Behind the Headlines

Tuesday August 4 2009

Brain activity of a human with epilepsy

Fixing a faulty gene “may cure epilepsy”, according to The Independent. The newspaper said that “epilepsy sufferers have been given fresh hope that a cure may be found after scientists prevented the condition being passed on to mice offspring”.

This report is based on a study looking at a mutant strain of mice that are prone to seizures. Scientists found that the mutations that caused these seizures were in a particular gene that contains instructions for making a protein that helps to maintain the sodium and potassium balance in the cell. The researchers found that introducing an extra working copy of the gene into mice carrying the mutant gene prevented seizures from occurring.

This type of research helps to improve our understanding of the biology of seizures and identify genes that could be mutated in human forms of epilepsy. It also identifies potential targets for drug therapy. However, it is not yet clear whether mutations in the gene identified play a role in human epilepsy.

Also, the technique of introducing extra copies of the mutated gene involved genetic manipulation of mice embryos and then crossing the resulting offspring with affected mice, which would not be feasible in humans. Equally, while there are some forms of human epilepsy that are caused by mutations in single genes, in most other cases the causes are less clear and both genes and environment are likely to play a role.


Where did the story come from?

Dr Steven J Clapcote and colleagues from Mount Sinai Hospital in Canada and other research centres in the UK, Canada and Denmark carried out this research. The study was funded by Canadian Institutes of Health Research, the Lundbeck Foundation, the Novo Nordisk Foundation, the Danish Medical Research Council and the Danish National Research Foundation. It was published in Proceedings of the National Academy of Sciences of the USA, a peer-reviewed scientific journal.


What kind of scientific study was this?

This was an animal study that analysed the genetics of a strain of mutant mice that were genetically predisposed to have epileptic seizures.

The researchers initially carried out a process called “mutagenesis screening”, looking for mice carrying mutations that might aid understanding of human biology and diseases. In this particular experiment male mice were treated with a chemical called ENU, which caused mutations in the DNA of their sperm. These males were mated with untreated female mice to produce various offspring.

The offspring were examined at eight weeks of age to look for visible signs that they were unwell or not developing normally, which could indicate that they carried genetic mutations. Once the researchers identified a mouse with unusual characteristics, they bred it with normal mice to see if their offspring inherited the unusual characteristics too.

Researchers carried out further breeding of these offspring. The results of these kinds of breeding experiments can suggest whether the mouse has one or more mutations, indicate how the mutation is having an effect and locate where the mutation lies on the chromosomes.

The type of breeding experiments performed in this study can also show whether this mutation is:

  • dominant, which means that only one copy needs to be present to have an effect,
  • recessive, which means two copies need to be present to have an effect, or  
  • sex-linked, meaning that the mutation lies on  the X or Y sex chromosomes that determine gender.

If a mouse was thought to carry only a mutation in a single gene the researchers would go on to try and identify which gene had been mutated and carry out further experiments to see what effect the mutation was having on the function of the gene.

The researchers carried out these experiments for one mutant mouse strain that they identified as having seizures. They also looked to see what effect treatment with an anti-epileptic drug would have and whether they could stop the seizures by introducing a working copy of the mouse’s mutated gene. They did this by injecting embryos from non-mutant mice with DNA containing a working copy of the Atp1a3 gene, which the mutant mice strain did not possess. Once these mice had matured they were crossbred with the affected mice.

The researchers carried out several more experiments to investigate the effects of the mutation.


What were the results of the study?

Through mutagenesis screening the researchers identified a female mouse that had a smaller body than usual. Breeding experiments showed that she passed this trait on to half of her offspring. The small mice also showed repeated, unprovoked seizures from the point at which they were weaned.

The mutation causing these effects was named the Myshkin (Myk) mutation. The mother of these offspring carried only a single copy of the mutation, as did the affected offspring. Mice that were bred to have two copies of the Myk mutation died shortly after birth.

Breeding experiments showed that Myk mutation lay on chromosome 7, and researchers looked at the sequence of the DNA on this chromosome to identify the mutation. They found that the mice actually had two mutations in a gene called Atp1a3.

This gene carries the instructions for making one form (the α3 form) of a protein called Na+,K+-ATPase. This protein lies in the membrane of cells and pumps sodium ions (electrically charged sodium atoms) out of the cell and potassium ions into the cell. The pumping of ions across cell membranes plays an important role in many functions in the cell, including generating impulses in nerve cells.

The mutations caused changes to two of the building blocks (amino acids) of the protein. The researchers found that these changes made the α3 form of the Na+,K+-ATPase protein inactive, and mice carrying one mutated copy of the Atp1a3 gene had Na+,K+-ATPase that worked less than half as well as normal within the brain.

Treating the mutant mice with valproic acid, an anti-epilepsy drug, reduced the severity of their seizures. If mice with the mutation were bred with mice carrying extra working copies of the Atp1a3 gene, offspring that carried both the mutation and the extra working copies of the Atp1a3 gene did not have seizures.


What interpretations did the researchers draw from these results?

The researchers conclude that they have identified a mutation in the Atp1a3 gene that is a cause of epilepsy in mice. They say that mutations in the human form of the Atp1a3 gene (ATP1A3) could potentially have a role in human epilepsy, and that the α3 form of the Na+,K+-ATPase that is encoded by this gene could be a target for anti-epileptic drugs.


What does the NHS Knowledge Service make of this study?

This research has identified a gene that when mutated can cause seizures in mice. This type of research is important as it helps to improve our understanding of the biology of seizures and identify mutant genes that could present in humans with epilepsy. The genes and the proteins they produce could be potential targets for drug therapy.

However, it is not yet clear whether mutations in the Atp1a3 gene are involved in human epilepsy. It is also important to note that the technique of introducing extra copies of the mutated gene used in this study would not be feasible in humans. In mice it involved genetic manipulation of embryos and crossing the resulting offspring with the affected mice.

Some forms of human epilepsy are caused by mutations in single genes, in most other cases the causes are less clear, with both genes and the environment likely to play a role.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Scientists make epilepsy breakthrough. The Daily Telegraph, August 4 2009

Fix for faulty gene may cure epilepsy. The Independent, August 4 2009

Discovery of epilepsy gene paves way for more effective treatments. The Times, August 4 2009

Scientists halt epilepsy in mice. BBC News, August 4 2009

New hope for epilepsy sufferers as scientists identify defective gene which could help beat the condition. Daily Mail, August 4 2009

Links to the science

Clapcote SJ, Duffy S, Xie G et al. Mutation I810N in the α3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS. PNAS [Published online before print] August 3, 2009

Supporting information


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