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). 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.
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