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.

该项目的目标是分离并表征该基因 色素性视网膜炎综合征 (RP) 的一种形式，称为 Hallervorden-Spatz 综合征（HSS），其特征是视网膜电图异常， 脂褐质在视网膜色素上皮中积累，并且早期， 快速进展的色素性视网膜病变。 这种常染色体隐性遗传 儿童期疾病包括铁锥体外系功能障碍 沉积在基底神经节。 虽然脂质过氧化是 导致 HSS 表型的假设机制，不存在任何知识 分子或生化缺陷。 我们提出了分子遗传学 理解这种 RP 综合征形式的方法。 我们的具体目标是 1) 识别 HSS 基因，命名为 NBIA1 （脑铁积累引起的神经变性，1 型）通过完成 关键区域的物理图，识别和筛选 候选基因，并展示有害突变； 2）开发 利用突变研究和基因型-表型进行 HSS 分子诊断 相关性; 3) 表征HSS基因及其蛋白质产物 使用同源性在组织、细胞、亚细胞和分子水平上 模式生物、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) 隔离小鼠 HSS 基因的同源物并开发 HSS 小鼠模型，以便 研究其病理生理学。 有关 HSS 基因的知识将有助于进行分子诊断 疑似患有这种疾病的人。 还有产前诊断 这种致命的情况将是可行的。 通过描绘 HSS 的病理生理过程，我们可以开始开发合理的方法 疗法，这可能有助于治疗其他形式的 RP，例如 出色地。 罕见疾病常常阐明共同的、相关的工作机制 失调。研究综合征 RP 的一个优点是多效性 表现提供了一个背景来帮助描述机制 视网膜病变。 HSS 基因不是视网膜特异性的，并且存在缺陷 必须考虑杆光感受器变性以及区域性 脑铁积累。 此外，由于这种非视网膜缺陷 特定过程可能会导致其他形式的综合征和孤立性 RP 和 可能是脂褐素积累疾病（包括衰老）中不可或缺的一部分 黄斑变性，HSS基因的鉴定可能会导致更大的黄斑变性 了解 RP 以及与之相关的黄斑营养不良 衰老。