A new study has shown how an uncommon genetic mutation causes intellectual impairment. The P212L mutation in CaMKIIalpha, an enzymes critical for learning and memory, has been related to intellectual impairment. Until today, however, it was unknown how the mutation altered the enzyme’s function.
An estimated 1% of the worldwide population has an intellectual impairment. Infection, injuries, and hereditary disorders are some of the most typical reasons. CaMKIIalpha is an enzyme that modulates biochemical events in the brain and is essential for learning.
CaMKIIalpha activity must be controlled at suitable levels and at the proper timing for typical learning, and anomalies in it have previously been connected to a range of neurological diseases. A P212L mutation in CaMKIIalpha is one recognised cause of intellectual impairment. Although the link between intellectual impairment and the mutation is well established, it was previously unknown how the enzyme’s mutation impacts its activity. The P212L mutation is extremely rare, but a patient was identified in Japan who then took part in a study with researchers from the University of Tokyo and Nagoya University. “This is only the fourth known case of this P212L mutation in the world,” said researchers from the University of Tokyo and Nagoya University.
The association between this single gene mutation and symptoms, on the other hand, is quite evident, making it crucial in the research of intellectual impairment “said Hajime Fujii, a lecturer at the University of Tokyo’s Graduate School of Medicine.
Because responses at this size are not directly apparent to our eyes, they must be tracked using other methods. However, these investigations are frequently time-consuming and difficult. “It is difficult to analyse several samples in parallel, and measuring enzyme activity under physiological settings, such as living cells or synapses, is impossible. We desired something more straightforward, scalable, sensitive, and quantifiable. As a result, we devised a technique for measuring enzyme activity using a fluorescent probe “Fujii developed.
“The brightness or colour of this can indicate the development of a biological process. To make a fluorescent probe, we have to combine a biological response, such as molecule binding or changes in protein structure (at the nanoscale scale), with fluorescence brightness or colour. As a result, we employed a physical phenomena known as FRET (Forster resonance energy transfer), in which the probe may alter relative brightness between two colours based on CaMKIIalpha changes that occur when it is engaged. Our method is known as a FRET-based kinase phenotyping tool.”
The team was able to evaluate roughly a hundred cell extracts and study their biological activities using this novel technology. It discovered that CaMKIIalpha with the P212L mutation had more activation than typical. This suggests that rewiring or changes in the brain that occur during learning may be irregular in people who have this mutation compared to others who do not have it. The researchers also discovered that the CaMKIIalpha response to stimulation was enhanced in neurons obtained from rats in this investigation. The enzyme’s activation response climbed quicker and decreased slower, indicating an exceptionally elevated reaction.
“There has been no successful medical treatment for children with genetically related intellectual impairment up to this point.” “This study has the potential to give treatment to individuals with intellectual disabilities who have this unique version of CaMKII,” said Nagoya University Assistant Professor Hiroyuki Kidokoro, a paper co-author and paediatrician who worked with the patient.
“Mutations in CaMKIIalpha have been linked to various neurodevelopmental diseases, so we may be able to clarify the development of and treatment methods for these mutations in the same way, by using our FRET-based kinase phenotyping platform,” Fujii said. We will require fluorescent probes to monitor the functionality of the genes in order to adapt our method to mutations in other genes that cause diverse illnesses.
Currently, fluorescent probes are accessible for some genes but not others, thus new fluorescent probes must be developed, which may take some time.”