The GRI gene superfamily

The GRIN genes belong to the “ionotropic glutamate receptor superfamily” (iGluRs), which includes three other gene families: GRIA1-4 (encoding GluA1-4 – the AMPA receptors: AMPARs), GRIK1-5 (encoding GluK1-5 – the kainate receptors: KARs), and GRID1-2 (encoding GluD1-2 – the delta receptors). 

Each protein coded by the GRI genes is called a subunit. Four of these subunits come together in the surface of brain cells to form an ion channel – a tiny pore facilitating the passage of electrical signals. These electrical signals are the way by which neurons communicate with each other. Specifically, when a neuron wants to pass on a message to its neighbour, it releases a little puff of a molecule called glutamate – an important neurotransmitter. This glutamate acts on iGluRs on the neighbouring neuron, to open their ion channels which produces the electrical signal. If enough of these signals are received from the first neuron, the neighboring neuron will then pass on the signal to the next neuron, and so on.

Similar to the GRINs, the GRIAs, GRIKs and GRIDs are crucial for normal brain function. Genetic variations, often DNA “spelling mistakes” causing missense variants, are increasingly being associated with neurodevelopmental disorders. These changes, which happen very rarely and at random, can lead to defective receptors that negatively influence many aspects of brain activity including development, learning and memory, emotion and behavior, and the overall balance of excitation and inhibition. So GRIN, GRIA, GRIK and GRID kids differ from most people in a wide range of brain functions. 

Because we now know that mistakes in the GRI genes can produce these kinds of changes, children who show signs of developmental delays, intellectual disability and/or seizures have over the last few years been increasingly investigated to see if there could be changes in their GRIN, GRIA, GRIK and GRID genes. At the start of 2024, the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar) which lists the results of millions of genetic tests from patients with all kind of diseases, contained 2441 different missense variants in the GRIN genes, 394 in the GRIA genes, 238 in the GRIK genes and 138 in the GRID genes. So at this stage GRIN disorder is many times more prevalent than the other GRI disorders, however it should be noted that GRIA, GRIK and GRID genes were not routinely investigated until the last few years, so their detection will be underestimated at the moment.

Due to their rarity, even experienced neurologists and pediatricians may never have encountered GRI disorders, and there are very few specialists. Being proactive as a parent to contact associations like GRIN Europe and CureGRIN can help you find the most appropriate help and allow your family to contribute to a fantastic community. There may even be opportunities to help contribute to vital research as we try to better understand these disorders.If you have a child with GRIA, GRIK or GRID disorder, make sure you check outthe rest of this website as lots of the information for GRIN is also applicable to the other GRI disorders, including the “GRIN Diagnosis”, “Functional Analysis” and “What are GoF and LoF” sections.