Study points to cause of migraine

Scientists have discovered how to switch off the pain of migraines, The Daily Telegraph reported. The newspaper said that new drugs may soon be able to counteract the debilitating headaches.

The study behind the news analysed the DNA of over 1,200 people to look for mutations within a gene known to play a role in the working of nerve cells. The analysis found a particular mutation in a woman who had migraines with “aura” (visual disturbances that accompany a migraine). When the mutation was traced back through the woman’s family, it was found that all those who carried the mutation also had migraines with aura. Further testing of the mutation showed that it affects the way cells in the spinal cord and brain chemically transfer signals to each other.

As yet, we do not know how commonly people with migraine and aura are affected by the mutation, or whether mutations in the gene might play a role in migraine without aura. Also, there is likely to be a variety of genetic and environmental factors that increase the risk of getting migraines. While this genetic discovery may eventually help migraine sufferers, the media have been overly optimistic in interpreting this research as it is too soon to anticipate it leading directly to a treatment.

Where did the story come from?

The study was carried out by researchers from Université de Montréal in Canada and other research organisations across the world. It was funded by Genome Canada, Genome Quebec, Emerillon Therapeutics, the Wellcome Trust and the Pfizer pharmaceutical company. It was published in the peer-reviewed medical journal Nature Medicine.

This genetic study is an important but early step in the investigation of potential genetic causes of typical migraines with aura. It is unclear whether it will have an application for migraine treatments and it is too soon to claim that scientists have discovered how to “switch off” the pain of migraines. This study did not investigate a treatment.

What kind of research was this?

This was a type of genetic study called a “candidate gene study”. This is where researchers investigate a particular gene for mutations that may be linked with a condition, in this case migraines. It is a form of case-control study, in which the DNA sequences found in that particular gene are compared between people with the condition (cases) and a group of people without the condition (controls).

When communicating with each other, nerve and brain cells use ions (atoms or a group of atoms with an electrical charge) to transfer tiny electrical impulses from cell to cell. As part of this process, ions pass through “channel proteins”, which are complex proteins that act as gates and will only let specific substances through. Problems with channelling ions across cells have previously been linked to other types of migraine, although not to migraines with aura. Here, researchers were interested in a gene called KCNK18. This gene contains the code for producing a protein called TRESK K2P, which channels potassium ions in the spinal cord. TRESK K2P is known to have a role in the “excitability” of nerve cells, i.e. their ability to generate nerve impulses. The protein is also thought to play a role in pain.

Researchers assessed whether mutations in this particular gene were linked with migraine with aura. Some people experience aura before the onset of migraine, which often involves visual disturbances. For example, some people see black spots or flashing shapes before a migraine.

What did the research involve?

The study enrolled 110 people who experienced typical migraine with aura and determined the DNA sequence of their KCNK18 genes. This was then compared to the KCNK18 sequence in a group of 80 people who did not have migraines.

To verify their findings from the initial phase of the study, the researchers replicated their analysis in a group of 511 Australians with migraine and a group of 505 people, matched for ethnicity, who did not have migraines. The researchers investigated the genetics of one mutation, which they identified further by assessing DNA samples of family members of an individual with the mutation.

As well as looking at mutations of the KCNK18 gene, the researchers investigated where the TRESK protein it coded for was concentrated. Tissue from mice and humans was used to determine whether the TRESK protein was produced in regions of the brain that were relevant to migraine. The researchers also used frog cells to investigate how the mutations they identified might cause functional changes within the TRESK potassium channel.

What were the basic results?

The candidate gene analysis identified four variants in the KCNK18 gene that were present in migraine sufferers but not in people without migraines. Of the four variants, one would not have caused any change in the TRESK protein and one was already known to be common in African populations. These were unlikely to be involved in migraines. Another variant was identified in only one migraine sufferer, but no DNA samples were available from the family members of this individual, so the researchers did not study this variation further.

The final variant, called F139WfsX24, involved the deletion of two “letters” in the code of the DNA. This meant that the full-length TRESK protein could not be made. This was likely to have an impact on the protein’s function, and could possibly lead to migraines. When this mutation was subject to further study in a detailed family analysis, it was found to be present only in the eight family members who were migraine sufferers. This fitted with the idea that this mutation could cause migraine with aura in this family.

By tracing the family’s history, the researchers found that this mutation acted in a dominant way (i.e. people carrying just a single copy of the mutation were affected by migraine with aura). The mutation was also found to have “full penetrance”, which means that all people in the family with the mutation suffered from migraines.

The phase of the study which looked at mouse and human tissue found that the TRESK protein was present in mouse spinal cord and brain regions and in the trigeminal ganglion neurons (a group of nerve cells outside the central nervous system) of humans. As expected, during functional studies in frog cells, the mutation completely suppressed the appropriate functioning of TRESK potassium channels.

How did the researchers interpret the results?

The researchers say that they have identified a mutation in TRESK that is associated with typical migraine with aura in a large multigenerational family. They say that the results support the possibility that TRESK is involved in typical migraines with aura and that these channels may be a target for treatments.

Conclusion

The study was well conducted and well described, but the media’s interpretation of the results was overly optimistic. The study did not investigate a treatment for migraine or a method to “switch off” the pain of migraines. Several important details are still unknown, including the number of people whose migraines may be caused by this faulty gene. It appears that the key mutation identified (F139WfsX24) was found in only one person out of the 600 or so who had migraines in this study (although it was also found in their family members). Further research will be needed to see whether these findings can be generalised to a larger population. Even if they can be, treatments based on these findings will be a long way off. The findings also only apply to people who have auras with their migraines, while most sufferers do not.

Such research can be a first step in the development of drugs. The researchers have not only identified genetic variations associated with migraine, but they have also gone some way to investigating the functional consequences of the mutation in rat, human and frog cells. Additionally, they have attempted to clarify the complex biochemical pathways behind it.

It will now take further research to determine whether these findings will have a direct application to most migraine sufferers. Drug development is a long process, and few drugs make it all the way through to being a successful human treatment.