A new study led by researchers from Canada and the UK suggests that a faulty gene causes common migraines: when the gene is not switched on, it inhibits a protein that regulates the threshold of sensitivity of pain centres in the brain.

You can read how the study, led by researchers from the University of Montreal and the University of Oxford, with contributions from other members in the UK and Canada and also Portugal and Australia, arrived at this result in the 26 September online issue of the journal Nature Medicine.

Migraine headaches are a debilitating condition that affect one in five women and one in ten men worldwide; the World Health Organization rates it as a leading cause of disability worldwide and it is also thought to be the most costly neurological disorder in Europe.

The headaches are severe and long-lasting and usually start as a throbbing pain on one side or the front of the head. Sometimes the pain is preceded by a visual disturbance called an “aura”, often experienced as blind spots, zigzag lines, flashing lights, visual hallucinations, or tingling in an arm or leg.

The headache itself can also be accompanied by other symptoms such as sensitivity to light and smells, as well as nausea and occasional vomiting.

While previous studies have linked certain parts of human DNA to increased risk of migraines in the general population, none has yet, before this study, found genes directly responsible for common migraines.

In this latest study, the researchers found that a mutation in the KCNK18 gene inhibits the function of a protein called TRESK, which plays an important part in nerve cell communication: it helps to regulate the sensitivity threshold of pain centres in the brain.

The team compared the DNA of people who suffer from migraines with that of people who do not. They found that one large family of sufferers of migraine with aura carried the mutation.

Lead author Ron Lafreniere, Associate Director of the Centre of Excellence in Neuromics of the Université de Montréal (CENUM), said in a statement that:

“We found a mutation in the KCNK18 gene that interrupts TRESK function in one large family suffering from migraine with aura.”

“When we tested everyone in the family, all those who suffered from migraine also had the mutation,” he added.

Before this study, genes for migraine have only been found in a rare form of the disorder that is accompanied by limb weakness on one side of the body.

“We focused on the more common types of migraine, without this muscle weakness, in our study, and looked at genes controlling brain excitability,” explained Lafreniere.

Co-author Dr Zameel Cader, from the MRC Functional Genomics Unit at Oxford, told the press that:

“We have now made a major step forward in our understanding of why people suffer with migraine and how in certain cases, your family can literally give you a headache!”

He explained that they found migraines depend on how sensitive the nerves in the pain centres of the brain are.

The KCNK18 gene mutation results in incomplete production of the TRESK protein, so it can’t perform normally, which alters the electrical activity in the nerve cells:

“We now have direct evidence that migraine is a nerve excitability problem and have highlighted a key causal pathway in migraine”, said Cader.

Using cell culture and in vitro experiments, they found that TRESK is present in certain brain cell structures: the trigeminal ganglia and dorsal root ganglia, that have been linked to migraine and pain pathways before.

Senior author Guy Rouleau, a Université de Montréal professor and Director of the Sainte-Justine University Hospital Research Center, said this finding was important because:

“… activation of trigeminal ganglion neurons is central to migraine development and increased activation of these neurons could very plausibly increase the risk for developing a migraine attack.”

Cader said that he and his colleagues hope their discovery will help to pinpoint a target for new therapies to “fight migraines and improve the quality of life for those suffering”.

Rouleau said one possibility was that while TRESK mutations might only be present in a small number of people who suffer from migraines, if it proves to be a key player in controlling the excitability of nerve cells, as this study suggests, then increasing TRESK activity, say with drugs, might well work as a way to reduce the frequency or severity of migraines, regardless of what causes them.

Funds from the Medical Research Council, Genome Canada, Genome Quebec, Emerillon Therapuetics, the Wellcome Trust and Pfizer paid for the study.

“A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura.”
Ronald G Lafrenière, M Zameel Cader, Jean-François Poulin, Isabelle Andres-Enguix, Maryse Simoneau, Namrata Gupta, Karine Boisvert, François Lafrenière, Shannon McLaughlan, Marie-Pierre Dubé, Martin M Marcinkiewicz, Sreeram Ramagopalan, Olaf Ansorge, Bernard Brais, Jorge Sequeiros, Jose Maria Pereira-Monteiro, Lyn R Griffiths, Stephen J Tucker, George Ebers & Guy A Rouleau.
Nature Medicine, Published online: 26 September 2010.

Additional sources: University of Montreal, University of Oxford.

Written by: Catharine Paddock, PhD