Xu et al. (2005) reported a 3-generation family with autosomal dominant transmission of FASPS. Fifteen family members were interviewed for their typical work and vacation sleep-wake schedules, and 5 were identified with FASPS. In the absence of competing ... Xu et al. (2005) reported a 3-generation family with autosomal dominant transmission of FASPS. Fifteen family members were interviewed for their typical work and vacation sleep-wake schedules, and 5 were identified with FASPS. In the absence of competing psychosocial demands, both the average sleep onset time (18:12 +/- 1.4 hours vs 23:24 +/- 1.1 hour) and final wake time (04:06 +/- 0.7 hour vs 08:00 +/- 1.6 hours) of these subjects were significantly earlier (p less than 0.0001) than those of the 9 unaffected family members. Affected individuals reported onset of FASPS between early childhood and the mid-teen years. Brennan et al. (2013) found that 5 of the mutation carriers with FASPS2 in the family reported by Xu et al. (2005) had migraine with or without aura. One mutation carrier who did not have FASPS also had migraine. However, 3 family members who were offspring of carriers but did not carry the mutation also had migraine. A second unrelated family also segregated FASPS and migraine with or without aura.
Xu et al. (2005) identified a thr44-to-ala mutation in the CSNK1D gene (T44A; 600864.0001) that cosegregated with the FASPS phenotype in a 3-generation family.
In affected members of a family with FASPS2, Brennan et al. (2013) ... Xu et al. (2005) identified a thr44-to-ala mutation in the CSNK1D gene (T44A; 600864.0001) that cosegregated with the FASPS phenotype in a 3-generation family. In affected members of a family with FASPS2, Brennan et al. (2013) identified a heterozygous mutation in the CSNK1D gene (H46R; 600864.0002). In vitro functional expression studies showed that the T44A mutant enzyme had significantly reduced kinase activity compared to wildtype. Transgenic mice carrying the T44A mutation were more sensitive to pain after treatment with the migraine trigger nitroglycerin, and showed a reduced threshold for cortical spreading depression, which is believed to be the physiologic analog of migraine aura, as well as greater arterial dilation during cortical spreading depression. The mutant enzyme showed decreased phosphorylation of GJA1 (121014), which is a mediator of astrocyte signaling. Astrocytes derived from mutant mice showed increased spontaneous and evoked calcium signaling, which may underlie some of the vascular changes associated with cortical spreading depression. These results suggested that decreased CSNK1D activity can contribute to the pathogenesis of migraine.