title: A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders.
abstract: Recent studies have shown that functional variations in clock genes, which generate circadian 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 (CKIepsilon), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKIepsilon 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 CKIepsilon 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 CKIepsilon. 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 CKIepsilon with the S408N variation was approximately 1.8-fold more active than wild-type CKIepsilon. These results indicate that the N408 allele in CKIepsilon plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.
authors.affiliation: Division of Protein Metabolism, Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Takano
authors.forename: Makoto
authors.initials: M
authors.lastname: Uchiyama
authors.forename: Naofumi
authors.initials: N
authors.lastname: Kajimura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Mishima
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kamei
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kitajima
authors.forename: Kayo
authors.initials: K
authors.lastname: Shibui
authors.forename: Masaaki
authors.initials: M
authors.lastname: Katoh
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hashimotodani
authors.forename: Toru
authors.initials: T
authors.lastname: Nakajima
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ozeki
authors.forename: Toru
authors.initials: T
authors.lastname: Hori
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamada
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Toyoshima
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Masako
authors.initials: M
authors.lastname: Okawa
authors.forename: Katsuya
authors.initials: K
authors.lastname: Nagai
authors.forename: Kiyohisa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Isojima
authors.forename: Toshio
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ebisawa
mesh_terms: D000328:Adult; D000483:Alleles; D048149:Casein Kinase 1 epsilon / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D007438:Introns / Q000235:genetics; D007700:Kinetics; D008297:Male; D020125:Mutation, Missense / Q000235:genetics*; D010766:Phosphorylation; D018807:Polymorphism, Single-Stranded Conformational; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012893:Sleep Wake Disorders / Q000235:genetics*
chemical_list: D018076:DNA, Complementary; D048149:Casein Kinase 1 epsilon