Mutations Reveal Clues to Migraines

Worldwide, 15 to 20 percent of people suffer from migraines—excruciating headaches often presaged by dramatic sensations, or “auras.” By studying a rare inherited form of migraine, researchers at Vanderbilt University Medical Center have found clues to the biological basis of the debilitating disorder.

In the July 15, 2008, edition of the Proceedings of the National Academy of Sciences, Dr. Alfred George Jr. and colleagues reported that genetic mutations linked to this rare form of familial migraine alter the function of sodium channels—protein “tunnels” through brain-cell membranes involved in the electrical conduction of nerve impulses.

The findings identify cellular events that may prompt migraines—specifically, the aura that precedes them—and suggest that medications targeting sodium channels might warrant a closer look as potential treatments for some forms of migraine.

George and colleagues investigated the physiological basis of a severe, inherited form of migraine called “familial hemiplegic migraine type-3” (FHM3). The aura associated with FHM3 often includes a transient weakness or paralysis of one side of the body.

FHM3 is caused by mutations in a sodium-channel gene, SCN1A. Researchers in Europe had identified three mutations associated with the condition and contacted George about studying the cellular effects of these mutations.

“We were already studying this gene, SCN1A, in genetic forms of epilepsy,” says George, who is the Grant W. Liddle Professor of Medicine, professor of pharmacology, director of the Division of Genetic Medicine, and director of the Institute of Integrative Genomics. “This was a great opportunity to investigate the physiology of SCN1A mutants linked to another episodic neurological disorder.”

George and colleagues genetically inserted the mutant sodium channels into cultured human cells and recorded the cells’ electrical properties—the key function modulated by sodium channels.


Dr. Alfred George, left, and Kris Kahlig are uncovering clues to the
Dr. Alfred George, left, and Kris Kahlig are uncovering clues to the

One mutant failed to generate any measurable current, indicating that this mutant caused a complete loss of function of the sodium channel. The two other mutants “worked as sodium channels but were dysfunctional,” George says. “They didn’t operate normally.”


The mutations affected the opening and closing of the channel, a phenomenon known as “gating.” Under normal situations, sodium channels are usually closed but open briefly to allow sodium to flow into the cell, which helps generate the electrical current conducted by the cell.

“These dysfunctional sodium channels tend to stay open too long, as if the gating mechanism is stuck,” says George. “This problem may predispose neurons to fire more frequently.”

The enhanced predisposition to nerve-cell firing may be the spark that initiates the aura. “The aura has been linked to a brain phenomenon known as ‘cortical-spreading depression,’ which is essentially a wave of inexcitability that travels across the surface of the cortex,” George explains.

“The dysfunctional channels probably aren’t directly causing the headache. They’re likely involved in causing cortical-spreading depression, which then triggers other events ultimately culminating in the severe headache.”

Although FHM3 is a rare form of migraine, the findings open up the possibility that more common types of migraine might involve dysfunctional sodium channels. The results also suggest a link between migraine and epilepsy, which often occur together.

“There’s been evidence of some connection between migraine and epilepsy, but exactly how they’re related is not clear,” George says. “Now there’s a gene involved in both. So maybe what we’ve learned here is that a common genetic basis for epilepsy and migraine can exist in some people.”

Vanderbilt co-authors included Kristopher Kahlig and Thomas Rhodes. Their work was supported by the National Institutes of Health and the Epilepsy Foundation.

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