Genetics of Fuchs Corneal Dystrophy

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DESCRIPTION: Fuchs corneal dystrophy (FCD) is a degenerative disorder characterized by the proliferation of guttae, which are microscopic protrusions of the collagen-rich extracellular matrix that supports the corneal endothelium. Initial stages of FCD show progressively increasing numbers of these guttae, while end stage disease exhibits, in addition, functional defects in the endothelium that cause an influx of water and severe clouding of the corneal stroma. How the guttae relate to this endothelial dysfunction remains unknown. About 4% of those who are 40 or older are affected by FCD. The only effective treatment for end stage disease is corneal transplant surgery, and FCD is now the most common reason for such surgery. Mutations in the COL8A2 gene, which encodes a subunit of collagen VIII, have been definitively associated with a rare childhood-onset form of FCD. Whether mutations in COL8A2 are also involved in the common adult-onset forms of the disease is less clear. We plan to investigate adult-onset FCD as follows: 1) We have recently mapped the first locus for adult-onset FCD to the chromosome 13pTel-q12.13 interval, with a maximum LOD scores of 3.91 and 3.80. We plan to refine this map and identify the mutant gene. 2) Our genome-wide linkage analysis of 3 additional large families with adult-onset FCD has revealed that each of them is linked to the same locus at 18q21, with a combined multi-point LOD score of 5.94 at 85% penetrance. The current disease interval contains 28 candidates; we propose to identify the gene by narrowing the interval by screening gene candidates by sequence analysis and more detailed mapping of the interval by SNP haplotype association. Our long term goal is to identify the genes underlying adult-onset FCD. Ultimately, knowing the identity of these genes will provide important insights into disease mechanisms. This should contribute towards improved early diagnosis and the development of non-surgical treatments for Fuchs Corneal Dystrophy.