First gene clue to epilepsy in mice

UK scientists have identified a genetic cause of epilepsy in mice. If the same mutation proves to be associated with forms of human epilepsy, then this discovery could one day lead to the development of improved treatments or even a cure for the disorder.

Epilepsy is a relatively common condition, affecting nearly 500,000 people in the UK. It can be caused by trauma to the brain, for example through injury, stroke or a tumour, but around a third of cases are unexplained, and may have an underlying genetic cause. The research team, from the University of Leeds, studied a strain of mice that suffer from epileptic-like seizures, called Myshkin mice (after a Dostoevsky character that has epilepsy). In a report published in the US journal, Proceedings of the National Academy of Sciences, the scientists first demonstrated that these Myshkin mice were indeed suffering from a form of epilepsy, as treatment with valproic acid - a widely used epilepsy drug - reduced both the frequency and severity of the mice's seizures. They then examined DNA from these mice, and found that all the mice that developed seizures carried a faulty copy of a gene called ATP1A3.

The ATP1A3 gene is responsible for making an enzyme that controls the amount of sodium and potassium in the brain. Imbalances in the levels of these chemicals affect the electrical signals that brain cells use to communicate with each other, and this can result in a seizure. However, until now there has been no understanding of the genetic causes of disrupted levels of sodium and potassium in those suffering from spontaneously arising forms of epilepsy. Dr Steve Clapcote, who led the research, said that 'an imbalance of sodium and potassium levels has long been suspected to lead to epileptic seizures, but our study is the first to show beyond any doubt that a defect in this gene is responsible'.

The researchers provided further evidence of the role of ATP1A3 in causing epileptic seizures in mice by genetically engineering another strain of mice that carried extra copies of the normal ATP1A3 gene. When they bred these mice with the Myshkin mice, the offspring did not suffer from seizures, as although they had inherited one faulty copy of the ATP1A3 gene, they also inherited extra copies of the normal gene and this counteracted the effect of the faulty gene.

Humans have an ATP1A3 gene that has a similar function and DNA sequence as the one seen in mice. Research is now underway to see if mutations in human ATP1A3 are similarly associated with epilepsy. Dr Clapcote said: ‘Our study has identified a new way in which epilepsy can be caused and prevented in mice, and therefore it may provide clues to potential causes, therapies and preventative measures in human epilepsy'.