Joubert syndrome and related disorders of hindbrain development

描述（由申请人提供）：Joubert综合征和相关疾病（JSRD）是一组常染色体隐性疾病，其特征为独特的后脑畸形（“臼齿征”- MTS），伴有智力残疾（精神发育迟滞）、张力减退、共济失调和痴呆、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/基体（PC/BB）在大脑和视网膜发育/功能中的作用。具体来说，我们建议研究CC 2D 2A，一个新发现的基因负责JS的分子功能，并确定其他组件的遗传/蛋白质网络的基础JSRD使用几个高度信息化的家庭。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CC 2D 2A相互作用的其他蛋白质来研究CC 2D 2A的功能。在目标2中，我们将使用斑马鱼的cc 2d 2a感光细胞表型来剖析Cc 2d 2a的分子功能，并通过检查JSRD基因突变体/morphant组合的影响来建立寡基因遗传模型。鉴于<50%的JSRD患者在已知基因中存在突变，目标3的目标是确定负责JSRD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。更具体地说，它将增强我们对大脑，视网膜和肾脏的发育/功能的理解，为JSRD患者提供更好的诊断和预后信息，并可能确定治疗的分子靶点，以预防或延迟JSRD和其他纤毛病中观察到的进行性视网膜，肾脏和肝脏疾病。鉴于PC/BB在细胞功能和孟德尔疾病中的多变作用，结合PC/BB基因与更常见的神经系统疾病（如精神分裂症和自闭症）之间的新兴关联，这项工作也可能揭示脑，视网膜，肾脏和其他组织常见疾病的机制。 公共卫生相关性：Joubert综合征及相关疾病（JSRD）为研究智力残疾、共济失调性脑瘫、视网膜营养不良、囊性肾病和肝纤维化提供了一个模型。导致JSRD的基因也与自闭症、精神分裂症、失明和肥胖有关。这项研究将通过改善诊断、预后和复发风险信息，以及监测和早期治疗医疗并发症，使JSRD患者及其家庭直接受益。通过研究这种相对罕见的疾病，更好地了解大脑，视网膜，肾脏和肝脏的发育/功能，将有助于预防和治疗这些器官系统的更常见疾病，并使整个社会受益。

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. PUBLIC HEALTH RELEVANCE: Joubert syndrome and related disorders (JSRD) provide a model for studying intellectual disability, ataxic cerebral palsy, retinal dystrophy, cystic kidney disease and liver fibrosis. The genes responsible for JSRD have also been implicated in autism, schizophrenia, blindness and obesity. This research will directly benefit individuals with JSRD and their families through improved diagnostic, prognostic and recurrence risk information, as well as monitoring and early treatment for medical complications. Greater understanding of the development/function of the brain, retina, kidney and liver through the study of this relatively rare disorder will facilitate the prevention and treatment of more common disorders of these organ systems and benefit society as a whole.