MOLECULAR BASIS OF SYNDROMIC RETINITIS PIGMENTOSA

色素性视网膜炎的分子基础

• 批准号: 6138219
• 负责人: SUSAN J HAYFLICK
• 金额: $ 26.68万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6138219
• 关键词: clinical research; disease /disorder model; electroretinography; gene expression; gene mutation; genetic disorder diagnosis; genetic mapping; genetic markers; genotype; human genetic material tag; human subject; immunocytochemistry; in situ hybridization; magnetic resonance imaging; model design /development; molecular cloning; molecular genetics; molecular pathology; northern blottings; nucleic acid sequence; phenotype; pleiotropism; polymerase chain reaction; retinitis pigmentosa; single strand conformation polymorphism; southern blotting

The goal of this project is to isolate and characterize the gene for a form of syndromic retinitis pigmentosa (RP), called Hallervorden-Spatz syndrome (HSS) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and early, rapidly progressive pigmentary retinopathy. This autosomal recessive disorder of childhood includes extrapyramidal dysfunction with iron accumulation in the basal ganglia. Though lipid peroxidation is an hypothesized mechanism leading to the HSS phenotype, no knowledge exists of the molecular or biochemical defect. We propose a molecular genetic approach to understanding this syndromic form of RP. Our specific aims are to 1) identify the gene for HSS, designated NBIA1 (Neurodegeneration with Brain Iron Accumulation, type 1) by completing the physical map of the critical region, identifying and screening candidate genes, and demonstrating deleterious mutations; 2) develop the molecular diagnosis of HSS using mutation studies and genotype-phenotype correlation; 3) characterize the HSS gene and its protein product at the tissue, cellular, subcellular and molecular levels using homology to model organisms, sequence analysis, histopathology, immunohistochemistry and studies of tissue expression patterns; and 4) isolate the murine homolog of the HSS gene and develop a mouse model for HSS in order to study its pathophysiology. Knowledge about the HSS gene will allow molecular diagnosis in individuals suspected to have this disease. As well, prenatal diagnosis of this fatal condition will be feasible. By delineating the pathophysiologic process in HSS, we may begin to develop rational therapies, which may be of benefit in treating other forms of RP, as well. Rare diseases often illuminate the mechanisms at work in common, related disorders. An advantage to studying syndromic RP is that the pleiotropic manifestations provide a context to help delineate the mechanism of retinopathy. The HSS gene is not retina-specific, and a defect in it must account for rod photoreceptor degeneration as well as regional brain iron accumulation. Furthermore, since defects in this non-retina- specific process may cause other forms of syndromic and isolated RP and may be integral in disorders of lipofuscin accumulation, including aging macular degeneration, identification of the HSS gene may lead to greater understanding of RP as well as the macular dystrophies associated with senescence.

该项目的目的是隔离和表征 综合性视网膜炎色素（RP）的形式称为Hallervorden-Spatz 综合征（HSS），以异常电视图为特征， 脂蛋白在视网膜色素上皮和早期积累 快速进行性色素性视网膜病变。 这个常染色体隐性 童年障碍包括铁的锥体外功能障碍 在基底神经节中积聚。 虽然脂质过氧化是 假设导致HSS表型的机制，不存在知识 分子或生化缺陷的。 我们提出了一个分子遗传 理解这种RP综合征形式的方法。 我们的具体目的是1）确定HSS的基因，指定为NBIA1 （与脑铁的积累一起神经变性，1型）完成 关键区域的物理图，识别和筛选 候选基因，并证明有害突变； 2）开发 使用突变研究和基因型 - 表型对HSS的分子诊断 相关性; 3）表征HSS基因及其蛋白产物在 使用同源性的组织，细胞，亚细胞和分子水平 模型生物，序列分析，组织病理学，免疫组织化学 和组织表达模式的研究； 4）隔离鼠 HSS基因的同源物并为HSS开发小鼠模型 研究其病理生理学。 有关HSS基因的知识将允许分子诊断 个人怀疑患有这种疾病。 同样，产前诊断 这种致命状况是可行的。 通过描述 HSS中的病理生理过程，我们可能会开始发展理性 疗法，这可能有益于将其他形式的RP视为 出色地。 罕见疾病通常会照亮共同工作中的机制 疾病。研究综合征RP的优势是多效性 表现提供了一个背景，以帮助描述 视网膜病。 HSS基因不是视网膜特异性的，并且缺陷 必须考虑杆光感受器变性以及区域 脑铁的积累。 此外，由于在这个非retina-中存在缺陷 特定过程可能导致其他形式的综合症和孤立的RP，以及 在脂肪霉素积累的疾病中可能是不可或缺的，包括衰老 黄斑变性，HSS基因的鉴定可能导致更大 了解RP以及与之相关的黄斑营养不良 衰老。