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 language | English |
|---|---|
| Pages (from-to) | 1901-1909 |
| Number of pages | 9 |
| Journal | Neuropsychopharmacology |
| Volume | 29 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 01-10-2004 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Psychiatry and Mental health
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A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders. / Takano, Atsuko; Uchiyama, Makoto; Kajimura, Naofumi; Mishima, Kazuo; Inoue, Yuichi; Kamei, Yuichi; Kitajima, Tsuyoshi; Shibui, Kayo; Katoh, Masaaki; Watanabe, Tsuyoshi; Hashimotodani, Yuki; Nakajima, Toru; Ozeki, Yuji; Hori, Toru; Yamada, Naoto; Toyoshima, Ryoichi; Ozaki, Norio; Okawa, Masako; Nagai, Katsuya; Takahashi, Kiyohisa; Isojima, Yasushi; Yamauchi, Toshio; Ebisawa, Takashi.
In: Neuropsychopharmacology, Vol. 29, No. 10, 01.10.2004, p. 1901-1909.Research output: Contribution to journal › Article
TY - JOUR
T1 - A missense variation in human casein kinase I epsilon gene that induces functional alteration and shows an inverse association with circadian rhythm sleep disorders
AU - Takano, Atsuko
AU - Uchiyama, Makoto
AU - Kajimura, Naofumi
AU - Mishima, Kazuo
AU - Inoue, Yuichi
AU - Kamei, Yuichi
AU - Kitajima, Tsuyoshi
AU - Shibui, Kayo
AU - Katoh, Masaaki
AU - Watanabe, Tsuyoshi
AU - Hashimotodani, Yuki
AU - Nakajima, Toru
AU - Ozeki, Yuji
AU - Hori, Toru
AU - Yamada, Naoto
AU - Toyoshima, Ryoichi
AU - Ozaki, Norio
AU - Okawa, Masako
AU - Nagai, Katsuya
AU - Takahashi, Kiyohisa
AU - Isojima, Yasushi
AU - Yamauchi, Toshio
AU - Ebisawa, Takashi
PY - 2004/10/1
Y1 - 2004/10/1
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=5044224429&partnerID=8YFLogxK
U2 - 10.1038/sj.npp.1300503
DO - 10.1038/sj.npp.1300503
M3 - Article
C2 - 15187983
AN - SCOPUS:5044224429
VL - 29
SP - 1901
EP - 1909
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 10
ER -