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Keywords:

  • migraine;
  • ion channel;
  • potassium channel;
  • genetics;
  • KCNK18;
  • KCNG4

Background.— Migraine is a common form of headache affecting about 12% of the population. Genetic studies in the rare form of familial hemiplegic migraine have identified mutations in 3 genes (CACNA1A, ATP1A2, and SCN1A) encoding proteins involved in ion homeostasis and suggesting that other such genes may be involved in the more common forms of migraine.

Objectives.— To test this proposition, the coding regions of 150 brain-expressed genes involved in ion homeostasis (ion channels, transporters, exchangers, and accessory subunits) were systematically screened to identify DNA variants in a group of 110 migraine probands and 250 control samples.

Methods.— DNA variants were analyzed using a number of complementary in silico approaches.

Results.— Several genes encoding potassium channels, including KCNK18, KCNG4, and KCNAB3, were identified as potentially linked to migraine. In situ hybridization studies of the mouse Kcnk18 ortholog show that it is developmentally expressed in the trigeminal and dorsal root ganglia, further supporting the involvement of this gene in migraine pathogenesis.

Conclusions.— Our study is the first to link variations in these K+ channel genes to migraine, thus expanding on the view of migraine as a channelopathy and providing potential molecular targets for further study and therapeutic applications.