Autism spectrum disorders, Medical News, Neurodevelopmental disorders, Neuroscience, Pediatrics

Human gene variant directly linked to autism spectrum disorders

When wild-type mice were given the challenge of switching between two activities at random, they adapted quickly, but SUV39H2-deficient animals took much longer. Critical genes that are typically repressed throughout early development were discovered to be switched on in the experimental mice, according to the researchers.

Throughout human development, genes are turned on and off. However, because of genetic diversity, genes that are turned off in some people remain on in others. In humans, this has been demonstrated to be the primary source of histone methylation deficits and the onset of autism spectrum disorders.

A lack of histone methylation could lead to the development of autism spectrum diseases (ASD), according to research from the RIKEN Center for Brain Science (CBS) in Japan. The lack of the SUV39H2 gene in mice prompted researchers to investigate a human variation of the gene.

Adult mice showed cognitive inflexibility comparable to that seen in autism when the gene was missing, while embryonic mice showed a misregulated expression of genes important to brain development when the gene was missing. This is the first time a direct relationship between the SUV39H2 gene and ASD has been discovered.

Takeo Yoshikawa, the head of the RIKEN CBS research team commented, “Suv39h2 is known to be expressed in early neurodevelopment and to methylate H3K9. This keeps an eye on genes that need to be turned off. In embryonic mice, however, genes in the protocadherin cluster were inappropriately expressed at high levels without it.”

During brain development, variations in genes associated with methylation might cause major issues. Kleefstra Syndrome is a rare illness in which a mutation prohibits methylation of H3K9—a specific region on histone H3—due to a mutation. Because Kleefstra Syndrome contains several characteristics linked to autism, RIKEN CBS researchers led by Takeo Yoshikawa sought for autism-specific mutations in genes that affect H3K9.

The researchers discovered one mutation in an H3K9 methyltransferase gene—SUV39H2—that was associated with autism, and found that the mutant SUV39H2 blocked methylation in the lab. The mouse form of the mutation showed similar loss-of-function findings.

The mice used in the experiment were taught to gain a reward by performing a particular task— poking a door at alternating diagonal corners of a cage. The available prize locations change to the other two diagonal corners once they have mastered this. This was accomplished by both genetically engineered and wild-type mice.

After learning to alternate between the two diagonal corners in another assignment, only the placement of one reward was changed. When mice were given the job of alternating between these two tasks at random, wild-type mice adapted fast, while SUV39H2-deficient mice took substantially longer.

When the H3K9 methylation in the mouse model failed, the researchers found that critical genes that are normally silenced during early development were turned on in the experimental mice. The researchers believe they have discovered an important biological route that could be central to various neurodevelopmental disorders.

“What started with a single loss-of-function mutation in one person with ASD has evolved to a broad causative landscape for ASD that culminates in brain circuit abnormalities,” Yoshikawa says.


The study was published in Molecular Psychiatry, on July 15th, 2021.

Balan, S., Iwayama, Y., Ohnishi, T. et al. A loss-of-function variant in SUV39H2 identified in autism-spectrum disorder causes altered H3K9 trimethylation and dysregulation of protocadherin β-cluster genes in the developing brain. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01199-7

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