1. ¹Division of Protein Metabolism, Institute for Protein Research, Osaka University, Osaka, Japan
2. ²Department of Psychophysiology, National Center of Neurology and Psychiatry (NCNP), Chiba, Japan
3. ³Musashi Hospital, NCNP, Tokyo, Japan
4. ⁴Department of Psychiatry, Akita University School of Medicine, Akita, Japan
5. ⁵Department of Psychiatry, Juntendo University, School of Medicine, Tokyo, Japan
6. ⁶Kohnodai Hospital, NCNP, Chiba, Japan
7. ⁷Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan
8. ⁸Department of Neuropsychiatry, Kyorin University, School of Medicine, Tokyo, Japan
9. ⁹Department of Psychiatry, Shiga University of Medical Science, Shiga, Japan
10. ¹⁰Department of Neuropsychiatry, Saitama Medical School, Saitama, Japan
11. ¹¹Project Research Division in Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan

Correspondence: Dr T Ebisawa, Department of Neuropsychiatry, Saitama Medical School, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-0495, Japan. Tel: +81 492 76 1213; Fax: +81 492 76 1622; E-mail: tebisawa@saitama-med.ac.jp

Received 12 August 2003; Revised 9 April 2004; Accepted 12 May 2004; Published online 9 June 2004.

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 (CKI), which phosphorylates clock proteins and plays a pivotal role in the circadian clock. To determine whether variations in CKI 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 CKI 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 CKI. 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 CKI with the S408N variation was 1.8-fold more active than wild-type CKI. These results indicate that the N408 allele in CKI plays a protective role in the development of DSPS and N-24 through alteration of the enzyme activity.