Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors
Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors
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DOI：
10.1016/j.ajhg.2011.07.001
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发表时间：
2011-08-12
影响因子：
9.8
通讯作者：
Krauss, Robert S.
中科院分区：
文献类型：
--
作者：
Bae, Gyu-Un;Domene, Sabina;Krauss, Robert S.
无前脑畸形(HPE)是一种常见的人类先天畸形，其特征是不能描绘出前脑和/或面中部的中线，在这些结构的发育过程中，与Sonic Headgehog(SHH)途径的活性降低有关。ShH信号受配体结合因子网络的调控，包括主要受体ptch1和可能的辅助受体CDON(也称为CDO)、BOG和GAS1。尽管SHH与这些受体的结合促进了通路的活性，但尚不清楚这些受体之间的相互作用是否重要。我们在这里报告了人类HPE中CDON错义突变的鉴定。这些突变降低了CDON在基于细胞的信号分析中支持SHH依赖的基因表达的能力。突变发生在CDON的SHH结合域之外，编码的CDON变异体蛋白在与SHH结合时不显示缺陷。相反，野生型CDON与ptch1和GAS1相关，但变异体的效率很低，其方式与它们在基于细胞的分析中的活性相似。我们的发现认为，CDON必须与配体和其他刺激性受体成分，特别是ptch1，才能产生信号，而破坏后者的相互作用是HPE的一种机制。
Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding factors, including the primary receptor PTCH1 and the putative coreceptors, CDON (also called CDO), BOG, and GAS1. Although binding of SHH to these receptors promotes pathway activity, it is not known whether interactions between these receptors are important. We report here identification of missense CDON mutations in human HPE. These mutations diminish CDON's ability to support SHH-dependent gene expression in cell-based signaling assays. The mutations occur outside the SHH-binding domain of CDON, and the encoded variant CDON proteins do not display defects in binding to SHH. In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. Our findings argue that CDON must associate with both ligand and other hedgehog-receptor components, particularly PTCH1, for signaling to occur and that disruption of the latter interactions is a mechanism of HPE.