Genetic Predisposition & Prevention of Neural Tube Defects (NTDs)

神经管闭合失败是一种复杂的遗传疾病，很少被视为简单的孟德尔特征。在临床人群中，NTD可能最常由多个基因的部分失活和/或功能突变的获得引起，与妊娠环境一起起作用。将这些变化识别为疾病相关的突变而不是简单的多态性是对单个家庭风险评估的挑战。另一个挑战是确定减少特定夫妇NTD发生的最适当方法。这三个合作实验室的最新研究使我们假设，在小鼠模型中对基因网络相互作用的系统检查将阐明适用于人类NTD风险评估和预防的模式。 在叶酸（FA）响应NTD的小鼠品系中，我们确定了Lrp 6（Wnt经典信号的共受体）的点突变，这涉及临床上可能遇到的几个重要的发育遗传途径。使用这种弯曲尾巴（Cd）小鼠，我们确定了肝脏组织和血液中可能的基因表达和代谢“签名”，预测了通过预防NTD来响应FA补充的遗传组成。此外，我们使用ENU诱变筛选来鉴定NTD相关的小鼠突变，这些突变为人类测试提供了候选物，并且可以测试对FA和其他潜在NTD预防剂的反应。 我们建议进行多机构的努力，以表征小鼠的遗传易感性，并确定对预防措施（如膳食补充剂）作出反应的遗传背景。实验将使用FA和肌醇补充剂来测试这些药物是否能预防具有确定的ENU产生的突变的Lrp 6缺失和NTD易感小鼠中的NTD。基因转录物阵列将使用聚类分析来比较突变体与野生型同胞中的模式，从而检查这些突变体在闭合期间神经管中的表达。此外，将在Cd非神经组织中鉴定的遗传和代谢特征与其他ENU产生的和天然存在的NTD小鼠突变体中的特征进行比较，以确定该模式的预测能力。该项目将建立一个基于分子途径的新治疗方法的合理方法的框架。为此，将在几种小鼠品系中检查被破坏的生化途径与对FA补充的反应性或抗性之间的关系。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.