Rescue of holoprosencephaly in fetal alcohol-exposed Cdon mutant mice by reduced gene dosage of Ptch1.
Rescue of holoprosencephaly in fetal alcohol-exposed Cdon mutant mice by reduced gene dosage of Ptch1.
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DOI：
10.1371/journal.pone.0079269
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发表时间：
2013
期刊：
影响因子：
3.7
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）是一种常见的发育缺陷，其中前脑和面中部的中线图案被破坏。在吻腹中线发育的多个阶段需要Sonic hedgehog（SHH）信号传导，并且SHH通路组分中的杂合突变与HPE相关。然而，HPE的临床表现是高度可变的，并且杂合突变的携带者通常缺乏明显的缺陷。因此，人们认为，这种突变必须与更常见的修饰，遗传和/或环境相互作用。我们在小鼠中模拟了这种情况。Cdon突变小鼠在SHH信号传导中具有很大程度上的亚阈值缺陷，通过额外的命中使它们对广谱HPE表型敏感，所述额外的命中本身不足以产生HPE，包括子宫内短暂暴露于乙醇。这些可变的HPE表型可能出现在胚胎中，这些胚胎在特定的发育阶段未能达到SHH信号传导的阈值水平。为了证明这种可能性，我们测试了从Cdon−/−胚胎中去除一个负调节因子Ptch 1的影响，并将它们对乙醇的反应与Cdon−/−; Ptch 1 +/+胚胎进行了比较。Ptch 1杂合性使该系统中HPE的表达率降低> 75%。减少Ptch 1基因剂量的主要影响是对HPE的影响，因为那些表现出HPE的Cdon−/−; Ptch 1 +/−胚胎与乙醇诱导HPE的Cdon−/−; Ptch 1 +/+胚胎在表型上没有表现出重大差异。我们的研究结果是一致的概念，即使在一个病因复杂的模型HPE，水平的SHH途径的活动是限速的。此外，携带SHH途径突变的个体的临床结果可能反映有害和保护性修饰等位基因的总和效应及其与非遗传风险因素（如胎儿酒精暴露）的相互作用。
Holoprosencephaly (HPE) is a commonly occurring developmental defect in which midline patterning of the forebrain and midface is disrupted. Sonic hedgehog (SHH) signaling is required during multiple stages of rostroventral midline development, and heterozygous mutations in SHH pathway components are associated with HPE. However, clinical presentation of HPE is highly variable, and carriers of heterozygous mutations often lack apparent defects. It is therefore thought that such mutations must interact with more common modifiers, genetic and/or environmental. We have modeled this scenario in mice. Cdon mutant mice have a largely subthreshold defect in SHH signaling, rendering them sensitive to a wide spectrum of HPE phenotypes by additional hits that are themselves insufficient to produce HPE, including transient in utero exposure to ethanol. These variable HPE phenotypes may arise in embryos that fail to reach a threshold level of SHH signaling at a specific developmental stage. To provide evidence for this possibility, here we tested the effect of removing one copy of the negative regulator Ptch1 from Cdon−/− embryos and compared their response to ethanol with that of Cdon−/−;Ptch1+/+ embryos. Ptch1 heterozygosity decreased the penetrance of HPE in this system by >75%. The major effect of reduced Ptch1 gene dosage was on penetrance, as those Cdon−/−;Ptch1+/− embryos that displayed HPE did not show major differences in phenotype from Cdon−/−;Ptch1+/+ embryos with ethanol-induced HPE. Our findings are consistent with the notion that even in an etiologically complex model of HPE, the level of SHH pathway activity is rate-limiting. Furthermore, the clinical outcome of an individual carrying a SHH pathway mutation will likely reflect the sum effect of both deleterious and protective modifier alleles and their interaction with non-genetic risk factors like fetal alcohol exposure.
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影响因子：
9.2
作者：
Cole, F;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：
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通讯作者：
Rasmussen, Sonja A.
影响因子：
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作者：
Bae, Gyu-Un;Domene, Sabina;Krauss, Robert S.
通讯作者：
Krauss, Robert S.
影响因子：
4
作者：
Mercier, Sandra;Dubourg, Christele;Odent, Sylvie
通讯作者：
Odent, Sylvie
影响因子：
2.7
作者：
Marcucio, RS;Cordero, DR;Helms, JA
通讯作者：
Helms, JA