Two Forms of Corneal Endothelial Dystrophy Caused by Mutations in COL8A2: The Gene Encoding the Alpha-2 Chain of Type VIII Collagen

Abstract

Abstract: : Purpose: To demonstrate the molecular genetic mechanisms underlying the corneal endothelial dystrophies. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD) and posterior polymorphous dystrophy (PPMD). Methods: A genome-wide search was undertaken on a 3 generation family with early-onset FECD. This successfully demonstrated significant linkage with D1S2830 (Zmax = 3.72, θ = 0.0). Refinement of the critical region defined a 6-7cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha-2 chain of type VIII collagen, a short chain collagen which is a major structural component of Descemet's membrane therefore representing a strong candidate gene. The coding region of this gene was defined and sequenced in all members in this family. Mutation analysis was extended to other families with inherited endothelial dystrophies and simplex cases. Results: Analysis of the coding sequence of COL8A2 defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPMD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPMD. Ultrastructural examination of excised corneas from affected individuals demonstrated a thickened posterior collagenous layer in the posterior zone of Descemet's membrane comprising type VIII collagen deposited in a deranged manner. Conclusion: This is the first description, with ultrastructural correlates, of the molecular basis of any of the corneal endothelial dystrophies or of mutations in the gene encoding type VIII collagen in association with human disease. Type VIII collagen in Descemet's membrane may influence the terminal differentiation of the neural crest derived endothelial cell. The pathogenesis of FECD and PPMD may be related to dysfunctional interaction between the endothelial cell and Descemet's membrane.

Keywords: 476 molecular biology • 371 cornea: endothelium • 420 genetics