4 August 2011

Sniffing out a cause of childhood epilepsy

A gene mutation discovered in truffle dogs might help scientists to understand childhood epilepsy, say Finnish scientists.
Lagotto Romagnolo

A female Lagotto Romagnolo. Credit: Wikimedia

MUNICH: A gene mutation discovered in truffle dogs might help scientists to understand childhood epilepsy, say Finnish scientists.

About 1 in every 200 children develops epilepsy between the age of 2 and 10, but then the seizures suddenly stop. Scientists think that there is a genetic basis to most epilepsies that aren’t associated with brain injury or trauma, but they don’t have an explanation for the puzzling trend of remission.

A genetic mutation found to cause epilepsy in Lagotto Romagnolo puppies may be a new candidate gene for human benign childhood epilepsies characterised by seizure remission.

“This gene discovery is significant for both dogs and humans. Every third Lagotto Romagnolo carries the gene mutation in its genome and we have now developed a gene test to be used by breeders to eliminate the disease from the breed,” said geneticist Hannes Lohi from the University of Helsinki in Finland and lead author of the paper published in PLoS Genetics.

“Furthermore, the gene has not previously been linked to human epilepsies, which makes it a new candidate gene for especially childhood epilepsies.”

Pure-breeds ideal candidates

Scientists suspect there may hundreds of different genes that cause epilepsy. One way of looking for these is by studying dogs, which can also be affected by epileptic seizures.

‘Pure-bred’ dogs are genetically very similar, which is a great advantage for scientists looking for genes that cause disease, because the ‘signal to noise’ ratio in genetic comparisons between sick dogs and healthy dogs is much higher than it would be in a more genetically mixed population.

Lohi and his team studied a breed of dogs called Lagotto romagnolo – also known as truffle dogs, for their ability to sniff out the prized fungi. Some Lagotto dogs start having seizures when they are 5-9 weeks old, but the fits stop by four months, which is a similar pattern, in dog age, to human remitting epilepsies in people.

Linking directly with remission

The researchers compared the genes of 11 dogs with epilepsy and 11 healthy dogs, and found a mutation in a gene called Lgi2 in the affected dogs. By testing more dogs, they concluded that if both copies of the gene are mutated, this causes the epilepsy.

“So far we only know the genes behind about 1% of childhood epilepsy patients, and this is first gene that we can link directly to remission,” said Lohi. He hopes that studying this mutation will provide new information on the neurobiology of epileptic seizures.

The Lgi2 gene encodes for a protein, LGI2, which is secreted by brain cells called neurons and helps to control synapses – chemical connections between brain cells.

“The Lgi2 mutation is exciting because almost all mutations associated with epilepsy that we know about so far are in genes coding for ion channels, not secreted proteins,” said Ruth Ottman, a genetic epidemiologist at Columbia University in New York. Ottman’s group previously found that a mutation a similar secreted protein, LGI1, causes epilepsy in people, although this form of epilepsy comes on mostly after the age of 10. She said these findings show that faults in different parts of the brain can lead to epilepsy.

Why the seizures stop

Lohi thinks that LGI2 might function in brain formation during childhood. As the human brain develops after birth, one quadrillion synapses – that’s 1×1015 – are formed.

Between the ages of about 2-10 years in humans, these synapses are ‘pruned’ to about half that number, which then makes up the stable adult brain. The same pruning process happens in other animals too.

When Lohi’s group measured LGI2 expression in mice, they only found the protein until mid-way through the pruning phase. “We think that LGI2 might be involved in pruning, and so the seizures stop when pruning is finished and LGI2 is no longer important,” he said.

“The similar timing of LGI2 secretion stopping and the seizures remitting is great circumstantial evidence, but I’d really like to see if there are any changes in the brain without LGI2,” added Ottman.

Screening for mutation in humans

Scientists can quantify how much pruning occurs in the brains of animals by microscopy, and Lohi and his team are currently making a mouse that lacks the LGI2 gene to try to answer this question. They are also screening human families with remitting epilepsy to see if there are Lgi2 mutations in people too.

Meanwhile, the finding has already been put into use in dogs. Lagotto breeders are now using a genetic test to screen for the mutation.

If dogs with a mutated copy of the gene – referred to as carriers – are only bred with dogs without the mutation, this will almost guarantee that the puppies will be healthy. “We think we can wipe out epilepsy in this breed really quickly”, said Lohi.


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