Fibulin-Associated Age-Related Macular Degeneration

描述（由申请人提供）：年龄相关性黄斑变性-发达国家严重视力丧失的最常见原因，具有重要的遗传成分。这一事实提出了一种可能性，即人类基因组知识的不断扩展可以用来提高我们诊断和治疗这种疾病的能力。最近，我们证明了编码细胞外基质蛋白纤维蛋白5的基因突变是年龄相关性黄斑变性的一个统计显著亚群的原因。在本提案中，我们将在四个不同的层面上探索这一发现。首先，我们将筛选作为年龄相关眼病研究（AREDS）的一部分收集的AMD患者和对照组的三种纤维蛋白基因（2、5和6）的部分，以确定我们之前的结果是否可以在这一特征明确的个体组中得到证实。我们还将使用一种新颖的、集中的筛选方法来评估至少25个其他基因，这些基因的蛋白质在功能上与纤维蛋白相关，以确定这些基因是否也参与了AMD的发病机制。此外，我们将通过仔细评估纤维蛋白2、3和5异常小鼠的眼睛，以及将这些小鼠与ABCA4缺陷小鼠杂交，试图增加其表型，在组织水平上探索纤维蛋白相关AMD的病理生理。最后，我们将仔细研究37个已知含有纤维蛋白基因突变的人类物种，以验证我们在先前研究中在纤维蛋白5患者中观察到的表型是纤维蛋白相关AMD整体特征的假设。研究的这一部分还将评估这些类型中纤维蛋白突变的年龄依赖性外显率，这将是决定大规模的纤维蛋白变异分子测试是否有价值的关键因素。

DESCRIPTION (provided by applicant): Age-related macular degeneration - the most common cause of severe visual loss in the developed world has a significant genetic component. This fact raises the possibility that the expanding knowledge of the human genome can be used to improve our ability to diagnose and treat this disorder. Recently, we demonstrated that mutations in the gene encoding an extracellular matrix protein known as fibulin 5 are responsible for a statistically significant subset of age-related macular degeneration. In this proposal, we will pursue this discovery at four different levels. First we will screen portions of three fibulin genes (2, 5, and 6) in the cohort of AMD patients and controls that were gathered as part of the Age-Related Eye Disease Study (AREDS) to determine whether our previous results can be confirmed in this well characterized group of individuals. We will also use a novel, focused screening approach to evaluate a minimum of 25 other genes whose proteins are functionally related to the fibulins to determine whether any of these are also involved in the pathogenesis of AMD. In addition, we will explore the pathophysiology of fibulin associated AMD at the tissue level by carefully evaluating the eyes of mice with abnormalities in fibulins 2, 3 and 5 as well as by crossing these mice to ABCA4 deficient mice in an attempt to augment their phenotype. Finally, we will carefully study 37 human kindreds already known to harbor mutations in fibulin genes to test the hypothesis that the phenotype we observed in the fibulin 5 patients in our previous study is characteristic of fibulin associated AMD as a whole. This part of the study will also assess the age-dependent penetrance of fibulin mutations in these kindreds, which will be a critical factor in determining whether large scale molecular testing for fibulin variations will someday be of value.