A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders

Atsuko Takano, Makoto Uchiyama, Naofumi Kajimura, Kazuo Mishima, Yuichi Inoue, Yuichi Kamei, Tsuyoshi Kitajima, Kayo Shibui, Masaaki Katoh, Tsuyoshi Watanabe, Yuki Hashimotodani, Toru Nakajima, Yuji Ozeki, Toru Hori, Naoto Yamada, Ryoichi Toyoshima, Norio Ozaki, Masako Okawa, Katsuya Nagai, Kiyohisa TakahashiYasushi Isojima, Toshio Yamauchi, Takashi Ebisawa

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Abstract

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.

Original languageEnglish
Pages (from-to)1901-1909
Number of pages9
JournalNeuropsychopharmacology
Volume29
Issue number10
DOIs
Publication statusPublished - 10-2004

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

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    Takano, A., Uchiyama, M., Kajimura, N., Mishima, K., Inoue, Y., Kamei, Y., Kitajima, T., Shibui, K., Katoh, M., Watanabe, T., Hashimotodani, Y., Nakajima, T., Ozeki, Y., Hori, T., Yamada, N., Toyoshima, R., Ozaki, N., Okawa, M., Nagai, K., ... Ebisawa, T. (2004). A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. Neuropsychopharmacology, 29(10), 1901-1909. https://doi.org/10.1038/sj.npp.1300503