Molecular basis of Joubert syndrome and related diseases

Joubert综合征及相关疾病的分子基础

• 批准号: 6879585
• 负责人: MELISSA ANN PARISI
• 金额: $ 16.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-16 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879585
• 关键词: autosomal recessive trait; brain disorders; brain imaging /visualization /scanning; brain stem; cerebellar disorders; clinical research; developmental genetics; family genetics; gene expression; gene mutation; genetic markers; genetic screening; genotype; high performance liquid chromatography; human genetic material tag; immunocytochemistry; in situ hybridization; linkage mapping; molecular genetics; molecular pathology; neurogenetics; nucleic acid sequence; phenotype; polymerase chain reaction; restriction fragment length polymorphism; western blottings

DESCRIPTION (provided by applicant): The purpose of this training grant is to help establish the applicant's independent research career in the field of clinical neurogenetics by investigating the molecular and genetic basis of Joubert syndrome (JS), an autosomal recessive malformation syndrome associated with agenesis of the cerebellar vermis and brainstem malformations. The training environment is the laboratory of Dr. Phillip Chance at the University of Washington, with a track record in mapping and identifying the genes for hereditary neurological disorders. Clinical core features of JS are hypotonia, developmental delay, abnormal respiratory patterns and unusual eye movements. Furthermore, JS exhibits variable additional clinical features (e.g., retinopathy, nephropathy), and is likely to represent a spectrum of disorders with the common feature of cerebellar vermis hypoplasia. Genetic locus heterogeneity is evident. Although loci for JS have been proposed on chromosomes 9q34 and 17pl 1.2, in the majority of JS pedigrees, the locus is unknown and no specific gene has yet been found to be causal for JS. Genes crucial to cerebellar and brainstem development are functional JS candidates, particularly genes specifying the vermian domain and granule cell lineage during cerebellar development. To map an additional gene (or genes) for JS and to determine the molecular basis of this and related disorders, I propose to: 1) Ascertain and collect medical records and blood samples for DNA isolation form multiple families with JS, particularly consanguineous and multiplex pedigrees, 2) develop a prioritized list of candidate genes for JS utilizing genetic methods that include focused haplotype analysis of these genes in consanguineous and multiplex families as well as functional examination of candidate gene expression in human fetal brain tissue, and 3) screen the best candidate genes for mutations in individuals with JS. The fourth and final goal will be to carry out a genome-wide linkage scan to identify loci for JS utilizing a combination of methods employing homozygosity mapping and/or high-resolution linkage analysis in multiplex pedigrees. This project will allow the applicant to complement her experience in clinical genetics and developmental molecular biology with the clinical research skills to define the molecular basis of this important group of cerebellar malformation syndromes.

描述（由申请人提供）：这项培训补助金的目的是通过研究乔伯特综合征（JS）的分子和遗传基础（JS）（一种与Cerebellar vermis and Brainstele和脑部畸形相关的常染色体隐性畸形综合征）来帮助建立申请人在临床神经源性领域的独立研究职业。培训环境是华盛顿大学Phillip Chance博士的实验室，其记录记录在映射和识别遗传神经系统疾病的基因方面。 JS的临床核心特征是肌张力低下，发育延迟，异常呼吸模式和异常的眼球运动。此外，JS表现出可变的其他临床特征（例如视网膜病变，肾病），并且可能代表具有小脑vermis垂体性低下常见特征的疾病谱。遗传基因座异质性是显而易见的。尽管已在9q34和17pl 1.2的染色体上提出了JS的基因座，但在大多数JS的谱系中，该基因座是未知的，尚未发现尚无特定基因是JS的原因。对小脑和脑干发育至关重要的基因是功能性JS候选者，尤其是在小脑发育过程中指定vermian结构域和颗粒细胞谱系的基因。 To map an additional gene (or genes) for JS and to determine the molecular basis of this and related disorders, I propose to: 1) Ascertain and collect medical records and blood samples for DNA isolation form multiple families with JS, particularly consanguineous and multiplex pedigrees, 2) develop a prioritized list of candidate genes for JS utilizing genetic methods that include focused haplotype analysis of these genes in consanguineous and multiplex families as以及对人胎儿脑组织中候选基因表达的功能检查，以及3）筛选JS个体突变的最佳候选基因。第四个也是最终目标是进行全基因组链接扫描，以识别JS的基因座，利用在多重谱系中采用纯合性映射和/或高分辨率链接分析的方法组合。该项目将允许申请人通过临床研究技能来补充她在临床遗传学和发育分子生物学方面的经验，以定义这一重要的小脑畸形综合征的分子基础。