Published in the journal Cell, the study shows how in patients affected by Dup15q syndrome, the enzyme UBE3A becomes hyperactive and can lead to abnormal brain development because the mutation knocks out its ability to be turned off.
Dr Mark Zylka at the University of North Carolina School of Medicine and lead author of the study explains how the mutation causes the enzyme to continuously tag proteins for destruction. 'It's sort of like, if you have garbage and you want to get rid of it, you can tag it with a flag for somebody to pick it up and throw it out. That's essentially what UBE3A does.'
It was previously believed that too much UBE3A was associated with Dup15q syndrome – a known genetic cause of autism caused by the duplication of Chromosome 15 – but until now the precise mechanism was not known.
In order to observe how this mutation actually worked, the UNC School of Medicine team first sequenced genes from cells previously used to identify mutations in the UBE3A genes of patients, as well as from their parents. They observed that when some parents did not have the UBE3A mutation, their children did, suggesting the mutation arises during the production of the father's sperm.
The researchers then introduced the mutated UBE3A gene into mice and observed the growth of dendritic spines on the neural cells in the brain. Having too many dendritic spines has previously been associated with autism.
'Not only was this hyperactivating mutation identified in individuals with autism, when put into a mouse model it gave a brain pathology that looked like autism,' Dr Zylka said.
Last year researchers identified more than 1000 gene mutations in people affected by autism spectrum disorder, but precisely how these mutations cause autism remains to be identified.
'Genetic studies are showing that there will be about 1000 genes linked to autism. This means you could mutate any one of them and get the disorder. We found how one of these mutations works,' Dr Zylka said.
The researchers say it may be possible to treat patients with Dup15q-related autism using existing drug compounds known to reduce levels of UBE3A activity in the brain.
The team also found that mutations in patients affected by Angelman syndrome are also associated with impaired functioning of the UBE3A enzyme, a finding that could have implications for diagnosis of this rare disorder.