Fibulin-Associated Age-Related Macular Degeneration

描述(申请人提供)：老年性黄斑变性--在发达国家导致严重视力丧失的最常见原因，有显著的遗传因素。这一事实提出了一种可能性，即人类基因组知识的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5的基因突变是老年性黄斑变性的一个具有统计学意义的子集的原因。在这项提案中，我们将在四个不同的层面上探索这一发现。首先，我们将在年龄相关眼病研究(AREDS)中收集的AMD患者和对照人群中筛选三种纤毛蛋白基因(2、5和6)的一部分，以确定我们之前的结果是否可以在这组特征良好的个体中得到证实。我们还将使用一种新的、有重点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腓骨蛋白相关，以确定这些基因中是否有任何一个与AMD的发病机制有关。此外，我们将在组织水平上通过仔细评估腓蛋白2、3和5异常的小鼠的眼睛以及将这些小鼠与ABCA4缺陷小鼠杂交以试图增加它们的表型来探索纤维蛋白相关性AMD的病理生理学。最后，我们将仔细研究37个已知含有腓蛋白基因突变的人类家族，以检验我们在先前研究中在腓蛋白5患者中观察到的表型是整个腓蛋白相关性AMD的特征的假设。该研究的这一部分还将评估这些家族中与年龄相关的腓肠蛋白突变的外显率，这将是决定有一天大规模分子检测腓肠蛋白变异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.