Gene-Environment Interaction in Holoprosencephaly: Role of Fetal Alcohol Exposure

描述(申请人提供)：无前脑畸形(HPE)是一种常见的前脑和面中部出生缺陷，有环境(畸形)和遗传两种原因。环境因素之一是孕妇在怀孕早期饮酒。此外，在人类HPE中还发现了Sonic hedgehog(Shh)信号通路的突变。突变携带者的HPE表型差异很大，甚至在家系中也是如此，影响范围从没有临床表现的HPE到面部微型性HPE，再到包括睫状眼在内的全面HPE。这种变异的原因尚不清楚，但也可能需要的因素包括额外的遗传影响或胎儿发育期间的环境暴露。这些可能性并不是相互排斥的，基因-环境的相互作用很可能涉及像HPE这样的病因复杂的疾病。除了临床观察，动物模型还将胎儿酒精暴露与HPE联系起来，包括小鼠中一个发育良好的系统，以及与Shh信号中断有关的小鸡模型。这些观察提出了关于人类HPE病因学的重要问题，包括：1)致畸暴露是否会恶化具有HPE遗传易感性的胎儿的结局；以及2)HPE的遗传易感性是否会使个体对较低剂量的畸胎原敏感，而不是“正常”个体诱发HPE所需的剂量。这项提案首次在实验中解决了这些问题。我们已经建立了HPE的小鼠遗传模型，并将利用该模型在乙醇诱导的HPE的研究中建立新的基因-环境相互作用模型。缺乏Shh途径调节因子CDO的小鼠表现出特定菌株的严重HPE表型：129/Sv背景的突变株在-50%的外显率下显示微型HPE，而C57BI/6背景的突变株在&gt；80%的外显率下显示严重的形式。这项建议的具体目的是通过在子宫内将CDO缺乏的小鼠暴露于酒精中，评估基因-环境相互作用在HPE发生中的可能性。据推测，暴露在酒精中会恶化CDO-/-胚胎的表型，使129/Sv株的胚胎更接近C57BI/6株，而C57BI/6胚胎表现出最严重的HPE表型，通常不会伴随CDO缺失而观察到，如睫状眼。它还假设，暴露在酒精中将夸大在CDO/-胚胎中看到的Shh信号缺陷。这些研究涉及开发一种新的模型，该模型可以首次确定在常见出生缺陷的病因学中广泛使用的特定突变和致畸因素之间的基因-环境相互作用的相关性。这些信息可能会对公众健康产生重要影响，并最终可能有助于对HPE突变携带者的咨询。

DESCRIPTION (provided by applicant): Holoprosencephaly (HPE) is a common birth defect of the forebrain and midface with both environmental (teratogenic) and genetic causes. Among the environmental factors is maternal alcohol consumption during early pregnancy. In addition, mutations in the Sonic hedgehog (Shh) signaling pathway have been identified in human HPE. The HPE phenotype of mutation carriers is highly variable, even within pedigrees, with the spectrum of effects ranging from no clinical manifestation, to facial "microforms" of HPE, to full blown HPE, including cyclopia. The reason for this variability is unknown, but factors that may also be required include additional genetic influences or environmental exposures during fetal development. These possibilities are not mutually exclusive and gene-environment interactions are likely to be involved in an etiologically complex malady like HPE. In addition to clinical observations, animal models link fetal alcohol exposure to HPE, including a well-developed system in the mouse and a chick model associated with a disruption in Shh signaling. These observations raise important questions about the etiology of human HPE, including: 1) do teratogenic exposures worsen outcomes of fetuses with genetic predisposition to HPE; and 2) does genetic predisposition to HPE sensitize individuals to lower doses of teratogen than required to induce HPE in a "normal" individual. This proposal addresses such questions experimentally for the first time. We have established a mouse genetic model of HPE, and it will be used to develop a new model of gene-environment interactions in the study of ethanol-induced HPE. Mice lacking the Shh pathway regulator, Cdo, display strain-specific severity of HPE phenotypes: mutants of the 129/Sv background show microforms of HPE at -50% penetrance, while mutants of the C57BI/6 background show severe forms at >80% penetrance. The Specific Aim of this proposal is to assess the possibility of gene-environment interactions in the genesis of HPE, through in utero exposure of mice lacking Cdo to alcohol. It is hypothesized that exposure to alcohol will worsen the phenotypes of Cdo-/- embryos, such that those of the 129/Sv strain more closely resemble those of the C57BI/6 strain, while C57BI/6 embryos display the most severe HPE phenotypes, not normally observed with loss of Cdo, such as cyclopia. It is also hypothesized that exposure to alcohol will exaggerate the defect in Shh signaling seen in Cdo-/- embryos. These studies involve the development of a new model that could establish for the first time the relevance of gene-environment interactions between a defined mutation and a teratogen with wide use in the etiology of a common birth defect. Such information may have important public health impact and could ultimately aid in the counseling of HPE mutation carriers.