Jouberin and Nephrocystin in Joubert Syndrome

Jouberin 和肾囊肿素治疗 Joubert 综合征

• 批准号: 7430437
• 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/7430437
• 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; Condition; 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; Localized; Mediating; Mental Retardation; Microgyria; Midbrain structure; Molar tooth; Molecular; Morphogenesis; Motor; Mus; Muscle hypotonia; Mutation; Mutation Analysis; Names; Nephronophthisis; Neurons; Numbers; 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）：先天性共济失调出现在儿童早期，伴有非进行性肌张力低下、认知、粗大和精细运动迟缓。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。朱伯特综合征及相关疾病 (JSRD) 是这些病症的一个子集，包括小脑中线（蚓部）畸形和脑成像 (MTI) 上几乎特有的磨牙征象。 JSRD 存在显着的表型异质性：一些患者表现出经典形式（仅限于大脑），而另一些患者则表现出先天性视网膜失明、进行性肾衰竭、大脑皮质异常或显着的大脑接线表型，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。这些病症的细胞和发育基础尚不清楚。 NPHP1 和 AHI1 两个基因的突变与 JSRD 相关。在一项令人兴奋的新进展中，我们确定了第三个 JSRD 基因 CEP290（已提交）。令人信服的证据表明这些蛋白质在纤毛/中心体上发挥作用。在这里，我们建议应用分子技术通过进行突变分析、基因型-表型相关性来研究这三个基因的作用，测试编码蛋白在基于纤毛的鞭毛内运输中的可能作用，并测试动物模型的神经元增殖和轴突引导缺陷。这些数据将共同提供一个框架，以了解这些基因在 JSRD 的一系列病症中的作用。 1. 我们将对 180 名 JSRD 先证者进行全面的突变分析和基因型-表型相关性，以检验 NPHP1 或 CEP290 突变与 JSRD 合并肾衰竭相关，而 AHI1 突变与 JSRD 合并皮质异常相关的假设。 2. 我们将使用功能丧失和获得功能分析来测试这些基因在纤毛/中心体上发挥作用以介导 Wnt 或 Sonic Hedgehog 信号转导的可能性。 3. 我们将分析每个基因定向删除的小鼠的大脑表型，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。