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May 2, 2013

Migraines Linked to Gene Mutation

  • A genetic mutation has been found that is strongly associated with a typical form of migraine, researchers say. The team, led by a Howard Hughes Medical Institute investigator at the University of California, San Francisco, linked the mutation with evidence of migraine in humans, in a mouse model of migraine and in cell culture in the laboratory. The mutation is in the gene known as casein kinase I delta (CKIdelta).

    “This is the first gene in which mutations have been shown to cause a very typical form of migraine,” says senior investigator Louis J. Ptácek, M.D., an investigator at HHMI and a professor of neurology at UCSF. “It’s our initial glimpse into a black box that we don’t yet understand.”

    Migraines are characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. In the study, the scientists first analyzed the genetics of two families in which migraine was common, and found that a significant proportion of migraine sufferers in the families either had the mutation or were the offspring of a mutation carrier.

    In the laboratory, the team demonstrated that the mutation reduces the production of the casein kinase I delta enzyme, which carries out a number of vital functions in the brain and body. “This tells us that the mutation has real biochemical consequences,” says Dr. Ptácek.

    The scientists then investigated the effects of the mutation in a line of mice that carry it. “Obviously, we can’t measure headache in a mouse,” Dr. Ptácek notes, “but there are other things that go along with migraine that we can measure.” Pain threshold, explains Dr. Ptácek, can be lowered in mice by the administration of nitroglycerin. The mutant mice had a significantly lower threshold for nitroglycerin-induced peripheral pain than did normal mice.

    Another piece of evidence was cortical-spreading depression (CSD), a wave of electrical “silence” in the brain that follows electrical stimulation, spreading out from the point of stimulation in a predictable pattern. The researchers found that the mutant mice had a significantly lower electrical threshold for the induction of CSD.

    The CSD experiments are “especially intriguing,” says Dr. Ptácek, because it is known that CSD spreads through the brain at 3 millimeters per minute. “Functional brain imaging has shown that, in the occipital lobes of people with migraine aura, changes in blood flow spread at the same rate.”

    Finally, Dr. Ptácek and his team found that astrocytes from the brains of mutant mice showed increased calcium signaling compared with astrocytes from the brains of normal mice. “This is significant because we think astrocyte functioning is very, very relevant to migraine,” says Dr. Ptácek. “This is an enzyme, and so it modifies proteins. The question is, which protein or proteins does it modify that is relevant to migraine? How does it change astrocyte activity?”

    The research “puts us one step closer to understanding the molecular pathway to pain in migraine,” he says. “And, as we come to a clearer understanding, we can start thinking about better therapies. Certain molecules might be targets for new drugs.” There are good drugs now, says Dr. Ptácek, “but they only help some patients, some of the time. The need for better treatments is huge.”

    The CKIdelta mutation is “far from the only mutation likely to be associated with migraine,” Dr. Ptácek cautions. “There are likely several, in different combinations in different people. This is simply the first one we’ve found.”

    The study appears on the cover of the May 1 issue of Science Translational Medicine. The article is called “Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase”.


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