Genetic switch left in 'on' position identified by scientists as likely cause of autism in children

A genetic switch left in the “on” position has been identified as a likely cause of autism in some children affected by the developmental disorder, a study has found.

It is the first time that researchers have been able to identify a precise mutation that appears to lead to autism, which is known to have a strong inherited component as well as being influenced by non-genetic factors.

There are an estimated 700,000 people in Britain with some kind of autistic disorder, which is more than 1 in 100 people in the general population. There is no cure for the condition but the researchers behind the research believe that it might eventually lead to the development of drugs that could ameliorate the symptoms.

Scientists studying the cells of a child with autism found that a key enzyme needed for the developing brain seems to be permanently switched on rather than being able to be switched on and off at different times of normal brain development.

The researchers found that a mutation in the child’s DNA prevented the enzyme produced by the UBE3A gene from being controlled by the addition of a phosphate molecule – which normally turns the enzyme off. The UBE3A enzyme was already known to play a role in the development of the nerve cells in the brain.

As a result of the genetic change, which was not seen in either of the child’s parents, the UBE3A enzyme was switched permanently on and so became hyperactive, which caused the abnormal development of the brain leading to autism, said Mark Zykla of University of North Carolina at Chapel Hill.

“Genetic studies are showing that there will be about 1,000 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,” said Dr Zykla, a senior author of the study published in the journal Cell.

“The phosphate group is being added to the UBE3A protein, not to DNA. This phosphate group is added to one specific amino acid. The autism-linked mutation we studied changes this amino acid such that the phosphate group cannot be added. As a result, UBE3A cannot be turned off,” Dr Zylka said.

The scientists worked on the human cells growing in a laboratory dish to see what effect the mutation had on normal nerve-cell development. They also studied the mutation in mice used as an animal model of autism and found that their nerve cells over-produced small protrusions from the membrane known as dendritic spines, which are important for cell-to-cell communication.

“When this child's mutation was introduced into an animal model, we saw all these dendritic spines form on the neurons. We thought this was a big deal because too many dendritic spines have been linked to autism,” Dr Zykla said.

The researchers believe the mutation causing this effect arose de novo during the production of sperm by the child’s father, which explain why he showed no autistic traits.

“Men produce new sperm for their entire lives. To do this, the germ cells [which make sperm] are regularly copying themselves and their genome. Each time a copy is made, there is the chance for a mutation to be introduced,” Dr Zykla said.

“Thus, as a man ages, his germ cells slowly accumulate these de novo mutations, at a rate of about two new mutations per year of life. So many of these de novo mutations in autistic individuals likely come from mistakes that build up in [their] dads’ sperm germ cells,” he said.

Tests on cells growing in culture showed that drug compounds known to affect the attachment of phosphate molecules to the UVE3A ensyme can “tamp down” the activty of the enzyme, which could be used as a potential treatment for some autistic patients.

“Tamping down activity in these individuals may treat some of their symptoms,” Dr Zykla said.