How Gene Mutation Leads to Autism

Though earlier studies have established a relationship between various gene mutations and autism, but accurately how these mutations lead to the progression of autism has not been clear. Now, a new research presented in the journal Cell has revealed the processes behind one autism-related gene mutation.

Research performed by investigators from the University of North Carolina (UNC) School of Medicine in Chapel Hill, unveils how mutations in a gene known as UBE3A push it to turn hyperactive, resulting in abnormal brain growth and autism.

In people with autism, replication of the 15q chromosome region – known as Dup15q syndrome – is one of the very frequent genetic irregularities. It was earlier considered that too much UBE3A is the reason.

Study head Mark Zylka, and his team describe that in normal brain growth, the UBE3A gene can be switched on or off via the bond of a phosphate molecule, which serves as a regulatory switch.

On the other hand, the investigators found that mutations in UBE3A damage the regulatory switch – which they recognized as protein kinase A (PKA) – which means the gene can’t be switched off, resulting in it to become hyperactive.  The research team believes that his hyperactivity, may be responsible for autism.

Zylka and co-workers achieved their results by sequencing the genes of human cell lines from kids with autism and their parents. While the parents of the kids had no UBE3A mutations, the kids did. The investigators identified that the UBE3A gene in the kids was forever switched on.

On bringing out the mutated UBE3A gene to mouse designs, the team identified the development of dendritic spines on the brain cells, or neurons, of mice. Dendritic spines link neurons to the synapses. They describe this is a specifically essential finding since having too many dendritic spines has been linked to autism.

As a result, the investigators say their results suggest that hyperactivation of UBE3A – induced by the exploitation of PKA – is a trigger of Dup15q-related autism.

Present drugs could decrease UBE3A activity to cure autism

Zylka believes that it may be an option in near future to decrease UBE3A activity in patients with Dup15q-related autism.

“Actually,” he adds, “we examined known substances and showed that two of them considerably decreased UBE3A activity in neurons.”

One of the substances examined was a drug known as rolipram, which improves PKA activity. This medicine had earlier been examined in clinical studies for the treatment of depression, but its use was stopped because of side effects.

However, Zylka notes that for some Dup15q patients – like those who experience life threatening seizures – the advantages of rolipram may over-shadow the risks. He states that it may be worth evaluating whether low amounts of this or other PKA-boosting medication relieve symptoms of Dup15q syndrome.

Along with opening the door to possible autism treatments, the investigators say their results may also assist in the treatment of Angelman syndrome – an unusual neurological condition that leads to serious intellectual and physical impairment.

In their research, the team identified that a variety of mutations among people with Angelman syndrome are connected with reduced function or stability of UBE3A, which results in patients with no active form of the gene. This finding, the investigators say, may result in better recognition of a situation that is commonly wrongly diagnosed.