A new study, published in the American Journal of Human Genetics, sheds light onto how variations in genes can influence the activity of important proteins in the brain and may lead to neurological disorders.The study focused on two genes called GRIN2A and GRIN2B, which are linked to epilepsy, intellectual disability and a number of other neurological conditions. These genes encode for two components – known as the GluN2A and GluN2B domains-of NMDA receptors, which play a crucial role in communication between brain cells.Genetic variants in GluN2A and GluN2B are seen in the ‘general’ population without necessarily affecting the function of the NMDA receptor. However some rare variants do disrupt NMDA receptor activity, causing neurological disorders.During the study the team, led by Dr Hongjie Yuan, at Emory University School of Medicine, in Atlanta, assessed genetic variation in the GluN2A and GluN2B domains using data from the Exome Aggregation Consortium (ExAC). This is a large database that combines DNA sequences from more than 60,000 unrelated people. They were particularly interested in finding out what parts of the GLuN2 domains are most susceptible to disease-causing variations (identified via other gene databases).They discovered that three different regions of the GluN2 domains – the region that binds to the molecules that activate the receptor; the region that anchors the receptor to the cell surface and the region that links the two domains – are particularly vulnerable to genetic variation. In other words, variations that cause functional problems in the NMDA receptor are more likely to be found in the sections of DNA that encode these areas.In a press release, co-senior author Dr Stephen F. Traynelis, said:”This is one of the first analyses like this, where we’re mapping the spectrum of variation in a gene onto the structure of the corresponding protein. We’re able to see that the disease mutations cluster where variation among the healthy population disappears.”In order to better understand how genetic variations in the GluN2 domains can affect the function of the NMDA receptor, the researchers explored 25 rare genetic GluN2A and GluN2B variants that had already been linked to different neurologic conditions, including epilepsy and intellectual disability. They found most of the GluN2A variants in the DNA of people with epilepsy, and most of the GluN2B variants in the DNA of people with intellectual disability with or without seizures.Using the DNA, and genetic techniques, the team discovered that the effects of the GluN2 variants were complex and sometimes opposing. For example, variants that resulted in both the receptor losing its function or acquiring function when it shouldn’t were associated with similar neurological conditions.According to the authors, understanding how variants in GLuN2A and GluN2B cause disruption of NMDA receptor function could help scientists develop new strategies to restore it. These strategies could potentially serve as new treatments for epilepsy and other neurological disorders.Author: Dr Özge ÖzkayaClick here for more articles about brain science including genetics.