The role of genes in migraine

In recent years significant progress has been made in our understanding of the causes of migraine as well as new ideas for treatments. In 2010 a gene called TRESK was found to be directly linked to a common type of migraine.  This was an important step in working out why some people are predisposed to suffering with this condition. Here, we describe the background to this finding and explain what it means for migraine sufferers.

The role of genes in migraine

Our genes passed down from our parents are a key part of determining who we are – what we look like, how long we might live and the diseases we might suffer. For some disorders, genes play a particularly important role and migraine is a good example. We know this from clinical practice because we often see migraine running in families, and this is confirmed in formal scientific studies. In most cases a single gene defect or mutation probably does not cause migraine, instead it results from several different genes all coming together. However, even if you have many of the predisposing genes, you still might not get migraine – in addition influence by the environment, such as by stress or hormonal changes, is often necessary. We call conditions such as migraine, where genes and environment interact, complex genetic disorders.

Finding the genes for migraine

Complex genetic disorders are hard to understand because they are too complex! Many genes combining together differently in different people means picking out the genes responsible for a problem is very hard. There are rare examples where a single gene defect is severe enough to cause migraine all by itself. These conditions are worth studying because they can tell us a lot about how more common forms of migraine come about. We find these genes by looking at the DNA of large families where migraine is passed down at every generation. Familial hemiplegic migraine is exactly this type of ‘simple’ genetic disorder where sufferers experience limb weakness during a migraine attack. The weakness is part of the migraine aura and is more familiar to many migraineurs as the visual symptoms they experience such as flashing lights or loss of vision. Four different genes have now been found, each, on its own, capable of causing hemiplegic migraine. All of these genes produce proteins, which are involved in the movement of salts such as calcium, sodium and potassium in or out of our nerve cells.

Why are ion channel genes so important for migraine?

Genes involved in moving salts are called ion channel or transporter genes. They are important because they can determine how easily activated our nerves are and how they might react when stimulated. In recent years, it has become very clear that migraine is mainly a disorder of the nervous system. It is not, as had been thought for a long time, a disorder of blood vessels or a problem with inflammation. A very consistent finding in migraineurs is an increased responsiveness of the nervous system to stimulation, even between attacks. Since ion channels determine nerve excitability, we can immediately see how defects in

their genes could also explain why migraine sufferers’ nervous systems are more excitable. However, despite our looking very hard, mutations in the genes causing familial hemiplegic migraine are not usually found in more common types of migraine.

How TRESK was identified as a cause for migraine

Based on the idea that ion channels and transporters are important for migraine, some studies have specifically examined these genes in migraine sufferers.

TRESK was identified in this kind of study. The DNA was extracted from blood samples of individuals suffering with migraine with aura and also present in several generations of their family. Importantly, the type of attacks they experienced was very typical of the migraine with aura with disturbances of vision that many migraine sufferers experience.

Ion channel genes were then carefully searched for mutations using a technique called DNA sequencing. A defective mutation was found in the gene for TRESK in one individual having migraine with aura and later when tested, in all this person’s family members. This mutation has not been found in anyone outside this family. TRESK is a potassium ion channel – it allows potassium salts to leave cells. The mutation that was identified disrupts the normal function of this ion channel.

The next major discovery was that TRESK is abundant in the main sensory relay station of the brain – the trigeminal ganglion. The trigeminal ganglion is a very important site just outside the brain and is thought to have an important role in the migraine pain.

How TRESK might be involved in migraine

The experiments to show exactly how TRESK mutations might predispose to migraine still need to be performed. Nevertheless we can already begin to get an idea of what might be happening based on what TRESK normally does. TRESK is an ion channel, which usually controls how responsive a nerve cell is to stimulation.

With this mutation however, the channel can no longer work as well and so we expect nerve cells to show a greater sensitivity to stimulation.

The trigeminal ganglion is where the sensory (feeling) and pain nerves supplying the head and brain linings originate. If TRESK is not working properly in nerve cells in the trigeminal ganglion then it is possible these nerves are also more sensitive and perhaps are more liable to set off or sustain a migraine attack.

Do I have mutations in the TRESK gene?

The simple answer is almost certainly, no. The mutation so far has only been found in one family despite our looking at the DNA of many other migraine sufferers. It is not unusual for these types of mutations to be rare and it is likely that the vast majority of migraine sufferers will not have a mutation in the TRESK gene. With future research, less severe defects in TRESK may be found as a common mechanism for migraine and this may be through subtle alterations in the TRESK gene or other genes and proteins that interact with TRESK.

Will this lead to better treatments?

TRESK is an important ion channel in the trigeminal ganglion. If drugs can be found to increase TRESK activity, then this may reduce the sensitivity of these nerve cells – which might then reduce the likelihood of migraine. So new migraine treatments could be developed based on these discoveries. However drug discovery and development is a long process and drugs need to be found which not only work but are also safe.

Written by Dr Zameel Cader and Professor Peter J Goadsby. 2011