Though previous research has associated numerous different gene mutations with autism, exactly how these mutations contribute to the development of the condition has been unclear. Now, a new study published in the journal Cell has uncovered the workings behind one autism-related gene mutation.

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Researchers have found that mutations in a gene called UBE3A cause it to become hyperactive, leading to abnormal brain development and autism.

Conducted by researchers from the University of North Carolina (UNC) School of Medicine in Chapel Hill, the study reveals how mutations in a gene called UBE3A drive it to become hyperactive, leading to abnormal brain development and autism.

In individuals with autism, duplication of the 15q chromosome region – referred to as Dup15q syndrome – is one of the most common genetic abnormalities. It was previously believed that too much UBE3A is the cause.

Study leader Mark Zylka, associate professor of cell biology and physiology, and his team explain that in normal brain development, the UBE3A gene can be turned on or off via the attachment of a phosphate molecule, which acts as a regulatory switch.

However, the researchers found that mutations in UBE3A destroy the regulatory switch – which they identified as protein kinase A (PKA) – meaning the gene cannot be turned off, causing it to become hyperactive. This hyperactivity, according to the team, causes autism.

Zylka and colleagues reached their findings by sequencing the genes of human cell lines from children with autism and their parents.

While the parents of the children had no UBE3A mutations, the children did. The researchers found the UBE3A gene in the children was permanently switched on.

On introducing the mutated UBE3A gene to mouse models, the team discovered the development of dendritic spines on the brain cells, or neurons, of mice. Dendritic spines connect neurons to the synapses. They explain this is a particularly important finding since having too many dendritic spines has been associated with autism.

As such, the researchers say their findings indicate that hyperactivation of UBE3A – triggered by the destruction of PKA – is a cause of Dup15q-related autism.

According to Zylka, it may be possible to reduce UBE3A activity in patients with Dup15q-related autism.

“In fact,” he adds, “we tested known compounds and showed that two of them substantially reduced UBE3A activity in neurons.”

Fast facts about autism
  • Approximately 1 in 68 children in the US have autism, increasing from 1 in 150 in 2000
  • Boys are almost five times more likely to develop autism than girls
  • Among parents who have a child with autism, there is 2-18% chance of their second child having the condition.

Learn more about autism

One of the compounds tested was a drug called rolipram, which increases PKA activity. This drug had previously been tested in clinical trials for the treatment of depression, but its use was ceased due to side effects.

However, Zylka notes that for some Dup15q patients – such as those who experience life-threatening seizures – the benefits of rolipram may outweigh the risks. He says it may be worth assessing whether low doses of this or other PKA-boosting drugs alleviate symptoms of Dup15q syndrome.

As well as opening the door to potential autism treatments, the researchers say their findings may also help patients with Angelman syndrome – a rare neurological disorder that causes severe intellectual and physical disability.

In their study, the team found that a number of mutations among individuals with Angelman syndrome are associated with impaired function or stability of UBE3A, which leaves patients with no active form of the gene. This finding, the researchers say, may lead to better identification of a condition that is commonly misdiagnosed.

Last month, Medical News Today reported on a study published in Current Biology that identified differences in the way people with autism respond to smells. As such, researchers believe a “sniff test” could be feasible for early autism diagnosis.