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Identification of genes associated with susceptibility to schizophrenia

鉴定与精神分裂症易感性相关的基因

基本信息

批准号：
06454606
负责人：
HAMAGUCHI Hideo
金额：
$ 3.78万
依托单位：
University of Tsukuba
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

Dopamine D2 receptor variant, D2Cys311, a missense mutation changing serine 311 in the third intracellular loop to cysteine, and wild type, D2Ser311, were expressed stably in Chinese Ovary Cells and dopamine-induced sequestration was examined by measuring the loss of binding of the hydrophilic ligand sulpiride from the cell surface. A D2S (the short form isoform of dopamine D2 receptor) receptor variant containing Cys311 was found to be sequestered to a significantly smaller extent compared to wild-type D2S receptors, though sequestration of D2L (the long form isoform of D2 receptor) receptors was not so apparent as that of D2S receptors and no apparent difference was found between D2Ser311 and D2Sys311 in D2L receptors.5' flanking region of the dopamine D2 receptor gene was examined to search for nucleotide variants. Two common polymorphic sites, A-584G and Ins/DelG-486, were found. Bmax values for spiperone binding in the putamen were not significantly different between postmortem brains with G-584 and those without it. Each allele frequency of A-584G polymorphism was not significantly different between schizophrenics and controls. Bmax values for spiperone binding in the putamen were marginally significantly higher in postmortem brains with the Ins allele (p<0.03) than in those without it. The Ins allele frequency was significantly frequent in schizophrenics whose age of onset younger than 35 than in controls (p<0.008). These results suggest that some variants in the dopamine D2 receptor gene are involved in susceptibility to some types of schizophrenia.

多巴胺D2受体变异体D2Cys 311和野生型D2 Ser 311在中国人卵巢细胞中稳定表达，并通过测量细胞表面亲水性配体舒必利结合的损失来检查多巴胺诱导的螯合作用。D2S发现与野生型D2 S受体相比，含有Cys 311的多巴胺D2受体（多巴胺D2受体的短型同种型）受体变体的螯合程度显著更小，尽管D2 L的螯合（D2受体的长型同种型）在D2 L受体中，D2 Ser 311和D2 Sys 311的5 '侧翼区没有明显差异。检测多巴胺D2受体基因以寻找核苷酸变体。结果发现两个常见的多态性位点A-584 G和Ins/DelG-486，有和无G-584的脑组织壳核螺哌隆结合Bmax值无显著差异，A-584 G多态性各等位基因频率在精神分裂症组和对照组间无显著差异。在死后脑组织中，具有Ins等位基因的壳核螺哌隆结合的Bmax值略高于不具有Ins等位基因的壳核螺哌隆结合的Bmax值（p<0.03），而Ins等位基因频率在发病年龄小于35岁的精神分裂症患者中显著高于对照组（p<0.008）。这些结果表明，多巴胺D2受体基因的某些变异与某些类型的精神分裂症的易感性有关。