University of Vermont

Shapiro and Colleagues Identify New and Surprising Gene for Migraine

Robert Shapiro, M.D.
Professor of Neurological Sciences Robert Shapiro. M.D., Ph.D. (Photo by Raj Chawla, UVM Medical Photography)

A team co-led by Robert E. Shapiro, M.D., Ph.D., professor of neurological sciences at the University of Vermont College of Medicine, has discovered a new gene for migraine. Migraine is a highly disabling headache disorder which affects up to 60 million Americans each year. While migraine often runs in families, only a handful of genes has so far been identified that confer some susceptibility to variants of the disease.

Shapiro and colleagues initially identified a Vermont family with multiple members who experience migraine along with an unusual sleep/waking disorder called Advanced Sleep Phase Syndrome (ASPS). ASPS is a disorder of the body’s internal clock leading to an urgent need to fall asleep too soon each evening and awaken too early each morning. In collaboration with investigators from University of California, San Francisco and University of Utah, the team found a mutation in affected members of this family in a gene called casein kinase 1 delta (CK1δ). CK1δ had previously been shown to be pivotal in body clock regulation. Joined by investigators at University of California, Los Angeles and Brigham Young University, the group subsequently found a second family whose members also had ASPS along with migraine, and who also had a mutation in CK1δ, but one that was different from the mutation found in the Vermont family. The investigators created mice with the Vermont family’s CK1δ mutation which proved to have sleep/waking behaviors comparable to ASPS, as well as multiple behavioral and physiological changes strongly associated with migraine. These migraine-like traits in the mice included heightened sensitivity to touch and temperature, and an exaggerated excitability of the brain called CSD which is known to occur during the visual phenomenon of migraine called ‘aura’.

Taken together, the studies of families with two different human CK1δ mutations and the observations of mice with one of these mutations, provide solid evidence that altered functioning of CK1δ can increase susceptibility to migraine. These findings open new lines of investigation towards an understanding of the causes of migraine and possible new therapies.

In recognition of these research studies, the American Headache Society awarded Shapiro the 2012 Harold G. Wolff Lecture Award for “the best paper on headache, head or face pain, or the nature of pain itself.” The CK1δ migraine studies were published as the cover story in the May 1, 2013 edition of the journal Science Translational Medicine, and the CK1δ ASPS studies were originally reported in the journal Nature in 2005. Other members of the team include K.C. Brennan, M.D., and Christopher R. Jones, M.D., Ph.D., of the University of Utah, Emily Bates, Ph.D., of Brigham Young University, Andrew Charles, M.D., of UCLA, and Louis J. Ptáček, M.D., and Ying-Hui Fu, Ph.D., of UCSF.

In March 2013, Shapiro was also elected as a Fellow of the American Academy of Neurology and received the Academy’s Kenneth M. Viste, Jr., M.D., Patient Advocate of the Year Award in recognition of his “sincere interest and investment in working on behalf of patients with neurologic conditions.” In 2008, Shapiro founded the Alliance for Headache Disorders Advocacy, a national alliance of 12 national and regional non-profit organizations working on behalf of Americans with disabling headache disorders. For the past six years, he has organized an annual congressional advocacy event in Washington, D.C., to urge federal attention to these disorders. The most recent event on April 9th, brought 64 people from 28 states to visit 129 congressional offices. The Headache Cooperative of New England also recently recognized Shapiro’s overall contributions with their 2013 Annual Lifetime Achievement Award.