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An investigation of the involvement of methylation in the parhogenesis of mental diseases by differential genomic analyses of monozygotic twins discordant for the diseases.

通过对疾病不一致的同卵双胞胎进行差异基因组分析，研究甲基化在精神疾病单发中的作用。

基本信息

批准号：
13307027
负责人：
OKAZAKI Yuji
金额：
$ 33.28万
依托单位：
Mie University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

(1) Methylation and schizophreniaTotal me ethylated cytosine volumes in leucocytes were measured using HPLC and compared between patients with schizophrenia and age and sex matched normal controls. Leucocytes from male patients with schizophrenia contained significantly less total me ethylated cytosine than those from normal controls. The difference was observed especially in the young patients (<35 years old). There was no significant difference for female patients. Two Human endogenous retrovirus (HERV) that retain the transcriptional activity which is inhibited by methylation were located on chromosome 1q21-q22 and 22q12 which were susceptible loci repeatedly observed in the linkage study of schizophrenia. These suggest the involvement of methylation in the pathogenesis of schizophrenia(2) Differential genomic scans of discordant monozygotic twinsFluorescent representational genomic profiling (FRGP) was applied to DNAs from monozygotic twins discordant for schizophrenia, bipolar disorder, autism and narcolepsy. Discordant spots containing discordant DNA fragments between affected and non-affected twins from the monozygotic twins from autism, schizophrenia and bipolar disorder. Two candidate genes (4p14, 12q24.11) for autism, 1gnee (6q13) and 1 gene (7q31) were implicated by the direct cloning of the spots. Furthermore, the difference of an autism gene was revealed due to its different methylation status in the promoter region.(3) The discovery of bipolar disorder susceptibility gene, XBP1DNA Microarray analysis of lymphoblasted cells from two monozygotic twins discordant for bipolar disorder revealed lower expression of XBP1 and GRP78 genes that involved in the lowered endoplasmic reticulum (ER) stress. A polymorphism (-116 G/C) in the promoter region of XBP1 was responsible for lowered expression. The involvement of methylation in the expression of XBP1 is a next focus

(1)用高效液相色谱法测定了精神分裂症患者和年龄、性别相匹配的正常人白细胞中甲基化胞嘧啶的总量。男性精神分裂症患者的白细胞中甲基化胞嘧啶的总量明显低于正常对照组。尤其是在年轻患者（<35岁）中观察到差异。女性患者无显著差异。在精神分裂症连锁研究中反复观察到的染色体1 q21-q22和22 q12上，发现了两个具有转录活性的人类内源性逆转录病毒（HERV），其转录活性被甲基化抑制。（2）单卵双生子基因组差异扫描荧光代表性基因组分析（FRGP）应用于精神分裂症、双相情感障碍、孤独症和嗜睡症单卵双生子基因组差异分析。自闭症、精神分裂症和双相情感障碍的单卵双胞胎中受影响和未受影响的双胞胎之间含有不一致DNA片段的不一致斑点。通过直接克隆获得了2个与孤独症相关的候选基因（4p 14，12q24.11），即1gnee（6 q13）和1个基因（7 q31）。此外，自闭症基因的差异是由于其启动子区域的不同甲基化状态而揭示的。(3)双相情感障碍易感基因XBP 1DNA微阵列分析发现，来自两个双相情感障碍不一致的单卵双胞胎的淋巴母细胞的XBP 1和GRP 78基因表达降低，参与降低内质网（ER）应激。XBP 1基因启动子区-116 G/C多态性是导致其表达降低的原因。甲基化参与XBP 1的表达是下一个焦点