Casein Kinase Iδ Mutations in Familial Migraine and Advanced Sleep Phase

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Id (CKI delta), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKI delta, where they caused reduced enzyme activity. Mice engineered to carry the CKI delta-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKI delta-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKI delta-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKI delta activity can contribute to the pathogenesis of migraine.