A MULTI-CENTER STUDY TO MAP GENES FOR FUCH'S DYSTROPHY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 富克斯内皮性角膜营养不良(FECD；MIM136800)是一种常见疾病，约占美国总人口的1%。最初无症状，患者最终出现视力下降、异物感和醒来时疼痛。裂隙灯(显微镜)检查最初显示Descemet膜局限性增厚，称为角膜滴眼液，随后出现基质水肿(肿胀)，上皮水肿，晚期出现疼痛的大泡性角膜病变。FECD是单独进行角膜移植或联合白内障手术的常见适应症。此外，患有FECD的白内障手术患者有发生角膜失代偿的极大风险，需要随后进行角膜移植。关于角膜营养不良遗传基础的分子数据有限。由于有大量的人群处于危险之中，识别可能导致营养不良的基因(S)将对咨询、实施治疗干预的标准方法以及最终的基因调节和/或治疗非常有用。在这项研究中，我们建议使用积极的、多中心NEI资助的角膜捐赠者研究(CDS)建立的网络作为纽带，使用联盟模式识别500个FECD家庭。我们将确定晚期FECD的病例，并使用临床严重程度测量作为半定量特征来表征家族聚集的程度。家族史、临床和其他人口统计信息将使用标准化工具收集。将获得晚期指征病例的组织病理学确认。将采集血液样本进行分子遗传分析。正在建立一个基于网络的数据库，以便利多站点数据收集。将利用从索引病例和家庭(N=500个家庭；估计N=500个同胞对)收集的DNA进行全基因组扫描。二次病例对照分析将利用来自家系研究的先证者和配对对照(N=500例；N=500对照)。将结合FECD的临床数据和DNA标记数据进行无模型连锁分析，以识别连锁信号。通过先前对有限数量的家系(例如COL8A2)的调查确定的候选基因将被检查是否有突变。因此，我们将通过在更大的样本中表征它们的作用，在更全球的基础上调查这些基因的重要性。我们预计，这项研究将导致对FECD的病因和角膜内皮生物学的新见解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fuchs'endothelial corneal dystrophy (FECD; MIM136800) is a common disease affecting approximately 1% of the general US population. Initially asymptomatic, individuals eventually present with decreased vision, foreign body sensation and pain upon waking. Slit lamp (microscopic) examination initially shows focal thickenings of the Descemet's membrane known as corneal guttae, with subsequent stromal edema (swelling), epithelial edema and, in advanced stages, painful bullous keratopathy. FECD is a common indication for corneal transplantation alone or in combination with cataract surgery. In addition, individuals undergoing cataract surgery with FECD are at significant risk for corneal decompensation, requiring subsequent corneal transplantation. Molecular data on the genetic basis of corneal dystrophies is limited. With a significant population at risk, the identification of the gene(s) that may contribute to the dystrophy would be very useful for counseling, implementation of standard methods for therapeutic intervention, and ultimately gene modulation and/or therapy. In this study, we propose to use the network built by the active, multi-center NEI-funded Cornea Donor Study (CDS) as the nexus to identify 500 families with FECD using the consortium model. We will identify cases with advanced FECD and characterize the extent of familial clustering using a clinical measure of severity as a semi-quantitative trait. Family history, clinical, and other demographic information will be collected using a standardized instrument. Histopathologic confirmation of advanced index cases will be obtained. Blood samples will be collected for molecular genetic analyses. A web-based database is being constructed to facilitate multi-site data collection. A genome-wide scan will be conducted utilizing DNA collected from the index cases and families (N = 500 families; estimated N = 500 sib pairs). A secondary case-control analysis will be performed utilizing the probands from the family study and matched controls (N=500 cases; N = 500 controls).Model-free linkage analysis will be conducted using the DNA marker data in conjunction with the clinical data on FECD to identify linkage signals. Candidate genes identified through previous investigations of a limited number of families (e.g. COL8A2) will be examined for mutations. Thus, we will investigate the importance of these genes on a more global basis by characterizing their role in a larger sample. We anticipate that this study will lead to novel insights into the etiology of FECD and the biology of the corneal endothelium.