Genetic Complexity and Modifiers of Hirschsprung Disease

先天性巨结肠症的遗传复杂性和修饰因素

• 批准号: 6731091
• 负责人: E Michelle SOUTHARD-SMITH
• 金额: $ 35.06万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731091
• 关键词: autonomic ganglion; congenital megacolon; developmental neurobiology; embryogenesis; gastrointestinal motility /pressure; gene interaction; genetic mapping; genetic polymorphism; genetic strain; genetic susceptibility; laboratory mouse; mammalian embryology; neurogenetics; neuroregulation

DESCRIPTION (provided by applicant): Hirschsprung disease (HSCR) is a complex genetic disorder that gives rise to absence of intrinsic ganglia in the distal intestine and consequently produces gastrointestinal dysmotility. Mutations in any one of several genes can give rise to the intestinal aganglionosis that is the hallmark of this disease. Incomplete penetrance and variable expressivity of the neural crest (NC) defects exhibited by family members carrying identical gene mutations suggests that multiple genes modulate HSCR severity. Mouse models of HSCR have been extremely valuable for identifying genes that participate in pathogenesis of enteric nervous system (ENS) defects. Genetic and embryonic analysis of the mouse mutant Sox10Dom has defined a role for this transcription factor in development of the ENS. Our analysis of Sox10Dom mice in F1 hybrid and inbred strains demonstrates that genetic background impacts severity of intestinal aganglionosis. The phenotypic variation we observe mimics that seen in human HSCR sibs and suggests that modifier loci influence development of Sox10 derivatives in mouse and man. In the proposed experiments we will test the hypothesis that gene interactions between loci impact ENS development. Congenic lines of Sox10Dom mice will be used to define the timing and effect of genetic background on the enteric NC. Specifically we will evaluate survival, proliferation, and migration of enteric NC in embryos from Sox10Dom congenic lines. To identify the genes responsible for the phenotypic variation in the Sox10Dom HSCR model we will evaluate association between alleles at candidate modifier loci and severity of intestinal aganglionosis in Sox10Dom animals maintained on an F1 hybrid background. Potential gene interactions will be validated in vivo by examining severity of aganglionosis in crosses between Sox10Dom and mutants at candidate modifier loci. Our preliminary analysis has already identified a highly significant interaction between Sox10 and EdnrB and we have identified Sox10 consensus binding sites in EdnrB flanking regions. To investigate the biological interaction between Sox10 and EdnrB we will identify sequence variants at the EdnrB locus. The functional effects of polymorphisms on levels of EdnrB mRNA and function will be evaluated in neural tube (NT) and enteric ganglia cultures from our congenic lines. These experiments are part of a unified strategy to define the mechanisms of gene interaction that participate in development and pathogenesis of the ENS.

描述（由申请人提供）：先天性巨结肠（HSCR）是一种复杂的 一种导致远端内神经节缺失的遗传性疾病 肠，并因此产生胃肠动力障碍。突变 几种基因中的任何一种都可以引起肠道无神经节细胞症， 这种疾病的标志。不完全的表达和可变的表达 的神经嵴（NC）缺陷表现出的家庭成员携带相同的 基因突变表明多种基因调节HSCR的严重程度。鼠标 HSCR模型对于鉴定 参与肠神经系统（ENS）缺陷的发病机制。遗传 对小鼠突变体Sox10Dom的胚胎分析已经确定了这一作用， 我们对Sox10Dom小鼠的分析表明， 在F1杂种和近交系中表明遗传背景影响 肠无神经节细胞症的严重程度。我们观察到的表型变异 模拟人类HSCR同胞中所见，并表明修饰基因座影响 Sox10衍生物在小鼠和人中的开发。 我们将检验基因座之间的基因相互作用影响ENS的假设， 发展将使用Sox10Dom小鼠的同源系来确定时间 以及遗传背景对肠道NC的影响。具体来说，我们将 评估胚胎中肠NC的存活、增殖和迁移， Sox10Dom同源系。为了确定导致表型的基因， 在Sox10Dom HSCR模型中，我们将评估 候选修饰基因座的等位基因和肠无神经节细胞症的严重程度 Sox10Dom动物维持在F1杂种背景下。潜在基因 将通过检查无神经节细胞症的严重程度在体内验证相互作用 在Sox10Dom和候选修饰基因座的突变体之间的杂交中。我们 初步分析已经确定了一个非常重要的相互作用 在Sox10和EdnrB之间，我们已经确定了Sox10的共有结合位点， EdnrB侧翼区。研究Sox 10与人胚肾细胞的生物学相互作用， 和EdnrB，我们将鉴定EdnrB基因座处的序列变体。功能 将评估多态性对EdnrB mRNA水平和功能的影响 在神经管（NT）和肠神经节培养物中。这些 实验是定义基因机制的统一策略的一部分 参与ENS发展和发病的相互作用。