Synthetic Lethal Modifier of a New Ciliopathy Gene

描述（由申请人提供）：纤毛病包括由初级纤毛缺陷统一的一系列疾病。临床表现从主要累及单一器官（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，在几个器官中出现严重和多效性的发育表型。几个基因已经并将继续被确定为纤毛病疾病，其中绝大多数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果的修饰基因才刚刚开始与致病机制联系起来。本项目重点研究控制纤毛表型的转录调节因子Zfp423和Zfp423之间的合成致死相互作用

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.