SUV39H2 identified in autism spectrum disorders, causes altered H3K9 trimethylation and deregulation of the β-cluster protoadherin gene in the developing brain. Molecular psychiatry (2021). DOI: 10.1038 / s41380-021-01199-7

Quote: SUV39H2: https: //medicalxpress.com/news/2021-07-suv39h2-genetic-link-autism-spectrum.html Acquired July 19, 2021 from Autism Spectrum Disorders (July 19, 2021) Direct genetic link to (July )

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