Posterior polymorphous corneal dystrophy (PPCD, PPMD, PPD; OMIM # 122000) is a dominantly inherited disorder of the corneal endothelium that is associated with a wide spectrum of clinical features and courses ranging from benign to profound visual loss from corneal swelling with or without associated glaucoma, which develops in approximately 15% of patients. PPCD has been mapped to chromosome 20p11-q11 with a maximum observed LOD score of 5.54 at theta = 0.0 with marker D20S45. Analysis of recombination events in 4 of the 21 affected patients in a single large family revealed that the PPCD gene is located in the 30 cM region between markers D20S98 and D20S108. The objective of this proposal is to identify and characterize the gene(s) responsible for PPCD. This will be accomplished as follows: 1. Better define the minimal candidate genomic region for PPCD. Perform linkage analysis in previously identified and additional new families to continue to fine map the disease locus, narrowing the candidate region, and therefore the number of candidate genes for PPCD. Examine patients with deletions in the candidate gene region of chromosome 20 for clinical features of PPCD, thereby ruling in or out candidate genes in the affected portion of the disease interval. 2. Select and prioritize candidate genes. Determine which genes are expressed in the adult human corneal endothelium. Microarray analyses (normal corneal endothelium, corneal endothelium in PPCD). Serial analysis of gene expression (SAGE). Determine which of the genes found to be expressed in the corneal endothelium map to the candidate gene region (positional approach). Analyze the function of the genes that map to the defined candidate interval, selecting those that may, when mutated, result in the clinical and histopathologic abnormalities seen in PPCD (functional approach). 3. Perform candidate gene screening. Identify sequence variants in the candidate genes. Determine whether identified sequence variants are polymorphisms or mutations. Discovery of the genetic basis of PPCD will provide a definitive means to distinguish it from other conditions with overlapping clinical features and to identify those at increased risk for vision loss from glaucoma as well as provide a greater understanding of the mechanisms of glaucoma development. Additionally, manipulation of this gene may allow researchers to induce the controlled proliferation of corneal endothelial cells in vivo or in vitro, providing an alternative to corneal transplantation for patients with an insufficient number of corneal endothelial cells to maintain corneal clarity, one of the most common indications for corneal transplantation worldwide. ? ?
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