Research ArticleMigraine

Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

Science Translational Medicine  01 May 2013:
Vol. 5, Issue 183, pp. 183ra56
DOI: 10.1126/scitranslmed.3005784

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The Pain of Sleep

If you have experienced the excruciating pain of a migraine, chances are that some of your relatives have too. Despite this clear heritability, the genes that transfer this disease from generation to generation are known for only a few specialized types of migraine. While studying families with a sleep disorder called familial advanced sleep phase syndrome, Brennan et al. may have found another one of these genes. They discovered that mutations in a gene (casein kinase Iδ) that cause the sleep problems also seemed to cause migraine. In two families, everyone who carried the sleep-disrupting casein kinase Iδ mutation (each family had a slightly different mutation) also suffered from migraines, although there were several members who had migraines but not the mutation or the sleep disorder.

To see whether the casein kinase mutation might really be contributing to migraine, the authors took their experiments in vitro and into mice. In a test of whether the two mutations affected casein kinase Iδ enzyme activity, the authors found that neither mutated form of casein kinase Iδ was able to properly phosphorylate its substrate. But does this weakened enzyme activity cause headaches? To see, the authors generated mice carrying mutated casein kinase Iδ. Because migraine is a pain syndrome, patients’ reports of their pain are important for characterizing the disease. Although mice cannot tell us if they hurt, the authors found some mouse phenotypes that suggest they are experiencing a migraine-like disorder: When treated with nitroglycerin (a migraine trigger), the mice were more sensitive to pain, just as humans are. The mice also more easily exhibited cortical spreading depression (a wave of ionic disturbance thought to be similar to migraine aura), and their arteries were abnormally dilated during the spreading depression—both phenomena similar to those seen during migraine in humans.

The suggestive segregation of the casein kinase mutations in migraine patients and the ability of the same mutations to produce migraine-like phenomena in mice together make a strong case that casein kinase mutations can contribute to migraine, adding another gene to the small list associated with this debilitating headache syndrome.