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

描述（由申请人提供）：前脑畸形（HPE）是一种常见的前脑和中面部出生缺陷，有环境（致畸）和遗传原因。环境因素之一是孕妇在怀孕早期饮酒。此外，在人类HPE中发现了Sonic hedgehog （Shh）信号通路的突变。突变携带者的HPE表型是高度可变的，即使在系谱中也是如此，其影响范围从无临床表现到面部HPE的“微形态”，再到完全的HPE，包括独眼。造成这种差异的原因尚不清楚，但也可能需要其他因素，包括胎儿发育期间的额外遗传影响或环境暴露。这些可能性并不是相互排斥的，基因与环境的相互作用很可能涉及像HPE这样的病因复杂的疾病。除了临床观察外，动物模型将胎儿酒精暴露与HPE联系起来，包括小鼠中发育良好的系统和与Shh信号中断相关的小鸡模型。这些观察结果提出了关于人类HPE病因学的重要问题，包括：1)致畸暴露是否会使具有HPE遗传易感性的胎儿的结局恶化；2)与在“正常”个体中诱发HPE所需的剂量相比，HPE的遗传易感性是否使个体对较低剂量的致畸剂敏感？这一提议首次通过实验解决了这些问题。我们建立了小鼠HPE遗传模型，将为乙醇诱导HPE的研究提供一种新的基因-环境相互作用模型。缺乏Shh通路调节因子Cdo的小鼠表现出HPE表型的株特异性严重程度：129/Sv背景突变体表现出HPE的微观形式，外显率为-50%，而C57BI/6背景突变体表现出严重形式，外显率为bbb80 %。本提案的具体目的是通过将缺乏Cdo的小鼠在子宫内暴露于酒精中，评估HPE发生中基因-环境相互作用的可能性。据推测，暴露于酒精会使Cdo-/-胚胎的表型恶化，使129/Sv菌株的表型更接近于C57BI/6菌株，而C57BI/6胚胎表现出最严重的HPE表型，通常不会因Cdo的丧失而观察到，如独眼。还有一种假设是，接触酒精会放大Shh信号在Cdo /-胚胎中的缺陷。这些研究涉及到一种新模型的发展，该模型可以首次建立一个定义突变和致畸原之间基因-环境相互作用的相关性，致畸原广泛用于常见出生缺陷的病因学。这些信息可能具有重要的公共卫生影响，并可能最终有助于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.