Intellectual disability caused by a rare genetic mutation

Disruptions to the activity of an enzyme, CaMKIIalpha, which is responsible for learning and memory, has been found to cause profound intellectual disability. Following a newly-developed protein analysis method, researchers from the University of Tokyo, in Japan, discovered a single gene mutation known as P212L causes dramatic changes to the enzyme.

CaMKIIalpha mediates biochemical reactions in the brain and is essential to learning – for this, CaMKIIalpha activity must be regulated at appropriate levels and at the appropriate timing, else irregularities can lead to a variety of neurological disorders.

The P212L mutation in CaMKIIalpha is a known cause of disability, however, the process by which this mutation alters the enzyme’s function was not entirely clear.

To simplify the enzyme analysis process, the researchers developed a simple, scalable, sensitive, and quantitative method to measure enzyme activity in physiological conditions, such as living cells or synapses.

The “FRET (Förster resonance energy transfer)-based kinase phenotyping strategy,” according to Hajime Fujii, lecturer from the Graduate School of Medicine at the University of Tokyo, explains the minute biochemical reaction process by brightness and colour. The researchers used a fluorescent probe, which changes its relative brightness between two colours according to changes of the CaMKIIalpha.

This new method enabled the team to rapidly and accurately analyse nearly a hundred cell extracts and study their biological activity. What it found was that CaMKIIalpha with the P212L mutation exhibited enhanced activation compared to usual. This means that rewiring or changes in the brain that usually occur during learning may be irregular in people with this mutation, compared to people without it.

The researchers also found that in neurons, taken from rats in this study, the CaMKIIalpha response to stimulation was increased. The activation response of the enzyme rose faster and fell slower, again demonstrating an unusually enhanced response.

The team hopes that its research will help to identify treatment options for genetically-based intellectual disabilities. In this case, it found that memantine, a drug currently used to treat symptoms of Alzheimer’s disease, caused a suppression of the P212L mutation’s effect in neurons.

“The next step would be to determine in more detail how irregular CaMKIIalpha activation causes intellectual disability and examine whether suppressing irregular activation with memantine can treat intellectual disability,” said Fujii.

Category: Education, Features