| 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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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1998: ¥10,100,000 (Direct Cost: ¥10,100,000)
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| Keywords | delayed sleep phase syndrome / non-24-hour sleep-wake syndrome / clock-related genes / gene polymorphisms / therapeutic strategy / 概日リズム / メラトニン受容体 / 点突然変異 / 時計遺伝子 / 睡眠覚醒障害 / 概日リズム障害 / メラニン受容体 / 遺伝子変異 / 生体時計 |
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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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