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UNC scientists pinpoint how a single genetic mutation increases autism risk

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deadlast

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Title kind of says it all.
Link to the article - https://news.unchealthcare.org/news...single-genetic-mutation-increases-autism-risk

from the article said:
Last December, researchers identified more than 1,000 gene mutations in individuals with autism, but how these mutations increased risk for autism was unclear. Now, UNC School of Medicine researchers are the first to show how one of these mutations disables a molecular switch in one of these genes and causes autism.

[R]esearch shows that an enzyme called UBE3A can be switched off when a phosphate molecule is tacked onto UBE3A. In neurons and during normal brain development, this switch can be turned off and on, leading to tight regulation of UBE3A. But a research team led by Mark Zylka, PhD, associate professor of cell biology and physiology, found that an autism-linked mutation destroys this regulatory switch. Destruction of the switch creates an enzyme that cannot be turned off. As a result, UBE3A becomes hyperactive and drives abnormal brain development and autism.

When Jason Yi, PhD, a postdoctoral fellow in Zylka’s lab, sequenced the genes from the cell samples – including cells from the child’s parents – he found that the parents had no hyperactive UBE3A but the child did.

The child’s regulatory switch was broken, causing UBE3A to be perpetually switched on.


It was previously thought that too much UBE3A might cause autism because duplication of the 15q chromosome region – which encompasses UBE3A and several other genes – is one of the most commonly seen genetic alterations in people with autism. This is called Dup15q Syndrome.

As part of their study, Zylka and Yi found that protein kinase A (PKA) is the enzyme that tacks the phosphate group onto UBE3A. This finding has therapeutic implications, particularly since drugs exist to control PKA.

“We think it may be possible to tamp down UBE3A in Dup15q patients to restore normal levels of enzyme activity in the brain,” Zylka said. “In fact, we tested known compounds and showed that two of them substantially reduced UBE3A activity in neurons.”

One of the drugs, rolipram, previously had been tested in clinical trials to treat depression but was discontinued due to side effects. One of the symptoms associated with Dup15q syndrome is sudden unexpected death in epilepsy. In light of these life-threatening seizures, Zylka pointed out that it may be worth examining whether lower doses of rolipram, or other drugs that increase PKA activity, provide some symptom relief in Dup15q individuals. “The benefits might outweigh the risks,” he said.

Future work with an animal model of Dup15q could be used to test this therapeutic approach.

Medical Journal Publication - http://www.cell.com/cell/abstract/S0092-8674(15)00770-9

More info in the links.

I search couldn't find a thread.
 

lazygecko

Member
I'm not even going to pretend to understand half of this, but it sounds to me like a lack of UBE3A regulation is what contributes to the sensory overload which is prevalent in autism?
 
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