Mouse models feature: The quest for an epileptic mouse

By Graeme O'Neill
Friday, 11 October, 2002

As you read these words, charged sodium, potassium and calcium atoms are streaming through tiny pores in the membranes of billions of nerve cells in your brain, generating the seething electrical activity that underlies conscious thought.

The tiny doughnut-shaped protein molecules -- ion channels -- function like valves, regulating the flux of ions into and out of nerve cells. About eight in every 1000 individuals carry mutations that cause particular ion channels to function erratically, triggering epileptic seizures. The world's most successful team of epilepsy-gene hunters, at Melbourne University

The WCH team is headed by Prof Grant Sutherland, who works for Adelaide-based biotechnology company Bionomics. Bionomics also sponsors Melbourne University ion-channel expert Dr Steve Petrou, whose research is also supported by Bionomics, studying the basic mechanisms of ion-channel mutations by expressing the mutant genes in eggs of the African clawed toad, Xenopus.

But determining how such mutant genes disrupt the normal activity of the human brain and trigger epileptic seizures requires direct access to misfiring nerves in a living brain. The brains of human epilepsy patients are out of bounds -- you need a epileptic mouse.

Bionomics recently announced it had developed the world's first mouse models for an inherited form of epilepsy -- a disorder called generalised idiopathic epilepsy.

Perth-based Ozgene produced the mouse for Bionomics, which is working to identify molecular targets for a new generation of anti-epileptic drugs. Ozgene produces knockout, knock-in and transgenic mice for academic, biotechnology and pharmaceutical company research in Australia, Europe, Asia and North America. Some genetic disorders involve mutant genes that are inherited in simple, Mendelian fashion, and produce a well-defined set of symptoms. Epilepsy doesn't - it's a genetically complex spectrum of disorders. With generalised idiopathic epilepsy for example, affected individuals in the same family can exhibit very different symptoms because other genes influence the expression of the primary mutation. Some suffer severe seizures, others exhibit relatively mild "absences" in which they briefly become oblivious to what is happening around them.

These 'accessory' genes are inherited independently, and interact with the mutant gene in ways that cause affected individuals to express different forms or phenotypes of the primary disorder -- some relatively mild, others more severe.

Sutherland says that when the mutant gene has been established in a particular mouse strain, it can be transferred to other, genetically different mouse strains to explore how different genetic backgrounds influence its expression -- some of these genes are likely to offer new therapeutic targets. Sutherland says mouse models of epilepsy will allow researchers to explore the triggering effects of external stimuli such as flashing lights or loud noise. Later, the epileptic mice may be used to test drugs to suppress seizures.

With the Human Genome Project, geneticists can now explore how subtly different variants, or alleles, of normal genes, influence human health and behaviours. Alleles of the same gene that differ by only a single nucleotide -- a single nucleotide polymorphism (SNP) -- can profoundly influence an individual's susceptibility to disorders like Alzheimer's disease, cardiovascular disease or diabetes.

About 7000 SNPs, scattered around the human genome, account for virtually all the individual differences between the 6 billion-plus humans on Earth. Ozgene MD Dr Frank Koentgen says that the Human Genome Project has seen an increasing number of projects set up to investigate and contrast the phenotypic effects of SNPs, creating a burgeoning market for knock-in mice.

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