Jouberin and Nephrocystin in Joubert Syndrome

Jouberin 和肾囊肿素治疗 Joubert 综合征

• 批准号: 7591766
• 负责人: JOSEPH G GLEESON
• 金额: $ 34.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591766
• 关键词: Animal Model; Ataxia; Autistic Disorder; Brain; Brain imaging; Breathing; Cell Proliferation; Cells; Centrosome; Cerebellar malformation; Cerebellar vermis structure; Cerebellum; Cerebrum; Childhood; Cilia; Classification; Clinical; Cognitive; Complex; Consanguinity; Contralateral; Cytoplasmic Granules; DNA; Data; Data Analyses; Defect; Development; Diagnostic; Disease; Employee Strikes; Eye Movements; Functional Magnetic Resonance Imaging; Genes; Genetic; Genotype; Heterogeneity; Human; Incidence; Inherited; Ipsilateral; Joubert syndrome; Kidney; Kidney Failure; Knockout Mice; Lead; Light; Mediating; Mental Retardation; Microgyria; Midbrain structure; Molar tooth; Molecular; Morphogenesis; Motor; Mus; Muscle hypotonia; Mutation; Mutation Analysis; Names; Nephronophthisis; Neurons; Output; Pathway interactions; Patients; Pattern; Phenotype; Prevalence; Proteins; Publishing; Retinal; Role; SHH gene; Sampling; Screening procedure; Sensory; Side; Signal Transduction; Subgroup; Syndrome; Techniques; Termination of pregnancy; Testing; Therapeutic; axon guidance; base; cohort; congenital retinal blindness; early childhood; gain of function; gene cloning; gene function; hindbrain; indexing; malformation; neurobehavioral disorder; neuropsychological; novel; proband; protein function; smoothened signaling pathway

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.

描述（由申请人提供）：先天性共济失调在儿童早期表现为非进行性肌张力减退、认知、粗大和精细运动延迟。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综合征和相关疾病（JSRD）构成了这些疾病的一个子集，包括小脑中线（小脑蚓部）畸形和脑成像（MTI）上几乎特异性的臼齿征。在JSRD中存在显著的表型异质性：一些患者显示经典形式（限于大脑），其他患者还显示先天性视网膜盲、进行性肾衰竭、大脑皮质异常或显著的大脑布线表型，其中每个大脑皮质半球将输出投射到身体的同侧，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NPHP 1和AHI 1的突变与JSRD相关。在一个令人兴奋的新进展中，我们确定了第三个JSRD基因，CEP 290（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，测试编码的蛋白质在纤毛为基础的鞭毛内运输的可能作用，并测试动物模型的缺陷，神经元增殖和轴突的指导。这些数据将共同提供一个框架，以了解这些基因在JSRD中所见的疾病谱中的作用。1.我们将在180名JSRD先证者队列中进行全面的突变分析和基因型-表型相关性，以检验NPHP 1或CEP 290突变与JSRD加肾衰竭相关，而AHI 1突变与JSRD加皮质异常相关的假设。2.我们将测试的可能性，这些基因的功能在纤毛/中心体介导的Wnt或Sonic刺猬信号的转导，使用损失和获得的功能分析。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增殖和轴突导向。