Fuchs Corneal Dystrophy: Aberrant Collagen Distribution in an L450W Mutant of the COL8A2 Gene

• Published in: Investigative ophthalmology & visual science Vol. 46; no. 12; pp. 4504 - 4511
• Main Authors: Gottsch, John D, Zhang, Cheng, Sundin, Olof H, Bell, W. Robert, Stark, Walter J, Green, W. Richard
• Format: Journal Article
• Language: English
• Published: Rockville, MD ARVO 01.12.2005; Association for Research in Vision and Ophtalmology
• Subjects: Biological and medical sciences; Collagen Type IV - metabolism; Collagen Type VIII - genetics; Collagen Type VIII - metabolism; Descemet Membrane - metabolism; Descemet Membrane - pathology; Diseases of cornea, anterior segment and sclera; Eye and associated structures. Visual pathways and centers. Vision; Fibronectins - metabolism; Fluorescent Antibody Technique, Indirect; Fuchs' Endothelial Dystrophy - genetics; Fuchs' Endothelial Dystrophy - metabolism; Fuchs' Endothelial Dystrophy - pathology; Fundamental and applied biological sciences. Psychology; Humans; Laminin - metabolism; Medical sciences; Microscopy, Confocal; Mutation; Ophthalmology; Vertebrates: nervous system and sense organs; Eye disease; Gene; Corneal dystrophy; Collagen; Distribution; Keratopathy; Anomaly; Ophthalmology; Anterior segment disease
• ISSN: 0146-0404; 1552-5783; 1552-5783
• DOI: 10.1167/iovs.05-0497

To characterize histologically Descemet's membrane in an early-onset Fuchs corneal dystrophy (FCD) COL8A2 mutant and compare these findings with corneas from late-onset FCD and normal corneas. A corneal explant from a patient with the L450W COL8A2 mutation and others with late-onset disease were studied with antibodies to collagens IV, VIIIA1, VIIIA2, fibronectin, and laminin. Transmission electron microscopy was performed on a portion of the explant. Control explants included eye bank corneas without known disease and surgical explants from unrelated conditions. In normal corneas, a regular array of colocalized COL8A1 and COL8A2 was observed in the anterior half of Descemet's membrane. In the L450W mutant, Descemet's membrane was several times thicker than normal and traversed by refractile strands and blebs that stained intensely for COL8A2, a feature also observed in late-onset FCD. Both the alpha1 and alpha2 subtypes of collagen VIII were observed at high levels along the anterior edge of Descemet's, another abnormal feature also found in late-onset FCD. Ultrastructure of the L450W cornea revealed a well-formed anterior banded layer more than three times thicker than normal. An unusual, thin internal layer was rich in patches of wide-spaced collagen. The layer is a distinctive pathologic structure that is associated with FCD and is characterized by approximately 120 nm periodicity and the presence of collagen VIII. Depositions of collagen IV, fibronectin, and laminin were also greatly increased in the of posterior Descemet's membrane, yet another general feature shared between early- and late-onset disease. Early-onset COL8A2 L450W disease involves massive accumulation and abnormal assembly of collagen VIII within Descemet's membrane, a process that is presumed to begin during fetal development. Both early- and late-onset subtypes of FCD appear to be the result of abnormal basement membrane assembly rather than a primary defect in endothelial metabolism.