Migraines—pounding headaches sometimes preceded by a visual “aura,” and often coupled with vomiting, nausea, distorted vision, and hypersensitivity to sound and touch—can be highly debilitating if recurrent and prolonged. They affect millions of Americans and an estimated 10–20 percent of the global population. Yet what predisposes individuals to them is somewhat of a mystery. Though there are certainly environmental triggers, the tendency for migraines to run in families suggests that there’s likely an inherited component. Recently, a team of NIH-funded researchers, one of whom regularly suffered from migraines herself, found a gene that plays a part.
The clue that helped them to identify the rogue gene came from a family that suffers from both migraines and a rare sleep disorder, called familial advanced sleep phase syndrome. The syndrome disrupts their sleep cycle, causing family members to fall asleep early, about 7 pm, and rise around 4 am.
The researchers hunted for the cause of the sleep cycle disorder and discovered a mutation in the casein kinase I delta (CKIδ) gene. The gene produces an enzyme that’s important for brain signaling and for regulating our circadian rhythms. The particular mutation in this family seemed to reduce the activity of the CKIδ enzyme and made the researchers wonder whether the mutation was also responsible for causing migraines. To test the hypothesis, they engineered mice that carried the same mutation.
Just like the humans, the CKIδ mutant mice had disrupted sleep-wake cycles— but they were also more likely to suffer migraines compared to normal mice when given nitroglycerin. I admit, you can’t exactly ask a mouse if it has a headache. But because migraines cause a range of sensory issues, there are other physical signs the researchers could monitor in the mice. In this case, the CKIδ mutant mice became more sensitive to pain, temperature, and touch than normal mice. This mirrors the experience of many migraine sufferers.
The CKIδ mutant mice were also more vulnerable to a type of brain activity called cortical spreading depression—a wave of electrical silence that follows electrical stimulation. Brain cells called astrocytes from CKIδ mutants functioned differently from those from healthy mice, suggesting one possible mechanism through which the mutation wreaks havoc in the brain.
CKIδ affects several different proteins in the cell. The next step will be to tease apart which of these plays a role in triggering migraines. Once we understand how migraines begin, we have a better chance of identifying a new generation of drugs that can block that painful path.
Casein kinase Iδ mutations in familial migraine and advanced sleep phase. Brennan KC, Bates EA, Shapiro RE, Zyuzin J, Hallows WC, Huang Y, Lee HY, Jones CR, Fu YH, Charles AC, Ptácek LJ. Sci Transl Med. 2013 May 1;5(183):183ra56.
For More Information:
NIH support: National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences