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

描述（由申请人提供）：前脑无裂畸形（HPE）是一种常见的前脑和面中部出生缺陷，有环境（致畸）和遗传原因。环境因素之一是母亲在怀孕早期饮酒。此外，还在人类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，即使在家系内，其影响范围从没有临床表现到HPE的面部“微形态”，再到完全成熟的HPE，包括独眼畸形。这种变异性的原因尚不清楚，但可能还需要的因素包括胎儿发育期间的其他遗传影响或环境暴露。这些可能性并不是相互排斥的，基因-环境相互作用可能涉及像HPE这样的病因复杂的疾病。除了临床观察外，动物模型还将胎儿酒精暴露与HPE联系起来，包括小鼠中发育良好的系统和与Shh信号传导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;以及2）HPE遗传易感性是否会使个体对低于在“正常”个体中诱导HPE所需剂量的致畸剂敏感。这一提议首次通过实验解决了这类问题。本研究建立了小鼠HPE遗传模型，为乙醇诱导HPE的研究提供了一种新的基因-环境相互作用模型。缺乏Shh途径调节剂Cdo的小鼠显示HPE表型的品系特异性严重性：129/Sv背景的突变体在约50%的突变率下显示HPE的微形态，而C57 B1/6背景的突变体在>80%的突变率下显示严重形态。本提案的具体目的是通过缺乏Cdo的小鼠在子宫内暴露于酒精，评估HPE发生中基因-环境相互作用的可能性。假设暴露于酒精将使Cdo-/-胚胎的表型恶化，使得129/Sv品系的表型更接近于C57 BI/6品系的表型，而C57 BI/6胚胎显示出最严重的HPE表型，通常不会在Cdo丧失的情况下观察到，例如独眼症。还假设暴露于酒精会夸大在Cdo-/-胚胎中观察到的Shh信号传导的缺陷。这些研究涉及开发一种新的模型，该模型可以首次建立定义的突变和致畸剂之间的基因-环境相互作用的相关性，该致畸剂广泛用于常见出生缺陷的病因学。这些信息可能会对公共卫生产生重要影响，并最终有助于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.