2000 Fiscal Year Final Research Report Summary
Screening for polymorphisms of clock-related genes in circadian rhythm sleep disorders ; genetic approach to develop therapeutic strategies
| Project/Area Number |
10557089
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Psychiatric science
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| Research Institution | Saitama Medical School |
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Principal Investigator |
EBISAWA Takashi Saitama Medical School, Department of Psychiatry, Assistant Professor, 医学部, 講師 (00201369)
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| Co-Investigator(Kenkyū-buntansha) |
IWASE Toshio Saitama Medical School, Department of Psychiatry, Assistant Professor, 医学部, 助手 (80306307)
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| Project Period (FY) |
1998 – 2000
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| Keywords | delayed sleep phase syndrome / non-24-hour sleep-wake syndrome / clock-related genes / gene polymorphisms / therapeutic strategy |
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| Research Abstract |
Recent progress in molecular chronobiology has revealed that the mutations in clock-related genes alter activity rhythm in mammals. Therefore, it is likely that at least part of circadian rhythm sleep disorders in humans are genetically induced. We are in the process for analyzing those genes in patients with circadian rhythm sleep disorders.
Genomic DNA from patients and control subjects were collected at collaborating institutes in mainland, Japan. All of the coding exons were screened for polymorphisms in melatonin 1a (Mel1a) gene, 1b (Mel1b) receptor gene, and Per3 gene, using PCR-based strategies.
Two missense polymorphisms were identified both in Mel1a receptor gene and Mel1b receptor gene. The prevalence of R54W variant in Mel1a receptor gene was approximately three times more common in non-24-hour sleep-wake syndrome subjects than among control subjects, although the incidence was not significant in our study group. Both wild type and mutated melatonin receptor cDNAs were ligated into eukaryotic expression vector and expressed in COS-7 cells. Ligand binding studies revealed that the R54W receptors were expressed in smaller amounts and showed increased affinity for melatonin.
Four haplotypes, consisted of five missense polymorphisms, were identified in the Per 3 gene, one of the human homologues of the Drosophila clock gene period. The prevalence of one of the haplotypes was significantly associated with delayed sleep phase syndrome. These results indicate the involvement of the clock-related-gene polymorphisms in the pathogenesis of circadian rhythm sleep disorders. Further analysis of clock-related genes is necessary to elucidate the underlying mechanisms for pathological and physiological variations in circadian rhythmicity among individuals.
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[Publications] Takashi Ebisawa, Makoto Uchiyama, Naofumi Kajimura, Kazuo Mishima, Yuichi Kamei, Masaaki Katoh, Tsuyoshi Watanabe, Masanori Sekimoto, Kayo Shibui, Keiko Kim, Yoshinao Kudo, Yuji Ozeki, Mariko Sugishita, Ryoichi Toyoshima, Yuichi Inoue, Naoto Yamada, Takahiro Nagase, Norio Ozaki, Osamu Ohara, Norio Ishida, Masako Okawa, Kiyohisa Takahashi, and Toshio Yamauchi.: "Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome."EMBO Reports. (in press). (2001)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Masaaki Ikeda, Wangjie Yu, Momoki Hirai, Takashi Ebisawa, Sato Honma, Kazunori Yoshimura, Ken-Ichi Honma, Masahiko Nomura.: "cDNA cloning of a novel bHLH-PAS transcription factor superfamily gene, BMAL2 : Its mRNA expression, subcellular distribution, and chromosomal localization."Biochem.Biophys.Res.Commun. 275. 493-502 (2000)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Takashi Ebisawa, Makoto Uchiyama, Naofumi Kajimura, Yuichi Kamei, Kayo Shibui, Keiko Kim, Yoshinao Kudo, Toshio Iwase, Mariko Sugishita, Takako Jodoi, Masaaki Ikeda, Yuji Ozeki, Tsuyoshi Watanabe, Masanori Sekimoto, Masaaki Katoh, Naoto Yamada, Ryoichi Toyoshima, Masako Okawa, Kiyohisa Takahashi, Toshio Yamauchi.: "Genetic polymorphisms of human melatonin 1b receptor gene in circadian rhythm sleep disorders and controls."Neurosci.Lett.. 280. 29-32 (2000)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Takashi Ebisawa, Naofumi Kajimura, Makoto Uchiyama, Masaaki Katoh, Masanori Sekimoto, Tsuyoshi Watanabe, Yuji Ozeki, Masaaki Ikeda, Takako Jodoi, Mariko Sugishita, Toshio Iwase, Yuichi Kamei, Keiko Kim, Kayo Shibui, Yoshinao Kudo, Naoto Yamada, Ryoichi Toyoshima, Masako Okawa, Kiyohisa Takahashi, and Toshio Yamauchi.: "Alleic variants of human melatonin 1a receptor : function and prevalence in subjects with circadian rhythm sleep disorders."Biochem.Biophys.Res.Commun.. 262. 832-837 (1999)
Description
「研究成果報告書概要(欧文)」より
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