Jonathan Hardy, BYU
PROVO — After suffering intense migraines for years as a child, Emily Bates decided in high school that she would dedicate herself to searching for the cause of her illness.
K. C. Brennan has long sought the same thing, hoping to find a medication that might finally help ailing patients afflicted by the mysterious disorder.
Today, both are one step closer to their goal.
Bates, a BYU professor, and Brennan, an assistant professor at the University of Utah, are two of the three lead researchers who found a genetic cause for migraines. The team identified two families with similar genetic mutations that resulted in migraines and, after testing the mutated gene in mice, established a link that could nudge research toward effective medications for migraines, which afflict about 12 percent of Americans.
While this particular mutation is rare — a survey of 2,700 unrelated individuals failed to turn up even a single instance of the disordered gene — Brennan said the location of the mutation, and the normalcy of the symptoms experience by the families in the study, suggest this study has implications for the majority of migraine sufferers.
The affected gene is responsible for a wide variety of basic functions in the cell, making it a sort of "housekeeping" gene, Brennan said. Unlike other genes identified in similar migraine studies, which generally involved severe or unusual forms of the disorder, this suspect is much more likely to hit on more common causes of migraine.
The gene implicates two interesting accomplices for future research. In cultures of brain cells with the mutated genes, neurons appeared completely normal, but astrocytes, a middle-man type of cell in the brain, exhibited unusual behaviors. These cells are responsible for removing waste and extra neural transmitters, and for communicating the neurons' needs to blood vessels. The mutated astrocytes may make blood vessels in the brain hyper-responsive to brain activity, which could result in migraine pain, Brennan said.
"Migraine is, if you will, a disorder of housekeeping in the brain," he said. "The suspect here might be what links other cells together."
The gene is also responsible for the coding of a protein that interacts with estrogen receptors. This could explain why women, who account for two-thirds of all migraine sufferers, are much more susceptible to the disorder.
Leads like this are a rare find for migraine researchers, Brennan said. The large population of those who suffer migraines makes sifting through common genes among individuals difficult. Their study, however, featured a relatively small sample size. The two families involved had rare but similar mutations that resulted in identical symptoms — migraines and an unusual sleep disorder that caused those with the syndrome to fall asleep as early as 7 p.m., and wake up by 4 a.m.
The mutation also followed a dominant inheritance pattern in both families, making the mutated genes much easier to identify.
The researchers genetically engineered mice to carry a similar mutation, and began tests to determine whether the altered gene would result in migraine-like symptoms in other mammals. Brennan, who studies migraine auras, the fuzzy lights and vision loss, that accompany migraines in some individuals, looked for comparable brain activity in the mice.
Meanwhile, Bates, who suffered migraines as a child, developed a novel technique for detecting migraines' characteristic pain and sensitivity in mice. Mice with the mutation, and some without, were dosed with a medication known to reliably induce migraine, and were then exposed to a form of mild stimuli — either a small, hairlike fiber, or a warm light — that was placed below the mouse's paw. If the mouse quickly moved its paw away from the fiber or the light, researchers could deduce the mouse was experiencing the heightened sensitivity seen in humans with migraines.
Both tests suggested the mutated gene induced migraines, or something similar, in mice, further solidifying the link between the mutated gene and migraines in humans.
The results are especially encouraging for Bates, who decided in high school that she would dedicate her career to studying migraines.
"I just wanted to figure out what was happening to me," she said, "because the doctors weren't able to explain it and had no medication to offer."
The condition is also frustrating to doctors, who often find they have nothing to offer patients who come to them seeking help for migraines, Brennan said. This study, however, suggests that could change in the future.
"This gives me hope that we've got something to follow," Brennan said.
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