Joubert syndrome and related disorders of hindbrain development

描述（由申请人提供）：Joubert综合征及相关疾病（JSRD）是一组常染色体隐性遗传病，其特征为独特的后脑畸形（“磨牙征”- MTS），并伴有智力障碍（智力迟钝）、张力低下、共济失调，以及各种囊性肾病、视网膜营养不良和肝纤维化。该项目的总体背景是探索初级纤毛/基底（PC/BB）在大脑和视网膜的发育/功能中的作用。具体来说，我们建议研究CC2D2A（一个新发现的与JS有关的基因）的分子功能，并利用几个信息丰富的家族来确定JSRD背后的遗传/蛋白质网络的其他组成部分。在目标1中，我们将通过确定时间、空间和亚细胞表达以及鉴定与CC2D2A相互作用的其他蛋白质来研究CC2D2A的功能。在Aim 2中，我们将利用斑马鱼的cc2d2a光感受器表型来解剖cc2d2a的分子功能，并通过检查JSRD基因突变/突变体组合的影响来模拟cc2d2a的寡基因遗传。鉴于小于50%的JSRD患者在已知基因中存在突变，Aim 3的目标是确定与JSRD有关的遗传/蛋白质网络的其他组成部分。这项工作对人类疾病具有广泛的意义。最具体地说，它将增强我们对大脑、视网膜和肾脏发育/功能的理解，为JSRD患者提供更好的诊断和预后信息，并有可能确定治疗的分子靶点，以预防或延缓JSRD和其他纤毛病中出现的进行性视网膜、肾脏和肝脏疾病。考虑到PC/BB在细胞功能和孟德尔疾病中的多种作用，再加上PC/BB基因与精神分裂症和自闭症等更常见的神经系统疾病之间的新联系，这项工作也可能揭示大脑、视网膜、肾脏和其他组织常见疾病的潜在机制。

DESCRIPTION (provided by applicant): Joubert Syndrome and related disorders (JSRD) are a group of autosomal recessive conditions characterized by a distinctive hindbrain malformation (the "molar tooth sign" - MTS) combined with intellectual disability (mental retardation), hypotonia, ataxia, and variably, cystic renal disease, retinal dystrophy and hepatic fibrosis. The overall context of the project is to explore the role of the primary cilium/basal body (PC/BB) in the development/function of the brain and retina. Specifically, we propose to study the molecular function of CC2D2A, a newly discovered gene responsible for JS, and to identify additional components of the genetic/protein network underlying JSRD using several highly informative families. In Aim 1, we will investigate CC2D2A function by determining temporal, spatial and subcellular expression as well as identifying additional proteins that interact with CC2D2A. In Aim 2, we will use the cc2d2a photoreceptor phenotype in zebrafish to dissect the molecular function of Cc2d2a and model oligogenic inheritance by examining the effects of JSRD gene mutants/morphant combinations. Given that <50% of JSRD patients have mutations in the known genes, the goal of Aim 3 is to identify additional components of the genetic/protein network responsible for JSRD. This work has broad implications for human disease. Most specifically, it will enhance our understanding of the development/function of the brain, retina and kidney, provide improved diagnostic and prognostic information for patients with JSRD and potentially identify molecular targets for therapies to prevent or delay the progressive retinal, kidney and liver disease seen in JSRD and other ciliopathies. Given the protean role of the PC/BB in cellular function and Mendelian diseases, combined with the emerging associations between PC/BB genes and more common neurological diseases such as schizophrenia and autism, this work is also likely to reveal mechanisms underlying common diseases of the brain, retina, kidney and other tissues.