Inheritance of a Novel COL8A2 Mutation Defines a Distinct Subtype of Fuchs' Corneal Dystrophy

Abstract

Abstract: : Purpose:To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). Methods:DNA from blood was used for genome–wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR–amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet’s membrane that are characteristic of FCD. Results:We obtained linkage to 1p34.3–p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, as compared to an average onset age of 50 estimated for 201 familial FCD patients in 62 other families. Conclusions:We have identified a novel pathogenic L450W COL8A2 mutation and characterized its highly distinctive pathology, which indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2–FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late–onset FCD.

Keywords: cornea: endothelium • genetics • extracellular matrix