Genetic Predisposition & Prevention of Neural Tube Defects (NTDs)

神经管关闭失败是一种复杂的遗传性疾病，很少被视为简单的孟德尔特征。在临床人群中，NTDS可能最常见的原因是多个基因的功能突变部分失活和/或获得，与妊娠环境共同作用。认识到这些变化是疾病相关的突变，而不是简单的多态，这对个体家庭的风险评估是一个挑战。另一个挑战是确定最合适的方法来减少特定夫妇的NTD发生率。来自这三个合作实验室的最新研究引导我们假设，对小鼠模型中基因网络相互作用的系统检查将阐明适用于人类NTDS风险评估和预防的模式。 在一个对叶酸(FA)有反应的NTD小鼠中，我们发现了Wnt规范信号的辅助受体LRP6的一个点突变，这涉及到临床上可能遇到的几条重要的发育遗传途径。利用这只弯曲尾巴(CD)小鼠，我们确定了肝脏组织和血液中可能的基因表达和新陈代谢“特征”，预测了通过预防NTD而对FA补充做出反应的基因构成。此外，我们使用ENU突变筛选来鉴定与NTD相关的小鼠突变，这些突变为人类测试提供候选，并可以测试它们对FA和其他潜在的NTD预防药物的反应。 我们建议进行一项多机构的努力，以确定小鼠的遗传易感性特征，并确定对预防措施(如饮食补充剂)做出反应的遗传背景。实验将使用FA和肌醇补充来测试这些药物是否可以预防LRP6缺失和NTD易感小鼠的NTD，这些小鼠有明确的ENU产生的突变。基因转录阵列将使用聚类分析检查这些突变体关闭期间神经管中的表达，以比较突变体和野生型兄弟姐妹的模式。此外，在CD非神经组织中识别的遗传和代谢特征将与其他ENU产生的和自然发生的NTD小鼠突变的特征进行比较，以确定该模式的预测能力。该项目将为基于分子途径的新治疗方法建立一个合理方法的框架。为此，将在几个小鼠品系中检查被破坏的生化途径与对FA补充的反应性或抵抗力之间的关系。这将开始揭示FA和肌醇抑制NTD的机制。

Failure of neural tube closure is a complex genetic disorder, rarely if ever seen as a simple Mendelian trait. In the clinical population, NTDs are probably most often caused by partial inactivation and/or gain of function mutations of multiple genes, acting in conjunction with the gestational environment. Recognizing such changes as disease associated mutations rather than simple polymorphisms is a challenge for assessment of risk in individual families. Another challenge is determining the most appropriate means to reduce NTD occurrence for a particular couple. Recent studies from these three collaborating laboratories lead us to hypothesize that a systematic examination of gene network interactions in mouse models will elucidate patterns that are applicable to risk assessment and prevention of NTDs in humans. In a mouse line with a folic acid (FA) responsive NTD, we identified a point mutation in Lrp6, a co-receptor for Wnt canonical signaling, which implicates several important developmental genetic pathways likely to be encountered clinically. Using this Crooked tail (Cd) mouse, we identified a possible gene expression and metabolism “signature” in liver tissue and blood, predicting a genetic make-up that will respond to FA supplementation by preventing NTD. In addition, we used ENU mutagenesis screens to identify NTD associated mouse mutations that provide candidates for human testing and which can be tested for response to FA and other potential NTD preventive agents. We propose to pursue a multi-institution effort to characterize genetic susceptibility profiles in mice and identify genetic backgrounds that respond to prevention measures such as dietary supplementation. Experiments will use FA and inositol supplementation to test whether these agents prevent NTD in Lrp6 null and NTD-prone mice with defined ENU-generated mutations. Gene transcript arrays will examine expression in the neural tube during closure in these mutants using cluster analysis to compare patterns in the mutant vs. wildtype siblings. In addition, the genetic and metabolic signature identified in Cd non-neural tissues will be compared against signatures in other ENU-generated and naturally occurring NTD mouse mutants to determine the predictive power of this pattern. This project will build a framework for rational approaches to new treatments based on molecular pathways. To this end, the relationship between the biochemical pathway that is disrupted and the responsiveness or resistance to FA supplementation will be examined in several mouse lines. This will begin to reveal mechanisms by which FA, and inositol, acts to suppress NTD.