Study sheds light on the molecular biology behind genetic epilepsy

Generally, even the alteration of a single nucleotide in a gene may cause critical illness. In a younger boy with epilepsy, this type of mutation has not simply affected the functioning of the protein in query – it might additionally curb the functioning of a number of carefully associated proteins. This has been proven in a research, printed in the journal PNAS, by researchers in Sweden and the USA. The research sheds light on the molecular biology behind some types of genetic epilepsy.

On this research, the researchers have discovered a beforehand unknown mutation in a baby with epilepsy. He has a really delicate change – a single nucleotide that’s completely different – in the gene KCNA2, which produces an ion channel protein. Ion channels are proteins which kind pores in the cell floor membrane. When the channels open, they permit the circulate of particular electrically charged ions into or out of the cell. This triggers or terminates electrical impulses in cells, akin to nerve or muscle cells. Thus, ion channels are essential for, amongst different issues, mind perform.

Ordinarily, there’s a steadiness in the mind between indicators that enhance cell exercise and ones which suppress it. In epilepsy, the steadiness is disturbed, and the nerve cells ship indicators in an uncontrolled method. The ion channel which has mutated in the affected person usually has a dampening impact on nerve signaling.

What’s attention-grabbing with this ion channel is that each mutations that enhance perform and people who lower perform have been related to epilepsy. Plainly you want simply the correct quantity of exercise, in any other case the danger to develop seizures will increase.”

Antonios Pantazis, affiliate professor at the Division of Biomedical and Scientific Sciences, and the Wallenberg Heart for Molecular Medication at Linköping College

Utilizing various experimental strategies, the analysis crew discovered that cells might produce the mutant channel proteins, however they might not transport them to their floor membrane. As mutant channels stayed trapped inside the cell, there was no measurable ion channel exercise.

There are two copies of most of our genes. The affected person had one mutated copy and one regular one, so one would count on that he had 50% of useful ion channels. However when the scientists reproduced this situation in the lab, it turned out that the channel exercise was as little as 20 p.c, in comparison with regular. The mutation apparently decreased the perform of the regular proteins, too: a “dominant damaging” mutation. To know how this occurred, we have to take into account that this ion channel includes 4 interconnected proteins. The researchers confirmed that proteins from the mutant gene can join with proteins made by the regular copy, and likewise preserve them trapped inside the cell.

And right here comes the crux of the story: there are, actually, a number of ion-channel genes associated to KCNA2. Proteins produced from these completely different genes usually combine collectively to kind ion channels. When the scientists combined proteins from mutant KCNA2 with these of associated gene KCNA4, they discovered that KCNA4 proteins have been additionally prevented from transporting to the cell floor.

Pantazis explains that when completely different channel proteins mix with one another to create combined ion channels, this contributes to the nice range and complexity of nerve cell signalling. This range is essential for the processes that we affiliate with the functioning of the mind, akin to ideas, consciousness and the means to think about. But this means of channel proteins to mix additionally confers an obstacle, as the mind turns into weak to single, dominant-negative mutations, which might perturb the perform of a number of ion channels, and trigger neurological illness, as on this story.

“Learning the results of mutations on ion channels may give us important clues about the mechanisms of illness and potential therapeutic methods”, says Michelle Nilsson, a PhD scholar in Pantazis’ analysis group, and principal creator on the research.

“Since these mutations can have surprising results on ion-channel perform, learning them may result in new discoveries about how our our bodies work at the molecular stage,” Antonios Pantazis says.

The research has been funded by the Knut and Alice Wallenberg Basis via the Wallenberg Heart for Molecular Medication (WCMM) at Linköping College, and the Swedish Analysis Council.