Recent studies have shown that functional variations in clock genes, which generate arcadian rhythms through interactive positive/ negative feedback loops, contribute to the development of circadian rhythm sleep disorders in humans. Another potential candidate for rhythm disorder susceptibility is casein kinase I epsilon (CKIε), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIε induce vulnerability to human circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24), we analyzed all of the coding exons of the human CKIε gene. One of the variants identified encoded an amino-acid substitution S408N, eliminating one of the putative autophosphorylation sites in the carboxyl-terminal extension of CKIε. The N408 allele was less common in both DSPS (p = 0.028) and N-24 patients (p = 0.035) compared to controls. When DSPS and N-24 subjects were combined, based on an a priori prediction of a common mechanism underlying both DSPS and N-24, the inverse association between the N408 allele and rhythm disorders was highly significant (p = 0.0067, odds ratio = 0.42, 95% confidence interval: 0.22-0.79). In vitro kinase assay revealed that CKIε with the S408N variation was ∼ 1.8-fold more active than wild-type CKIε. These results indicate that the N408 allele in CKIε plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.
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