Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice.
Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice.
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DOI：
10.1371/journal.pgen.1002999
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Krauss RS
中科院分区：
文献类型：
--
作者：
Hong M;Krauss RS
前脑无裂畸形（HPE）是一种非常常见的先天性异常，其特征是前脑和面中部的中线无法确定。HPE与Sonic hedgehog（SHH）通路组分中的杂合突变相关，但临床表现极其多变，许多突变携带者不受影响。有人提出，这些观察结果最好用多次击中模型来解释，其中HPE突变的突变率和表达率通过第二次突变或存在合作但沉默的修饰基因来增强。非遗传性风险因素也与HPE有关，基因-环境相互作用可能为纯遗传性多击模型提供了替代性多击模型;然而，几乎没有证据支持这一论点。我们在这里报告了一个小鼠模型，其中有一个真正的HPE基因（Cdon，编码SHH共受体）和可疑的HPE致畸剂，乙醇突变之间的显着协同作用。129 S6小鼠中Cdon的丢失和子宫内乙醇暴露单独产生很少或没有表型，但共同产生早期中线图案化缺陷、发育中前脑中SHH信号传导的抑制和广谱HPE表型。我们的研究结果表明，乙醇确实是HPE的一个危险因素，但遗传易感个体，如SHH通路突变的个体，可能特别易感。此外，基因-环境相互作用可能在HPE的多因素病因学中很重要。前脑无裂畸形（HPE）是一种先天性畸形，其特征是前脑和面中部的中线无法形成，其发生率为1/250。指导前脑和面部中线形成的基因突变与HPE相关，但临床结果差异极大，许多突变携带者不受影响。这导致了一种假设，即需要一种以上的遗传损伤才能引起HPE。虽然在一些HPE患者中发现了多种突变，但它们只占总数的一小部分。非遗传风险因素也与HPE有关，这种缺陷可能是由于突变与环境暴露相互作用而引起的。然而，缺乏这种可能性的证据。我们已经开发了一种小鼠HPE模型，其中Cdon基因突变（在一些HPE患者中发生突变）与子宫内暴露于乙醇（一种疑似但未经证实的HPE风险因素）之间存在显著的协同作用。我们的研究结果表明，乙醇是HPE的一个危险因素，但遗传易感个体可能特别易感。此外，基因-环境相互作用可能在HPE的多因素病因学中很重要。
Holoprosencephaly (HPE) is a remarkably common congenital anomaly characterized by failure to define the midline of the forebrain and midface. HPE is associated with heterozygous mutations in Sonic hedgehog (SHH) pathway components, but clinical presentation is extremely variable and many mutation carriers are unaffected. It has been proposed that these observations are best explained by a multiple-hit model, in which the penetrance and expressivity of an HPE mutation is enhanced by a second mutation or the presence of cooperating, but otherwise silent, modifier genes. Non-genetic risk factors are also implicated in HPE, and gene–environment interactions may provide an alternative multiple-hit model to purely genetic multiple-hit models; however, there is little evidence for this contention. We report here a mouse model in which there is dramatic synergy between mutation of a bona fide HPE gene (Cdon, which encodes a SHH co-receptor) and a suspected HPE teratogen, ethanol. Loss of Cdon and in utero ethanol exposure in 129S6 mice give little or no phenotype individually, but together produce defects in early midline patterning, inhibition of SHH signaling in the developing forebrain, and a broad spectrum of HPE phenotypes. Our findings argue that ethanol is indeed a risk factor for HPE, but genetically predisposed individuals, such as those with SHH pathway mutations, may be particularly susceptible. Furthermore, gene–environment interactions are likely to be important in the multifactorial etiology of HPE. Holoprosencephaly (HPE), a congenital anomaly characterized by failure to form the midline of the forebrain and midface, occurs as frequently as 1 in 250 conceptions. Mutations in genes that direct formation of the forebrain and facial midline are associated with HPE, but the clinical outcome is extremely variable and many mutation carriers are unaffected. This has led to the hypothesis that more than one genetic insult is required to cause HPE. Although multiple mutations have been identified in some individuals with HPE, they represent a small percentage of the total. Non-genetic risk factors are also implicated in HPE, and it is possible that this defect may arise as a consequence of a mutation interacting with an environmental exposure. However, evidence for this possibility is lacking. We have developed a mouse HPE model in which there is dramatic synergy between mutation in the Cdon gene, which is mutated in some HPE patients, and in utero exposure to ethanol, a suspected but unproven HPE risk factor. Our findings argue that ethanol is a risk factor for HPE, but genetically predisposed individuals may be particularly susceptible. Furthermore, gene–environment interactions are likely to be important in the multifactorial etiology of HPE.
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影响因子：
3.7
作者：
Krauss RS
通讯作者：
Krauss RS
DOI：
10.1002/ajmg.c.30242
发表时间：
2010-02-15
影响因子：
3.1
作者：
Johnson, Candice Y.;Rasmussen, Sonja A.
通讯作者：
Rasmussen, Sonja A.
影响因子：
9.2
作者：
Cole, F;Krauss, RS
通讯作者：
Krauss, RS
影响因子：
9.8
作者：
Bae, Gyu-Un;Domene, Sabina;Krauss, Robert S.
通讯作者：
Krauss, Robert S.
影响因子：
2.7
作者：
Andersson, Olov;Reissmann, Eva;Ibanez, Carlos F.
通讯作者：
Ibanez, Carlos F.