Insidious genetic mutations provide new insights into epilepsy

Summary: New research sheds light on the biological mechanism behind some genetic forms of epilepsy.

A source: Linkoping University

Sometimes a change in a nucleotide in a gene can also lead to serious illness. In a young child with epilepsy, such a mutation can not only affect the function of the protein in question, but also disrupt several nearby proteins.

This is stated in a study published in the journal PNAS, By researchers in Sweden and the United States. The study sheds light on molecular biology behind some types of genetic epilepsy.

In this study, researchers found a previously unknown mutation in a child with epilepsy. There is a very subtle change in its gene – a nucleotide, in other words KCNA2, The ion channel forms the protein. Ionic channels are proteins that form pores in the cell surface membrane.

When the channels are opened, they allow certain electrically charged ions to enter or leave the cell. It stimulates or stops electrical impulses in cells, such as nerve or muscle cells. Thus, ion channels are important, among other things, for the brain to function.

In the brain, there is usually a balance between the signals that increase the cell’s activity and the signals that suppress it. In epilepsy, the balance is disturbed and nerve cells send signals uncontrollably. A mutated ion channel in a patient usually has a depressant effect on nerve signals.

“The most interesting thing about this ion channel is that both mutations that increase function and mutations that decrease function have been linked to epilepsy. According to Antonios Pantazis, an associate professor of biomedical and clinical sciences and the Wallenberg Center for Molecular Medicine at Linkoping University, it seems that you need the right amount of activity, otherwise the risk of seizures increases.

Using a variety of experimental methods, the team found that cells could produce mutant channel proteins, but were unable to deliver them to the surface membrane. Because the mutant channels were trapped inside the cell, the measured ion channel was not active.

Most of our genes have two copies. The patient had a mutated copy and a normal copy, so it can be expected that 50% of them have functional ion channels. However, when scientists recreated this condition in the laboratory, it was found that the activity of the channel was up to 20 percent lower than normal. The mutation also apparently reduced the function of normal proteins: a “dominant negative” mutation.

To understand how this happens, we must consider that this ion channel contains four interconnected proteins. Researchers have shown that proteins in a mutant gene can bind to proteins made from ordinary copies and retain them inside the cell.

Here is the gist of the story: in fact, several ion channels are linked by genes KCNA2. Proteins made from these different genes often mix to form ion channels. When scientists mix mutant proteins KCNA2 with related genes KCNA4they found it KCNA4 It also prevented proteins from being transported to the cell surface.

Pantasis explains that when different channel proteins combine to form mixed ion channels, this contributes to the diversity and complexity of nerve cell signaling. This diversity is important for processes such as thoughts, consciousness and imagination, which are linked to brain function.

In the brain, there is usually a balance between the signals that increase the cell’s activity and the signals that suppress it. Image in public domain

This ability of channel proteins to combine is another drawback, because the brain is vulnerable to single, predominantly negative mutations, disrupting the function of several ion channels, leading to neurological disorders such as this one.

“Studying the effects of mutations on ion channels can provide us with important information about the mechanisms of disease and potential therapeutic strategies,” said Michel Nielson, a doctoral student and co-author of the study.

“Because these mutations can have an unexpected effect on ion-channel function, their study could lead to new discoveries about how our bodies function at the molecular level,” says Antonios Pantazis.

Funding: The research was funded by the Knut and Alice Wallenberg Foundation through the Wallenberg Molecular Medicine Center (WCMM) at Linkoping University and the Swedish Research Council.

News about genetics and epilepsy research

Annotation: Karin Soderlund Leifler
A source: Linkoping University
The connection: Karin Söderlund Leifler – Linkoping University
Photo: Image in public domain

Original study: Open access.
“K1.2 charge-carrying center mutations associated with epilepsy impair trade in K1.2 and K1.4,” Michelle Nielson et al. PNAS


See also

This indicates a neuron

Disorders of the K1.2 charge-transport center mutation associated with epilepsy lead to K1.2 and K1.4 traffic disorders.

We report on heterozygotes KCNA2 An option in a child with epilepsy. KCNA2 K encodesIn1.2 subunits, which form homotetrameric potassium channels and participate in other heterotetrameric channel complexes with K.In1st family particles, regulation of neuronal excitation.

The mutation causes F233S substitution in KIn1.2 The charge-carrying center of a voltage-sensitive domain. Immunocytochemical traffic analysis showed that KIn1.2 (F233S) subunits reduce traffic and surface expression of wild K species.In1.2 and KIn1.4: Beyond the dominant-negative phenotype KCNA2apparently severely disrupted the electrical alarm.

However, some KIn1.2 (F233S) smuggled wild type KIn1.2 and KIn1.4 Subunits, presumably in permissible heterotetramer stoichiometries: electrophysiological studies using applied transcriptomies and concatemer constructions one or two K.InSubunits 1.2 (F233S) can participate in wild K-type heterotetramersIn1.2 or KIn1.4, respectively, and early and late events in the path of biosynthesis and secretion lead to disruption of traffic.

These studies hypothesized that F233S generates a depolarizing shift of 4848 mV at K.In1.2 voltage dependence. Optical tracking KIn1.2 (F233S) voltage-sensitive domain (rescued by wild-type K)In1.2 or KIn1.4) was found to operate in a slightly distorted dependence on voltage and to maintain the contact of the pores, as evidenced by uncharged immobilization.

The equivalent mutation in the shaker is K+ channel (F290S) has been reported to have a slight effect on traffic and a severe effect on function: ~ 80-mV depolarizing shift, voltage sensor activation, and pore connection interruption.

Our study reveals the multigenic, molecular etiology of the variant associated with epilepsy and the disruption of the charge transfer center.In1.2 and Shaker, archetypes for the structure and function of the potassium channel.

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