Sequencing a gene associated with migraine with aura may further the understanding of the pain pathways that trigger migraine.
WASHINGTON, DC—Rare genetic mutations may be linked to migraine with aura, according to research presented at the 53rd Annual Meeting of the American Headache Society. Investigators are hopeful that the discovery of genetic factors in a familial form of migraine with aura will lead to the development of effective treatments.
Guy Rouleau, MD, PhD, Director of the CHU Sainte-Justine Research Center and Full Professor in the Department of Medicine at the University of Montreal, and colleagues conducted a mutation screen of human ion channel genes with the aim of finding new drug targets for a range of episodic neurologic disorders.
Dr. Rouleau and his team screened 150 brain-expressed ion channel genes, including K+ channels and related subunits, exchangers and transporters, and gap junction proteins, in 368 patients with migraine, epilepsy, Tourette’s syndrome, bipolar disorder, or essential tremor. In subsequent analysis, the researchers identified and validated variants and genes involved in these episodic neurologic disorders.
Migraine Treatment Through TRESK Activation
“Twenty to 25% of migraines are preceded by aura,” Dr. Rouleau noted. “Linkage studies have identified multiple susceptibility loci for migraine with or without aura.” His goal was to determine if certain genes played a role in controlling neuronal excitability.
When the investigators focused on patients with migraine, they found 155 genetic variants that were unique or greatly enriched in migraine. “Genes showing several of these unique variants were prioritized for further genetic and biochemical validation,” Dr. Rouleau stated. They then found that rare mutations in KCNK18, which is expressed in trigeminal and dorsal root ganglia, are linked to migraine with aura.
“The TWIK-related spinal cord K+ channel [TRESK] may play a critical role in controlling hyperexcitability of trigeminal ganglia neurons,” Dr. Rouleau explained. “TRESK activation helps dampen excitability of nociceptors under conditions of stress (eg, nerve injury or inflammation) … and may help reduce the frequency or severity of migraine attacks.”
He proposed several possible TRESK activators that could potentially be used to treat migraine, including volatile anesthetics and activation of the phosphatase calcineurin. Dr. Rouleau cited previous studies that had established a connection between calcineurin inhibitors and migraine headaches and suggested that TRESK might be this link.
A Drug to Prevent Migraine?
“It may be possible to develop small compound activators of TRESK based on known structures of volatile anesthetics,” Dr. Rouleau stated. Because the trigeminal ganglion, where TRESK is expressed, is outside the blood-brain barrier, it may be more accessible to drugs, he continued. “TRESK is at the cell surface, so drugs may not need to go into cells to work. TRESK activators could be useful for the majority of migraine sufferers.”
Using this ion channel screening approach, the researchers were also able to identify several candidate genes for other neurologic disorders and two other K+ channels (KCND1 and KCNG4) that could serve as potential migraine targets.
“We may be moving toward developing a pill that would block the brain’s pain channel that reacts to stimulation and causes pain in migraine,” Dr. Rouleau concluded. “Sequencing the gene not only allows us to understand the disease, it also opens understanding of the pathways that trigger migraine pain.”
—Ariel Jones