GENETIC ANALYSIS OF HIRSCHSPRUNG DISEASE

先天性巨结肠症的遗传学分析

• 批准号: 2889037
• 负责人: ARAVINDA CHAKRAVARTI
• 金额: $ 29.15万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2889037
• 关键词: clinical research; congenital megacolon; family genetics; ganglion cell; gene expression; gene interaction; gene mutation; gene targeting; genetic disorder diagnosis; genetic mapping; genetic markers; genetic models; genetic polymorphism; human genetic material tag; human population genetics; human subject; laboratory mouse; linkage disequilibriums; nucleic acid sequence; phenotype; polymerase chain reaction; single strand conformation polymorphism; tissue /cell culture; yeast two hybrid system

DESCRIPTION (Adapted from the Investigator's Abstract): Hirschsprung disease (HSCR), or aganglionic megacolon, is a relatively common, multifactorial birth defect associated with the lack of intrinsic ganglion cells in the myenteric (Auerbach) and submucosal (Meissner) plexuses in the gastrointestinal tract. Clinically, the symptoms range from mild to severe and involve aganglionosis of the transverse colon and beyond (long segment HSCR), the splenic flexure and the descending colon (short segment HSCR), or the sigmoid colon only (classic HSCR). Research support by this grant has led to the mapping and identification of three genes that lead to HSCR susceptibility, namely, the genes for the receptor tyrosine kinase RET, the endothelin receptor B (ENDRB), and its physiological ligand endothelin-3 (EDN3). In the mouse, Ece1 (endothelin converting enzyme-1) has been identified as an additional HSCR gene, and the Dom mutation, also leading to aganglionosis, is close to being cloned. HSCR in a genetically heterogeneous multifactorial disorder, and additional susceptibility genes remain to be identified. The investigators' evidence indicates that HSCR is oligogenic requiring multiple, interacting disease susceptibility alleles for phenotypic expression. This hypothesis forms the basis of this proposal. To enable the genetic dissection of HSCR the investigators propose two major studies. First, they shall pursue the genetic mapping, identification, mutation and functional analyses of additional HSCR susceptibility genes, as well as the known HSCR genes, to distinguish between the hypotheses of non-allelic heterogeneity and multigenic inheritance. Second, genetic and biochemical methods will be used to assess the importance of genetic interactions between HSCR susceptibility genes in determining phenotypic expression. In particular, using the known HSCR genes, haplotype analysis in HSCR families, penetrance analysis in mouse models of aganglionosis segregating null or missense mutations, and in vitro yeast two-hybrid assays using normal and mutant proteins will be used to test known, and identify new, susceptibility genes for interactions. The long-term objective of this renewal proposal is to understand ganglion cell differentiation and development in the gut. More generally, the aim is to develop a paradigm for the genetic and molecular analysis of complex, multifactorial human diseases.

描述（改编自调查员的摘要）：hirschsprung 疾病（HSCR）或Aganglionic Megacolon是一个相对常见的 多因素出生缺陷与缺乏固有神经节有关 骨膜（Auerbach）和粘膜粘膜（Meissner）的细胞中的细胞中的细胞 胃肠道。 在临床上，症状从轻度到重度不等 并涉及横向结肠和超越横向结肠的僵尸病（长段 HSCR），脾弯曲和下降结肠（短节hscr）或 仅乙状结肠（经典HSCR）。 这笔赠款的研究支持 导致了导致HSCR的三个基因的映射和鉴定 敏感性，即受体酪氨酸激酶RET的基因， 内皮素受体B（ENDRB）及其生理配体内皮素-3 （EDN3）。 在鼠标中，ece1（内皮素转化酶-1）已经是 被识别为额外的HSCR基因和DOM突变，也导致 Aganglionisos几乎被克隆。 HSCR在遗传上 异质多因素障碍和其他敏感性基因 仍有待确定。 调查人员的证据表明HSCR是 需要多种相互作用的疾病易感性等位基因 用于表型表达。 这个假设构成了这一点的基础 提议。 为了使HSCR的遗传解剖提出了两个主要 研究。 首先，他们应追求遗传图，识别， 其他HSCR敏感性基因的突变和功能分析AS 以及已知的HSCR基因，以区分 非平行性异质性和多基因遗传。 其次，遗传和 生化方法将用于评估遗传的重要性 HSCR敏感性基因在确定表型中的相互作用 表达。 特别是，使用已知的HSCR基因，单倍型分析 在HSCR家族中，小鼠僵尸病模型中的渗透分析 隔离无效或错义突变，以及体外酵母双杂交测定 使用正常和突变蛋白将用于测试已知，并确定 相互作用的新的，敏感的基因。 这个长期目标 更新建议是了解神经节细胞分化和 肠道发展。 更一般地，目的是开发范式 用于复杂，多因素人的遗传和分子分析 疾病。