SELECTION OF THE PRIMARY HEMOCHROMATOSIS GENE

原发性血色病基因的选择

• 批准号: 2145067
• 负责人: JEFFREY R GRUEN
• 金额: $ 11.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2145067
• 关键词: artificial chromosomes; early diagnosis; family genetics; gene expression; genetic mapping; hereditary hemochromatosis; human subject; inborn metal metabolism disorder; iron storage disorder; molecular cloning; molecular pathology; nucleic acid sequence

The overall goal of this research proposal is to identify and characterize the gene which causes the common human genetic disease, primary hemochromatosis (PH). PH is an autosomal recessive disease that causes heart and liver failure due to iron overload. It is the most common genetic disease of the liver with a prevalence of 3-8/1,000, in the North American population. Unfortunately, pre-symptomatic diagnosis of PH is difficult; and it is often mis-diagnosed. Good, inexpensive, and accessible preventative treatment is available if the diagnosis can be made before irreversible organ damage occurs. Identifying the gene will permit pre-symptomatic diagnoses. Since the biochemical alteration that leads to PH remains unknown, a positional cloning strategy is proposed for finding the PH gene. The broad location of the gene within the HLA region on chromosome 6p2l.3 was discovered by its' linkage to the HLA serological marker, HLA-A3. The specific aims of this strategy are to construct physical and genetic maps of the relevant chromosomal region and in particular to carefully define the boundaries of the PH locus; To then select out all the genes encoded within the PH locus and characterize them in terms of sequence homologies and motifs, and patterns of expression; To functionally assay the selected genes for their potential affects on cellular iron flux in-vivo; And finally to confirm PH gene candidates by mapping mutations through affected pedigrees.

本研究计划的总体目标是确定和 描述导致人类常见遗传病的基因， 原发性血色病（PH）。 PH 是一种常染色体隐性遗传病， 由于铁超载导致心脏和肝脏衰竭。 这是最 常见的肝脏遗传病，患病率为 3-8/1,000， 北美人口。 不幸的是，症状前诊断 PH 很难；并且经常被误诊。 不错，价格便宜， 如果诊断可以，则可以进行预防性治疗 在发生不可逆的器官损伤之前进行。 识别基因 将允许症状前诊断。 由于导致 PH 的生化改变仍然未知， 提出了定位克隆策略来寻找PH基因。 这 该基因在染色体 6p2l.3 的 HLA 区域内的广泛位置是 通过其与 HLA 血清学标记 HLA-A3 的连接而发现。 这 该策略的具体目标是构建物理和遗传图谱 相关染色体区域，特别是仔细定义 PH位点的边界；然后选择所有编码的基因 在 PH 位点内并根据序列同源性来表征它们 以及主题和表达模式；功能分析 选择基因对体内细胞铁通量的潜在影响； 最后通过映射突变来确认 PH 候选基因 受影响的血统。