Synthetic Lethal Modifier of a New Ciliopathy Gene

描述(由申请人提供)：纤毛病变包括由初级纤毛缺陷统一的一系列疾病。临床表现从最初的单个器官受累(最常见的是后脑、肾脏、肝脏或眼睛)到更严重的表现，如Meckel综合征，几个器官的严重和多向性发育表型。有几个基因已经并将继续被发现与纤毛疾病有关，绝大多数基因编码初级纤毛的结构成分。控制纤毛依赖信号的调控基因和控制纤毛缺陷结局的修饰基因才刚刚开始与致病机制联系在一起。这个项目的重点是控制纤毛表型的转录调控因子Zfp423和Zfp423之间的合成致死相互作用 一种未知的修饰基因。Zfp423编码一个30个锌指转录因子，在多个信号转导通路和多个器官系统中都需要。缺乏Zfp423的动物有明显的脑畸形，脑积水的频率很高，以及几个外围组织的缺陷。存活动物的表型分布既取决于修饰基因，也取决于明显的随机过程。然而，在最常用的菌株背景下，没有突变动物存活下来。基因图谱确定了与胚胎和围产期致死性有关的单个主要基因座。这项建议的目的是确定这个合成的致死修饰基因座，阐明其机制，并将其放在纤毛疾病网络中其他基因的背景下。

DESCRIPTION (provided by applicant): The ciliopathies comprise a spectrum of disorders unified by defects in primary cilia. Clinical presentations range from primary involvement of a single organ (most often hindbrain, kidney, liver or eye) to more severe presentations, such as Meckel syndrome, with severe and pleiotropic developmental phenotypes in several organs. Several genes have been and continue to be identified for ciliopathy disorders, with the overwhelming majority encoding structural components of primary cilia. Regulatory genes that control cilium-dependent signaling and modifier genes that control the outcome of ciliary defects are only beginning to be tied to pathogenic mechanisms. This project focuses on the synthetic lethal interaction between a transcriptional regulator that control ciliary phenotypes, Zfp423, and an unknown modifier gene. Zfp423 encodes a 30-zinc finger transcription factor required in several signal transduction pathways and in multiple organ systems. Animals that lack Zfp423 have prominent brain malformations with a high frequency of hydrocephalus as well as defects in several peripheral tissues. The distribution of phenotypes in surviving animals is dependent on both modifier genes and apparently stochastic processes. However, on the most commonly used strain background, no mutant animals survive. Genetic mapping identifies a single major locus linked to embryonic and perinatal lethality. The aims of this proposal will identify this synthetic lethal modifier locus, elucidate its mechanism and place it in the context of other genes in the ciliopathy network.