Study sheds light on molecular biology behind genetic epilepsy

Sometimes even the alteration of a single nucleotide in a gene can cause serious disease. In a young boy with epilepsy, this type of mutation not only affected the functioning of the protein in question, it could also dampen the functioning of several closely related proteins. This was shown by a study published in the journal PNAS by Swedish and American researchers. The study sheds light on the molecular biology behind some forms of genetic epilepsy.

In this study, researchers discovered a previously unknown mutation in a child with epilepsy. It has a very subtle change – just one different nucleotide – in the gene KCNA2, which produces an ion channel protein. Ion channels are proteins that form pores in the cell surface membrane. When the channels open, they allow the flow of specific electrically charged ions into or out of the cell. This starts or stops electrical impulses in cells, such as nerve or muscle cells. Thus, ion channels are important, among other things, for the functioning of the brain.

Ordinarily, there is a balance in the brain between signals that increase cellular activity and those that suppress it. In epilepsy, balance is disturbed and nerve cells send signals out of control. The mutated ion channel in the patient normally has a moderating effect on nerve signaling.

What’s interesting about this ion channel is that mutations that increase function and those that decrease it have been linked to epilepsy. It looks like you need the right amount of activity, otherwise the risk of developing seizures increases.”

Antonios Pantazis, Associate Professor in the Department of Biomedical and Clinical Sciences and the Wallenberg Center for Molecular Medicine at Linköping University

Using various experimental methods, the research team found that cells could produce the mutant channel proteins, but could not transport them to their surface membrane. As the mutant channels remained trapped inside the cell, there was no measurable ion channel activity.

There are two copies of most of our genes. The patient had one mutated copy and one normal copy, so one would expect him to have 50% functional ion channels. But when the scientists reproduced this condition in the lab, it turned out that the channel’s activity was as low as 20%, compared to normal. The mutation apparently also decreased the function of normal proteins: a “dominant negative” mutation. To understand how this happened, we must consider that this ion channel comprises four interconnected proteins. The researchers showed that proteins from the mutant gene can connect to proteins made by the normal copy and also keep them trapped inside the cell.

And here’s the crux of the story: there are actually several ion channel genes linked to KCNA2. Proteins made from these different genes often mix together to form ion channels. When scientists mixed mutant proteins KCNA2 with those of the related gene KCNA4they found that KCNA4 proteins were also prevented from transporting to the cell surface.

Pantazis explains that when different channel proteins combine to create mixed ion channels, it contributes to the great diversity and complexity of nerve cell signaling. This diversity is important for the processes we associate with brain function, such as thoughts, consciousness, and the ability to imagine. Yet this ability of channel proteins to combine also confers a downside, as the brain becomes vulnerable to single dominant-negative mutations, which can disrupt the function of multiple ion channels and cause neurological diseases, as in this story.

“Studying the effects of mutations on ion channels can give us vital clues to disease mechanisms and potential therapeutic strategies,” says Michelle Nilsson, a doctoral student in Pantazis’ research group and lead author of the study. .

“Since these mutations can have unexpected effects on the function of ion channels, their study can also lead to new discoveries about the functioning of our body at the molecular level”, explains Antonios Pantazis.

The study was funded by the Knut and Alice Wallenberg Foundation through the Wallenberg Center for Molecular Medicine (WCMM) at Linköping University and the Swedish Research Council.


Journal reference:

Nilsson, M. et al. (2022) A mutation in the K1.2 charge transfer center associated with epilepsy impairs K1.2 and K1.4 trafficking. PNAS.

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