A new study from the University of Tokyo and the University of Nagoya shows how a rare genetic mutation can lead to intellectual disability.
It is well known that the P212L mutation that occurs in the CaMKIIalpha enzyme, which is important for learning and memory, is linked to intellectual disability. However, the process of how the mutation affects the activity of the enzyme has been unclear. Using a new method of protein analysis, researchers from the University of Tokyo and the University of Nagoya have found that the P212L mutation causes far more activation of CaMKIIalpha than previously thought.
These findings could improve intellectual disability treatment
These new findings have enabled researchers to identify potential treatments using existing medicine. The method of protein analysis could also be used to analyse other genetic causes of disability and disease.
Around 1% of the global population has some form of intellectual disability. Commonly these are caused by infection, injury, or genetic conditions. The CaMKIIalpha enzyme mediates biochemical reactions in the brain and is important to the brain’s ability to learn. Typical learning activity required CaMKIIalpha activity to be regulated at appropriate levels as irregularities can cause neurological disorders. Although rare, the P212L mutation is one of these irregularities.
Researchers identified a patient with the P212L mutation who then took part in the study. “This is only the fourth known case of this P212L mutation in the world. However, the relationship between this single gene mutation and symptoms is relatively clear, making it important in the study of intellectual disability,” said Hajime Fujii, a lecturer at the Graduate School of Medicine at the University of Tokyo.
A new method for analysing enzymes
Reactions at this level are not visible to the human eye, so they must be monitored through other techniques. These methods are usually time-consuming and laborious. “It is difficult to process many samples in parallel and not possible to measure enzyme activity in physiological conditions, such as living cells or synapses. We wanted something more simple, scalable, sensitive, and quantitative. So, we developed a method to measure enzyme activity by fluorescent probe,” explained Fujii.
Using this method, researchers were able to measure the biochemical reaction by its brightness or colour. This method allowed the team to rapidly and precisely analyse nearly a hundred cell extracts and examine their biological activity. The team found that CaMKIIalpha with the P212 mutation exhibited enhanced activation compared to usual.
This means that changes that normally occur during learning may possibly be irregular in people with this mutation, compared to those without it. The researchers also found that in neurons taken from rats, the CaMKIIalpha response to stimulation was increased. The activation response of the enzyme also rose faster and fell slower, demonstrating the unusually enhanced response.
The team hopes their research will help to identify new treatments for genetically based intellectual disabilities. In this case, the researchers found that memantine, a drug used to treat symptoms of Alzheimer’s disease, caused a suppression of the P212L mutation’s effect in neurons.
“So far, there has been no effective medical treatment for children with genetically based intellectual disability. This study can offer the possibility of treatment to patients with intellectual disability who have this rare variant of CaMKII” said co-author and Assistant Professor Hiroyuki Kidokoro from Nagoya University.