Modifiers of Autonomic Defects in Hirschsprung Disease

先天性巨结肠症自主神经缺陷的修饰因素

• 批准号: 6475168
• 负责人: E Michelle SOUTHARD-SMITH
• 金额: $ 17.95万
• 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: 2002-06-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6475168
• 关键词: autonomic disorder; autonomic ganglion; autosomal dominant trait; behavior test; chromosome aberrations; congenital megacolon; gene interaction; genetic disorder; genetic mapping; genetic susceptibility; genotype; histochemistry /cytochemistry; inbreeding; laboratory mouse; mutant; neural crest; phenotype

DESCRIPTION (provided by the applicant): Hirschsprung disease (HSCR) is a complex genetic disorder whose primary clinical feature is the absence of intrinsic ganglia in the distal intestine. Defects of sympathetic and parasympathetic function have also been described in HSCR patients. Mutations in any one of several genes can give rise to the peripheral nervous system (PNS) deficits of this disorder. Incomplete penetrance and variable severity of PNS defects, exhibited by HSCR family members carrying identical gene mutations, suggests that genetic background modulates disease severity. Sox10dom mice display all the features of aganglionosis and extra-intestinal autonomic deficits described in HSCR patients. Sox10dom mice have been extremely valuable for defining the role of the Sox 10 transcription factor in development of neural crest (NC) that contributes to the PNS. Our analysis of Sox10dom mice in F1-hybrid and congenic strains demonstrates that genetic background impacts the severity of 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 multiple modifier loci contribute to the severity of autonomic defects in Sox10dom mutants. To systematically localize all genomic regions that modulate the severity of aganglionosis, we will perform a genome survey of Sox10dom intercross progeny. Selective genotyping of progeny at the phenotypic extremes will be performed to establish linkage to loci that influence HSCR severity. Our preliminary analyses in candidate gene approaches have identified a major modifier of enteric development, and suggest that additional modifiers contribute to the severity of NC defects. We will use extended pedigrees of Sox10dom mice for fine-mapping through intervals of candidate loci and modifiers detected by genome survey. Intervals that associate with severity of phenotype will be investigated in our pedigrees with genotyping panels, derived from mouse genome sequence that can be posted as a shared resource for the genetics community. To investigate the relevance of enteric NC modifiers to autonomic phenotypes outside the gut, we will perform a comparative analysis of sympathetic and parasympathetic function in Sox10dom congenic lines. These studies will contribute to our knowledge of the genetic basis for variation in development and disease of autonomic phenotypes in the PNS.

描述（由申请人提供）：Hirschsprung病（HSCR）是 复杂的遗传疾病，其主要临床特征是没有 远端肠道中的内在神经节。同情和 HSCR患者还描述了副交感神经功能。突变 在几个基因中，任何一个都可以引起周围神经系统 （PNS）这种疾病的缺陷。不完整的渗透率和可变的严重程度 PNS缺陷，由携带相同基因的HSCR家族成员展示 突变表明遗传背景调节疾病的严重程度。 Sox10Dom小鼠显示了伴动性的所有特征和肠外 HSCR患者描述的自主缺陷。 Sox10Dom小鼠已经 对于定义Sox 10转录因子的作用非常有价值 神经rest的发展（NC）有助于PNS。我们的分析 F1杂交和先天性菌株中的Sox10Dom小鼠证明了遗传 背景会影响Aganglionisom的严重程度。表型变化我们 观察在人类HSCR SIBS中看到的模仿，并提出修饰基因座 影响小鼠和人类中的Sox10衍生物的发展。在提议中 实验，我们将检验以下假设：多个修饰基因座有贡献 Sox10域突变体中自主缺陷的严重程度。系统地 定位所有调节剧本病严重程度的基因组区域，我们 将对SOX10DON INTROSS后代进行基因组调查。选择性 后代在表型极端的基因分型将建立 与影响HSCR严重程度的基因座联系。我们的初步分析 候选基因方法已经确定了肠的主要修饰符 开发，并建议其他修饰符有助于严重性 NC缺陷。我们将使用Sox10dom小鼠的扩展血统 通过基因组调查检测到的候选基因座和修饰符的间隔。 与表型严重程度相关的间隔将在我们的 带有基因分型面板的血统，源自小鼠基因组序列，可以 作为遗传学界的共享资源发布。调查 肠NC修饰符与肠道外的自主表型的相关性，我们 将对交感神经和副交感神经功能进行比较分析 在Sox10 dom先生线中。这些研究将有助于我们了解 自主神经发展和疾病变化的遗传基础 PNS中的表型。