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Mutant Gene Implicated in Migraine

Talan, Jamie

doi: 10.1097/01.NT.0000431948.16009.83
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In a transgenic mouse model for migraine, investigators were able to identify a mutation in the gene encoding casein kinase delta that had been previously associated with familial advanced sleep syndrome.

Investigators have implicated a mutation in the gene encoding casein kinase delta (CKId) — previously associated with a sleep disorder — to migraine, as well. The findings, reported in the May 1 issue of Science Translational Medicine, resulted from an initial case report and a collaboration that brought together a multicenter team led by Louis J. Ptácček, MD, a professor of neurology at the University of California, San Francisco (UCSF) and a Howard Hughes Investigator.

This story of science began with a migraine sufferer in Vermont in 1998 who also reported that she and five other family members exhibited circadian patterns consistent with familial advanced sleep phase syndrome (FASPS) — they went to bed before the sun came down and started their days earlier than most. Family members also reported migraines with aura, asthma, flushing spells, and fibromyalgia.

“When you see four or five traits segregating in a family you think about the possibility of a point mutation,” said Robert E. Shapiro, MD, PhD, professor of neurological sciences at University of Vermont College of Medicine, who saw the patient and her family.

Dr. Shapiro, co-author of the current study, called Dr. Ptácček, MD, after reading a study he published on episodic neurological disorders. Dr. Ptácček had been collecting families with advanced sleep phase disorders and had worked with of team of investigators at the University of California, Los Angeles (UCLA) that had identified CKId mutations in other families with advanced sleep phase disorders.

Dr. Ptácček called on Andrew Charles, MD, a professor of neurology and director of the headache program at the University of California, Los Angeles, to draw on his work developing migraine assays in mice. He utilized a way to look at the wave of electrical activity across the cortex, which would model the aura that precedes the migraine in many patients.

Dr. Charles and his UCLA colleagues created transgenic models and conducted behavioral assays that showed hypersensitivity to light and noise. They studied animals with and without the mutation, and used nitroglycerin — a migraine trigger — to increase hypersensitivity, and sumatriptan to prevent the sensory hypersensitivity.

They found that the mice with the mutations in the CKId gene exhibited the same type of cortical depression spreading that can be seen on brain scans of migraine patients. Mice with the human mutation had a lower threshold for cortical spreading depression. Migraine medicines increased the threshold. They also found changes in signaling patterns of astrocytes in mice with the human CKId mutation.

“There is now strong evidence that this gene plays a primary role in migraine,” said Dr. Charles. The investigators are now trying to figure out how the enzyme works to predispose to migraine.

“This may be more common than we think,” said Dr. Charles. “We are now asking our migraine patients about their sleep cycles. We know that there is a significant interaction between sleep and migraine, but we don't know whether this mutation has anything to with it. But this study tells us that there is shared machinery underlying the sleep-wake cycle and migraine.”



“The genetics is proof that these two conditions are tied to this mutation,” said Dr. Ptácček. “It is a clue to understanding migraine, the pathophysiology that is still a black box. This is an opening of a window.”

The findings, he added, “underscore the power of human genetics. A handful of genes have been identified in rare familial migraine disorders but they all involve ion channels and pumps. This is the first human migraine gene linked to an enzyme involved in phosphorylating proteins. …By studying the pathways that are changing in our animal model, we will better understand the triggers of migraine,” said Dr. Ptácček.

Clinically, patients often say that changes in sleep can bring on a migraine. “This finding strengthens the link between sleep and migraine,” he added.

The team is now working to identify specific proteins that are not being properly phosphorylated. They are interested in the gap junction protein, connexin 43. The mutant mice do not phosphorylate it, said Dr. Shapiro.

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“They did a good job of establishing that this mutation can also predispose to migraine. This is new,” said Clifford B. Saper, MD, PhD, the James Jackson Putnam professor at Harvard Medical School and chairman of the department of neurology at Beth Israel Deaconess Medical Center. “The finding suggests a possible reason that migraine and cluster headaches may be circadian. They did as good a job of establishing that as you can in a mouse, which you cannot really ask if it has migraine headaches.

“The implication for migraine is that gene mutations can increase spreading depression, which is thought to cause migraine,” said Dr. Saper. “This is nice collateral evidence to support the spreading depression theory.”

Peter Goadsby, MD, professor of neurology at the University of California, San Francisco (UCSF) and director of the UCSF Headache Program, called Dr. Ptácček “one of the great gene hunters of the era,” and said that “this is the first migraine gene identified that is involved in more common forms of migraine. That this gene turns up in sleep and migraine is key, I think. Many of our patients tell us that altering sleep patterns increases their migraines. If we can understand the biology, it would tell us a great deal about how we might go about treating migraines.”

In an accompanying editorial, Aarno Palotie, MD, PhD, a geneticist at the Wellcome Trust Genome Campus in Cambridge; Mikko Kallela, MD, PhD, at Helsinki University; and Verneri Anttila, PhD, a research fellow in medicine in the program in medical and population genetics at the Broad Institute of the Massachusetts Institute of Technology and Harvard, wrote that the key challenge in genetics is “to decipher how each puzzle piece adds to our picture of the brain's complexity and the phenotypes it manifests.” They said the findings suggest that “phenotyping can be used to illuminate potential connections between divergent phenotypes.”

The editorialists added that it “also supports the hypothesis that the brain has a limited number of ways to react to a disruption in homeostasis, and because migraine is a common secondary symptom in a range of conditions, migraine attacks appear to be one of those ways.”

The link to sleep, they wrote, “is most evident in cluster headaches, a close cousin to migraine, in which the attacks demonstrate a striking diurnal and seasonal periodicity; attacks tend to strike like clockwork within a few hours after falling asleep. Observations that too little or too much sleep can trigger a migraine headache have spurred scientists to link brain centers that control circadian and sleep mechanisms with migraine pathophysiology.”

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•. Brennan KC, Bates EA, Ptácček LJ. Casein kinase Id mutations in familial migraine and advanced sleep phase. Sci Transl Med 2013: 5 (183): 183ra56.
    •. Palotie A, Kallela M, Anttila V. Migraine headaches: Probing the brain of comorbidity. Sci Transl Med 2013: 5(183): 183fs15.
      © 2013 American Academy of Neurology