Jouberin and Nephrocystin in Joubert Syndrome

描述(申请人提供)：先天性共济失调表现在儿童早期，表现为非进行性低眼压、认知、粗大和精细运动延迟。这些疾病与进行性共济失调不同，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)是这些疾病的一个子集，包括小脑中线(Vermis)畸形和大脑成像上近乎病理性的磨牙征(MTI)。JSRD具有显著的表型异质性：一些患者表现出经典的形式(仅限于大脑)，另一些患者还表现出先天性视网膜失明、进行性肾功能衰竭、大脑皮质异常或显著的大脑连接表型，其中每个大脑皮质半球将输出信号投射到身体的同侧，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。两个基因NPHP1和AHI1的突变与JSRD有关。在一个令人兴奋的新发展中，我们鉴定了第三个JSRD基因，CEP290(提交)。令人信服的证据表明，这些蛋白质在纤毛/中心体起作用。在这里，我们建议应用分子技术来研究这三个基因的作用，通过执行突变分析，基因-表型关联，测试编码的蛋白质在基于纤毛的鞭毛内运输中的可能作用，并测试动物模型在神经元增殖和轴突引导方面的缺陷。总而言之，这些数据将提供一个框架，以了解这些基因在JSRD疾病谱中的作用。1.我们将对180名JSRD先证者进行全面的突变分析和基因-表型相关性分析，以验证NPHP1或CEP290突变与JSRD合并肾功能衰竭相关，而AHI1突变与JSRD合并皮质异常相关的假设。2.我们将利用功能损失和功能增益分析，测试这些基因在纤毛/中心体上发挥功能以介导Wnt或Sonic Hedgehog信号转导的可能性。3.我们将分析每个基因靶向缺失的小鼠的脑表型，以测试这些通路是否调节小脑颗粒神经元的增殖和轴突引导。

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.