Jouberin and Nephrocystin in Joubert Syndrome

描述（由申请人提供）：纤毛病代表了一类新兴的人类发育障碍，影响脑、眼、肝、肾、手指、骨骼肌和肺，所有这些都由初级纤毛的结构或功能破坏联合起来。Joubert综合征（JS）是一种以脑结构异常、智力迟钝和共济失调为特征的纤毛病，常伴有视网膜失明、肾功能衰竭、多指畸形和肝纤维化。确定JS的致病机制很重要，原因有三个：1]怀疑小脑疾病经常导致妊娠终止，因此了解这些原因可以提高对妊娠结局的预测。[2] JS是儿童脑部疾病中并发自闭症发生率最高的疾病之一，这表明我们所了解的可以影响我们对更复杂疾病的理解。[3]随着对基本机制的了解的提高，该领域将处于更好的位置来考虑潜在的治疗方法。我们已经在JS患者中发现了AHI1、NPHP1、CEP290、ARL13B和INPP5E基因以及一些未发表的基因突变。我们已经确定了这些基因在肾脏稳态、视紫红质运输、Wnt-、小GTPase-和磷脂酰肌醇信号传导中的基本信号功能，使用小鼠模型、细胞生物学和生化方法相结合。然而，这些基因在纤毛病发病机制中的生理作用及其遗传网络尚不清楚。这项更新应用的总体目标是阐明多器官参与JS的纤毛病基因的发育，信号传导和细胞生物学机制，特别是在大脑发育的背景下。我们将利用小鼠的传统和条件敲除技术，斑马鱼的遗传建模，以及先进的活细胞成像能力，这些技术将协同作用，帮助我们加深对这类重要疾病机制的理解。

DESCRIPTION (provided by applicant): The ciliopathies represent an emerging class of human developmental disorders affecting brain, eye, liver, kidney, digit, skeletal muscle, and lung, all united by disruption of structure or function of the primary cilium. Joubert syndrome (JS) is a ciliopathy, characterized by structural brain anomalies, mental retardation and ataxia, with frequent accompanying retinal blindness, renal failure, polydactyly and hepatic fibrosis. Identifying the pathogenic mechanisms of JS is important for three reasons: 1] A suspicion of a cerebellar disorder frequently leads to pregnancy termination, so understanding these causes can lead to improved predictions about pregnancy outcome. 2] JS has among the highest incidence of co-existent autism among pediatric brain disorders, suggesting what we learn can impact our understanding of more complex disorders. 3] With an improved understanding of basic mechanisms, the field will be in a better position to consider potential treatments. We have identified the genes AHI1, NPHP1, CEP290, ARL13B, and INPP5E as well as several unpublished genes as mutated in patients with JS. We have identified essential signaling functions of these genes in kidney homeostasis, rhodopsin transport, Wnt-, small GTPase-, and phosphatidyl inositol signaling using a combination of mouse modeling, cell biology and biochemical approaches. However, the physiological role of these genes in the pathogenesis of the ciliopathies and the genetic networks remain unknown. The overall goal of this renewal application is to elucidate the developmental, signaling and cell biological mechanisms of the ciliopathy genes underlying the multi- organ involvement in JS, particularly in the context of brain development. We will utilize both traditional and conditional knockout technologies in mouse, genetic modeling in zebrafish, and advanced live-cell imaging capability that will synergize to help advance our understanding of the mechanisms of this important class of disease.