MOLECULAR ANALYSIS GENETIC MUTATIONS IN VISUAL DISEASES

视觉疾病中的基因突变的分子分析

• 批准号: 6164726
• 负责人: ESTHER Elissa BISWAS-FISS
• 金额: $ 15.83万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164726
• 关键词: adenosine triphosphate; adenosinetriphosphatase; chemical binding; gene mutation; human genetic material tag; hydrolysis; membrane transport proteins; molecular pathology; polymerase chain reaction; protein structure function; site directed mutagenesis; vision disorders

DESCRIPTION (Adapted from applicant's abstract): The ROS ABC protein (ABCR) plays an important role in retinal rod cells. Genetic studies have linked mutations in the ABCR gene to a number of inherited human diseases including Stargardt's macular degeneration and age related macular degeneration (ARMD). Like other members of the ABC gene family, the ABCR protein is characterized by two nucleotide binding motifs and two transmembrane domains, each consisting of six membrane-spanning helices. Biochemical studies have suggested that this protein may function as a flipase, moving compounds from the lumenal to the cytosolic face of the disc membrane. Pivotal to this function are the ATP binding and hydrolysis, which presumably provide the energy for this translocation process. Nearly all the ABCR mutations identified in patients with recessive Stargardt's, age related macular degeneration, and fundus flavimaculatus map within the ATP binding cassettes. In addition, these domains are highly conserved between species. The overall aim of this application is to carry out a detailed molecular analysis of the ATP binding domains in the energy transduction process. In particular, we wish to test the hypothesis that mutations previously associated with Stargardt's disease and ARMD influence the energy transduction in retinal transport, particularly the ATP binding and hydrolysis step. We shall investigate this question by analyzing the energetics of recombinant proteins harboring mutations in these domains. Information gained from these studies will not only lead to an understanding of the mechanism of action of the ABCR protein, but will also give insight into the molecular basis of the diseases arising from mutations in this gene. This is in keeping with our long-term goal, which is a systematic molecular analysis of genetic mutations that are responsible for inherited visual disorders so that new and accurate therapies can be developed in the near future.

描述（改编自申请人摘要）：ROS ABC蛋白（ABCR） 在视网膜视杆细胞中起重要作用。基因研究表明 ABCR基因的突变导致许多遗传性人类疾病，包括 Stargardt黄斑变性和年龄相关性黄斑变性（ARMD）。 与ABC基因家族的其他成员一样，ABCR蛋白的特征在于： 两个核苷酸结合基序和两个跨膜结构域，每个由以下组成： 六个跨膜螺旋。生物化学研究表明， 蛋白质可以作为脂肪酶，将化合物从内腔移动到 盘膜的胞质面。与此功能相关的是ATP 结合和水解，这大概为这提供了能量。 易位过程几乎所有在患者中发现的ABCR突变 患有隐性Stargardt's，年龄相关性黄斑变性和眼底 flavimaculatus地图内的ATP结合盒。此外，这些领域 在物种之间是高度保守的。 本申请的总体目标是进行详细的分子生物学研究。 能量转导过程中ATP结合结构域的分析。在 特别是，我们希望测试的假设，突变先前相关 Stargardt病和ARMD对视网膜能量传导的影响 运输，特别是ATP结合和水解步骤。我们将 通过分析重组蛋白的能量学来研究这个问题 在这些结构域中携带突变。从这些研究中获得的信息 不仅有助于理解ABCR的作用机制， 蛋白质，但也将深入了解疾病的分子基础， 由该基因突变引起的。这符合我们的长期 目标，这是一个系统的基因突变的分子分析， 负责遗传性视觉障碍，使新的和准确的治疗方法， 可以在不久的将来开发。