One bad gene: Mutation that causes rare sleep disorder linked to migraines

Further study is needed to understand how this genetic pathway relates to migraines. But the finding is exciting because it most likely will shed light on all types of migraines, meaning hundreds of millions of people worldwide could benefit, according to K.C. Brennan, M.D., University of Utah assistant professor of neurology and first author of a study published May 1, 2013, in Science Translational Medicine.

"We don't get the chance very often to isolate one molecule that we're confident is related to migraines," Brennan says. "Once we understand which molecules and cells this mutation changes, we can develop drugs specifically targeted to them."

The mutation occurs when an enzyme, CKIδ, becomes impaired. CKIδ has many "housekeeping" responsibilities in the body, one of which is to help control the circadian rhythm that determines the sleep cycle. The story of how the CKIδ mutation's association with migraines was identified is one of cross-country collaboration.

In the mid-1990s a University of Vermont neurologist, Robert E. Shapiro, M.D., Ph.D., was treating a family for migraines. Shapiro recognized that along with migraines his patients showed signs of familial advanced sleep phase syndrome, a rare disorder in which people's circadian rhythm causes them to go to bed extremely early in the evening and wake up well before dawn. For example, someone might regularly go to bed at 7 p.m. and wake up at 4 a.m.

Shapiro contacted Louis J. Ptáček, M.D., a University of California, San Francisco, neurogeneticist and former U of U faculty member, a top expert in the field of sleep-related genes. Ptáček, who was collaborating with U of U sleep expert and Professor of Neurology Christopher R. Jones, M.D., Ph.D., began searching for a gene related to the sleep disorder. Jones then started identifying the characteristics of familial advanced phase sleep disorder in the Vermont family members.

"The sleep disorder was the clue that allowed us to identify the needle in the haystack -- the mutated gene," Jones says. "Migraine is so common that we could not have identified the gene based on migraine features alone."

Ptáček identified the CKIδ mutation as a cause of the sleep disorder and then contacted Andrew C. Charles, M.D., a migraine expert at the University of California, Los Angeles, to investigate a potential link between the same mutation and migraines. At the time, Brennan was a postdoctoral fellow in Charles' lab. Beginning in Charles's lab and continuing in his own lab, Brennan used advanced imaging techniques to determine that mice carrying the human CKIδ mutation were more susceptible to cortical spreading depression, a wave of electrical activity that moves through the brain preceding a migraine attack. This strongly indicated that migraines are related to the CKIδ mutation.

"Nobody would have predicted that this gene would have been relevant to migraines," he says.

While Brennan pursued his work, a post-doctoral fellow in Ptáček's lab, Emily A. Bates, Ph.D., was investigating the potential link as well. Bates, who received her undergraduate degree in biology from the U of U, is now an assistant professor of chemistry and biochemistry at Brigham Young University. She developed a test for migraine in mice using nitroglycerin, which (in addition to being used for chest pain) induces migraine in humans. Bates, a co-first author on the study, found that CKIδ mutant mice given nitroglycerin had lower pain thresholds than mice without the mutation, again indicating that the CKIδ mutation was associated with migraines.

"You can't ask a mouse if it has a headache, so we had to think creatively to find a way to study migraine in mice," Bates says. "Migraine is more than just a headache. It is a neurological disorder that affects many sensory systems, so we can measure migraine using some of the other symptoms like sensitivity to touch and heat."

After confirming the CKIδ mutation's role in migraines, the researchers found a second mutation in the CKIδ gene, which also appears to cause the headaches. This brings to six genes the total number of genes that have been isolated and found to cause migraines.

Migraines are an understudied disease, according to Brennan, and consequently have been difficult to treat, because so little is known about what causes them. All drugs currently prescribed for migraines were developed for other disorders. While these medications offer varying degrees of relief, much more is needed. Discovery of the CKIδ mutation's role in migraines offers hope for a new type of migraine drug therapy. Although it will take years to bring such drugs to market, they eventually could help many more of the estimated 12 percent of people worldwide who suffer from migraines.

"We'll have to look in much finer detail at this genetic pathway before we get to new treatments," Brennan says. "But you can't get to that point without this first step."