Why is it important to know if my child is a GOF or LoF?
At first glance, a child with GoF or LoF can have similar symptoms and one can therefore NOT conclude whether the child has a LoF or GoF mutation on the basis of the clinical symptioms. However, when it comes to possible treatments, the approach to personalized therapies for each of these groups will be very different. Although a specific and broadly effective treatment has not yet been developed to cure or alleviate either of these two abnormal receptor functions, there are some drugs, supplements and experimental therapies that could help with either one of these conditions. For more information about this, please see the Treatment Section of this website.
What does Loss of Function (LoF) or Gain of Function (GoF) mean?
GRIN variants/mutations cause disruptions in the proteins that make up the NMDA neuroreceptor. These changes are classified in two broad categories, LoF (Loss of Function) and GoF (Gain of Function).
Gain of Function (GoF)
This functional alteration occurs when the mutation in the GRIN gene leads to the production of an abnormal protein that alters the neuroreceptor and causes the neurons to be overexcited (overactive). This in turn leads to miscommunication between neurons as they fire too much.
If we imagine the neuroreceptor as a door that opens and closes according to the stimulation of other neurons, it would be as if the door was left open and the information did not stop entering the cell. This can damage or destroy the nerve cell, therefore treatments that can stop this hyperactivity would be desirable for these types of mutations.
Loss of function (LoF)
This occurs when the mutated protein causes the neuroreceptor to function below its normal capacity, leading to poor connectivity between neurons in the brain and slowing down brain processes. In this case, the door is only partially opened and only part of the information that the cell should receive actually enters.
LoF can also occur if a mutated gene is totally or partially deleted or the protein product of the mutated gene is shorter than expected (this is the case with a so-called truncated mutation or nonsense mutation). This non-existent or abnormally short protein reduces the number of functional NMDA receptors found on the neurons and causes the activity between the cells to also be decreased.
Mixed or Complex function:
There are a few mutations that by today’s analysis tools and knowledge cannot be classified as either LoF or GoF. These mutations, experimentally show a combined effect of LoF and GoF that is difficult to determine. These mutations are thought to have a Mixed or Uncertain function. If you child has this kind of alteration, please corroborate this information with one of the GRIN researchers studying GRIN variants.