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。 公共卫生相关性：纤毛病是一大群个别罕见的疾病，在一个特定的细胞成分，初级纤毛共同缺陷。该组中的疾病导致脑、眼、肾、肺或肝的缺陷;个体疾病可能由一个以上的基因引起，单个基因可能导致这些疾病中的一种以上。在某些情况下，在两个或更多个基因座上的三个等位基因的遗传似乎驱动表型。纤毛病似乎经常对遗传修饰剂敏感。本身是良性的修饰剂可能具有治疗潜力。本申请使用遗传和分子工具来识别和理解纤毛病小鼠模型Zfp 423中的遗传修饰剂。PI实验室先前的工作已经建立了具有品系依赖性表型范围的Zfp 423小鼠模型。本申请提出鉴定一种品系依赖性修饰基因，其保护某些品系背景的小鼠免受常见C57 BL/6品系背景中的合成致死性，并确定其作用机制。

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. PUBLIC HEALTH RELEVANCE: Ciliopathies are a large group of individually rare disorders that have in common defects in a specific cell component, the primary cilium. Disorders in this group cause defects in brain, eye, kidney, lung or liver; individual disorders may be caused by more than one gene and single genes may contribute to more than one of these disorders. In some cases, inheritance of three alleles at two or more loci appear to drive phenotypes. Ciliopathies appear to be frequently sensitive to genetic modifiers. Modifiers that are by themselves benign may have therapeutic potential. This application uses genetic and molecular tools to identify and understand a genetic modifier in a ciliopathy mouse model, Zfp423. Previous work from the PI's laboratory has established Zfp423 mouse models with strain-dependent range of phenotypes. This application proposes to identify a strain-dependent modifier gene that protects mice on some strain backgrounds from synthetic lethality in the common C57BL/6 strain background and to determine its mechanism of action.