Migraine Gene Found By Scientist Inspired By Her Own Illness

Date: May-02-2013A scientist who was plagued by migraines as a teenager has identified a gene mutation that makes people more susceptible to the
condition. She and her colleagues write about their findings online this week in Science Translational Medicine.

As a teenager, Emily Bates was a keen athlete and student who hated not knowing when the next migraine would strike. The condition interfered
with her studies, and ability to practise and compete as an athlete.

It was this personal experience of migraine that inspired Bates, now a chemistry professor at Brigham Young University in the US, to become a
scientist and research the illness.

"I had migraines really frequently and severely," she says in a statement.

"I would lose my vision, vomit uncontrollably - it would wipe out an entire day. I decided then as a high school student that I was going to work on
migraines, that I was going to figure them out and help find a cure," she adds.

Migraine is not a simple condition, there are various forms and symptoms, usually characterized by severe headache and often accompanied by
nausea, vomiting, and light sensitivity. Previous studies have already pinpointed some genetic causes.

For instance, in 2011, scientists revealed how they found three genes linked
to an increased risk for migraine headache in the general population, while in 2012, another group reported finding four new genes that predispose people to migraine without aura.

Bates' migraines eventually stopped, but she continued on her mission. She got a PhD in genetics from Harvard and then joined a team of
geneticists led by senior author Louis Ptáček at the University of California San Francisco (UCSF) medical school, where the bulk of the work on this
study was done.

In the study paper, Bates and colleagues describe working with two families that appeared to have a dominantly inherited form of the
condition.

After searching for genetic mutations that were common to both families, they found one that affects the production of a protein called casein
kinase delta. This was present in a significant proportion of the migraine sufferers in the two families, or their offspring.

To confirm that this was not a coincidence, Bates designed an experiment that would show whether the same mutations would cause migraine
symptoms in mice.

Obviously you can't measure headaches in mice, but you can measure changes in sensitivity to stimuli. One way to do this is to administer
nitroglycerin, which lowers their pain threshold.

They worked with two groups of mice, one genetically engineered to have the new-found migraine mutation and the other were normal lab
mice.

They found that the mutant mice had a significantly lower threshold for nitroglycerin-induced sensitivity than the normal mice.

"All sensations become amplified with migraines, including touch, heat, sound and light," says Bates.

She and her colleagues tested this heightened sensitivity in the mice in very subtle ways, such as using the warmth of a tiny light and the pressure
of a single hair-like filament.

A less common form of migraine is migraine with aura, where before the headache sets in, the person experiences strange symptoms such as
dizziness, ringing in the ears, seeing zigzag lines, and increased light sensitivity.

Bates and colleagues found that their migraine mice also showed a reduced threshold for induction of cortical spreading depression (CSD), a wave
of electrical silence in the brain that follows electrical stimulation.

CSD has been proposed as a surrogate way of testing for migraine with aura because is spreads through the brain at the same rate as the changes
in blood flow rate seen in brain imaging of people experiencing migraine with aura.

And in a final set of tests, the team found that astrocytes (star-shaped cells that provide essential support to brain cells) in the brains of the
mutant mice showed increased calcium signalling compared with those of normal mice.

Ptáček believes astrocyte functioning is very relevant to migraine.

Bates says discovering the link to the gene mutation is a "molecular clue" and now they "can try to figure out
what this specific protein affects in the body and how that is involved with migraines."

Ptáček says "as we come to a clearer understanding, we can start thinking about better therapies. Certain molecules might be targets for new
drugs."

There are already some good drugs for migraine, but they don't work for everyone.

"The need for better treatments is huge," says Ptáček.

Unfortunately there aren't many scientists working on migraine research, says Bates, who suggests it's because the condition is very complex and
unpredictable.

Nearly 12% of Americans experience at least one migraine each year, and women are three times more likely to have them than men.

Written by Catharine Paddock PhD

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