Researchers linked an abnormal gene to both a common type of migraine and a rare sleep disorder. The finding offers insight into the mechanisms of migraines and provides a new avenue for exploring treatment options.
By some estimates, more than 1 in 10 people experience intense headaches, often accompanied by pulsing or throbbing pain, known as migraines. About a third of migraine sufferers also experience visual or sensory disturbances known as migraine aura shortly before the headache begins. Although the causes of migraine are poorly understood, the condition is known to run in families, and so genes likely play a role.
In earlier NIH-funded research, Dr. Louis J. Ptácek and his colleagues identified the gene responsible for a rare sleep disorder in a Vermont family. This family also tended to suffer from migraine with aura, which is how they originally came to medical attention. The sleep disorder, called familial advanced sleep phase syndrome, drives people to be “early birds”—going to sleep and waking up unusually early each day. Nearly a decade ago, Ptácek’s team showed that affected family members had mutations in an enzyme called casein kinase Iδ (CKIδ). The enzyme plays a key role in sleep-wake cycles, or circadian rhythms, of species ranging from fruit flies to mice to people.
In the new study, a multicenter research team headed by Ptácek, who is at the University of California, San Francisco, took a closer look at the potential role of CKIδ in migraine. Their research was funded in part by NIH’s National Heart, Lung and Blood Institute (NHLBI), National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of General Medical Sciences (NIGMS). Results were published in Science Translational Medicine on May 1, 2013.
The researchers first analyzed the CKIδ gene in 14 members of the original family. Five who had identical mutations in the CKIδ gene also met the diagnostic criteria for migraine. The scientists then sequenced the gene in blood samples from 70 additional families with the rare sleep disorder. One family had a slightly different mutation in the CKIδ gene. In this family, too, all 5 members with CKIδ mutations had migraine, aura without migraine or probable migraine. In further analysis, the researchers showed that the CKIδ mutations in both families reduce the enzyme’s activity.
To investigate the gene’s effects on the body, the researchers created transgenic mice with the same CKIδ mutation found in the original family. Several tests suggested that the mutant mice had many characteristics akin to human migraines. When treated with a migraine-triggering compound, the mice showed increased sensitivity to pain. Imaging and electrophysiological studies showed waves of brain activity and brain artery dilation believed to be similar to what occurs during migraine auras in humans.
Studies by other groups have linked unusual forms of migraine to proteins involved in transporting ions across membranes. CKIδ codes for a different kind of protein that affects many biological pathways, which might now be studied as potential contributors to migraines.
“This is the first gene in which mutations have been shown to cause a very typical form of migraine,” says Ptácek. “It’s our initial glimpse into a black box that we don’t yet understand.” (Vicki Contie/National Institutes of Health)
