Synthetic Lethal Modifier of a New Ciliopathy Gene

描述（由申请人提供）：纤毛病包括一系列由初级纤毛缺陷统一的疾病。临床表现范围从单一器官（最常见的是后脑、肾脏、肝脏或眼睛）的原发性受累到更严重的表现，如Meckel综合征，在几个器官中具有严重和多效性发育表型。几个基因已经并将继续被确定为纤毛疾病，绝大多数编码初级纤毛的结构成分。控制纤毛依赖性信号传导的调节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在一起。该项目的重点是控制纤毛表型的转录调节因子Zfp 423和 一种未知的修饰基因Zfp 423编码一个30-锌指转录因子，在多种信号转导途径和多器官系统中是必需的。缺乏Zfp 423的动物具有显著的脑畸形，具有高频率的脑积水以及几种外周组织的缺陷。存活动物的表型分布取决于修饰基因和明显的随机过程。然而，在最常用的菌株背景下，没有突变动物存活。遗传图谱确定了一个单一的主要基因座与胚胎和围产期致死。这项建议的目的是确定这种合成的致死修饰基因位点，阐明其机制，并将其置于纤毛病变网络中的其他基因的背景下。

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.