Jouberin and Nephrocystin in Joubert Syndrome

描述(申请人提供)：纤毛病是一种新兴的人类发育障碍，影响大脑、眼睛、肝脏、肾脏、手指、骨骼肌和肺，所有这些疾病都是由于初级纤毛的结构或功能中断而引起的。Joubert综合征(JS)是一种以脑结构异常、智力低下和共济失调为特征的纤毛疾病，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的发病机制很重要，原因有三：1)怀疑小脑疾病往往会导致终止妊娠，因此了解这些原因可以改善对妊娠结局的预测。2]在儿童大脑疾病中，JS并存自闭症的发生率最高，这表明我们所学到的东西可以影响我们对更复杂的疾病的理解。3]随着对基本机制的更好理解，该领域将更好地考虑可能的治疗方法。我们已经在JS患者中发现了AHI1、NPHP1、CEP290、Ar13b和INPP5E基因以及几个未发表的基因突变。我们结合小鼠模型、细胞生物学和生化方法，确定了这些基因在肾脏内稳态、视紫红质转运、Wnt、小GTP酶和磷脂酰肌醇信号转导中的重要信号功能。然而，这些基因在纤毛疾病发病机制和遗传网络中的生理作用仍不清楚。这一更新应用的总体目标是阐明JS多器官参与的纤毛病变基因的发育、信号和细胞生物学机制，特别是在大脑发育的背景下。我们将利用传统的和有条件的小鼠基因敲除技术，斑马鱼的基因建模，以及先进的活细胞成像能力，这将有助于促进我们对这一重要类别疾病的机制的理解。

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 We have identified the genes AHI1, NPHP1, CEP290, ARL13B, and INPP5E as well as several unpublished genes as mutated in patients with JS.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.