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Analysis for molecular-pathogenesis of Hirschsprung disease. As a model of multifactorial disease

先天性巨结肠症的分子发病机制分析。

基本信息

批准号：
15590289
负责人：
MAKITA Yoshio
金额：
$ 2.24万
依托单位：
Asahikawa Medical College
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

[Background] Rapid proceeding of human genome project, we got many knowledge for genetic defects of simple mendelian diseases. But simple mendelian diseases were rare diseases ; frequency was 1.25% of born infants. Now our interest goes toward common disease. Multifactorial disease occurs under influence of genetic basis and environmental status. Now we do not have a tool to understand these complicated phenomena. Simple scheme was necessary to understand multifactorial disease. Now we choose the Hirschsprung disease as model of multigenetic disease without environmental factors[Subjects and method] Hirschsprung disease is a common digestive disease in young children. Evidence was 1/5000 and predominance in male. The disease has relatively high incidence and is genetic disease without environmental factors. Hirschsprung disease is a good candidate for simple multigenetic disease. To date, extensive mutational analysis of candidate genes of Hirsch sprung disease, only 50% of patients were identified disease causative mutation. We think this disease has occurred gene and gene interactions among candidate genes (EDN3,EDNRB, SOX10 and GDNF). We applied two-combined approach, RET gene mutational analysis and haplotype based case control study.[Results] We found RET mutation in 5 cases (total 34 sporadic cases) and 1 familial case. Haplotype based case control study showed no relationship between specific haploype and disease.

[背景]随着人类基因组计划的快速进行，人们对单纯孟德尔病的遗传缺陷有了更多的认识。但单纯性孟德尔病是少见疾病，发生率为1.25%。现在我们的兴趣转向常见疾病。多因素疾病的发生受遗传基础和环境状态的影响。现在我们还没有工具来理解这些复杂的现象。简单的方案是理解多因素疾病所必需的。现在我们选择先天性巨结肠作为无环境因素的多基因疾病模型。[对象和方法]先天性巨结肠是一种儿童常见的消化系统疾病。证据为1/5000，男性占优势。该病发病率较高，是一种无环境因素的遗传病。先天性巨结肠症是简单多基因疾病的一个很好的候选对象。到目前为止，对Hirsch Sprrung病候选基因的广泛突变分析表明，只有50%的患者被确定为致病突变。我们认为该病存在基因和候选基因(EDN3、EDNRB、Sox10和GDNF)之间的相互作用。[结果]共发现5例RET突变病例(共34例)和1例家族性突变病例。基于单倍型的病例对照研究显示，特定的单倍型与疾病无关。