title: Fuchs corneal dystrophy: aberrant collagen distribution in an L450W mutant of the COL8A2 gene.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Center for Corneal Genetics, Cornea and External Disease Service, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. jgottsch@jhmi.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Gottsch
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Olof H
authors.initials: OH
authors.lastname: Sundin
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bell
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Stark
authors.forename: W Richard
authors.initials: WR
authors.lastname: Green
mesh_terms: D024141:Collagen Type IV / Q000378:metabolism*; D024102:Collagen Type VIII / Q000235:genetics / Q000378:metabolism*; D003886:Descemet Membrane / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007797:Laminin / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation
chemical_list: C443712:COL8A2 protein, human; D024141:Collagen Type IV; D024102:Collagen Type VIII; D005353:Fibronectins; D007797:Laminin