Jouberin and Nephrocystin in Joubert Syndrome

描述（由申请人提供）：先天性共济失调表现为儿童早期非进行性张力低下、认知、大、细运动迟缓。这些疾病不同于进行性共济失调，因为存在先天性小脑畸形和隐性遗传模式。Joubert综合征及相关疾病（JSRD）构成了这些疾病的一个子集，包括小脑中线（蚓部）畸形和脑成像（MTI）上几乎典型的磨牙征象。JSRD存在显著的表型异质性：一些患者表现为经典形式（仅限于大脑），另一些患者表现为先天性视网膜失明、进行性肾衰竭、大脑皮质异常或显著的脑线路表型，其中每个大脑皮质半球向身体的同侧输出输出，但从对侧接收感觉信息。这些疾病的细胞和发育基础尚不清楚。NPHP1和AHI1两个基因的突变与JSRD有关。在一个令人兴奋的新进展中，我们发现了第三个JSRD基因CEP290（已提交）。令人信服的证据表明，这些蛋白质在纤毛/中心体中起作用。在这里，我们建议应用分子技术来研究这三个基因的作用，通过进行突变分析，基因型-表型相关性，测试编码蛋白在基于纤毛的鞭毛内运输中的可能作用，并测试神经元增殖和轴突引导缺陷的动物模型。这些数据将提供一个框架，以了解这些基因在JSRD中所见的一系列条件中的作用。1. 我们将对180个JSRD先证进行全面的突变分析和基因型-表型相关性，以验证NPHP1或CEP290突变与JSRD合并肾衰竭相关的假设，而AHI1突变与JSRD合并皮质异常相关。2. 我们将测试这些基因在纤毛/中心体中发挥作用的可能性，通过功能丧失和功能获得分析来介导Wnt或Sonic Hedgehog信号的转导。3. 我们将分析每个基因靶向缺失小鼠的脑表型，以测试这些通路是否调节小脑颗粒神经元增殖和轴突引导。

DESCRIPTION (provided by applicant): Congenital ataxia presents in early childhood with non-progressive hypotonia, cognitive, gross and fine motor delays. These disorders are distinct from the progressive ataxias because of the presence of congenital cerebellar malformations and recessive modes of inheritance. Joubert Syndrome and Related Disorders (JSRD) constitutes a subset of these conditions, consisting of a cerebella midline (vermis) malformation, and a nearly pathognomonic Molar Tooth sign on brain Imaging (MTI). There is significant phenotypic heterogeneity in JSRD: some patients display the classical form (limited to brain), and others display additionally congenital retinal blindness, progressive kidney failure, cerebral cortical abnormalities or a striking brain wiring phenotype in which each cerebral cortical hemisphere projects output to the ipsilateral side of the body, but receives sensory information from the contralateral side. The cellular and developmental bases of these conditions are not understood. Mutations in two genes, NPHP1 and AHI1, are associated with JSRD. In an exciting new development, we identified the third JSRD gene, CEP290 (submitted). Compelling evidence suggests these proteins function at the cilia/centrosome. Here we propose to apply molecular techniques to study roles of these three genes by performing mutational analyses, genotype-phenotype correlations, test the encoded proteins for a possible role in cilia-based intraflagellar transport, and test animal models for defects in neuronal proliferation and axon guidance. Together this data will provide a framework to understand the role of these genes in the spectrum of conditions seen in JSRD. 1. We will perform comprehensive mutation analysis and genotype-phenotype correlations in a cohort of 180 JSRD probands to test the hypothesis that NPHP1 or CEP290 mutations are associated with JSRD plus kidney failure, whereas AHI1 mutations are associated with JSRD plus cortical abnormalities. 2. We will test the possibility that these genes function at the cilia/centrosome to mediate transduction of Wnt or Sonic Hedgehog signals, using loss- and gain-of-function analyses. 3. We will analyze the brain phenotype of mice with targeted deletions of each gene to test whether these pathways regulate cerebella granule neuron proliferation and axon guidance.