Molecular bases of corneal endothelial dystrophies - PubMed (original) (raw)

Review

Molecular bases of corneal endothelial dystrophies

Thore Schmedt et al. Exp Eye Res. 2012 Feb.

Abstract

The phrase "corneal endothelial dystrophies" embraces a group of bilateral corneal conditions that are characterized by a non-inflammatory and progressive degradation of corneal endothelium. Corneal endothelial cells exhibit a high pump site density and, along with barrier function, are responsible for maintaining the cornea in its natural state of relative dehydration. Gradual loss of endothelial cells leads to an insufficient water outflow, resulting in corneal edema and loss of vision. Since the pathologic mechanisms remain largely unknown, the only current treatment option is surgical transplantation when vision is severely impaired. In the past decade, important steps have been taken to understand how endothelial degeneration progresses on the molecular level. Studies of affected multigenerational families and sporadic cases identified genes and chromosomal loci, and revealed either Mendelian or complex disorder inheritance patterns. Mutations have been detected in genes that carry important structural, metabolic, cytoprotective, and regulatory functions in corneal endothelium. In addition to genetic predisposition, environmental factors like oxidative stress were found to be involved in the pathogenesis of endotheliopathies. This review summarizes and crosslinks the recent progress on deciphering the molecular bases of corneal endothelial dystrophies.

Copyright © 2011 Elsevier Ltd. All rights reserved.

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Figures

Fig. 1

Fig. 1

A. Confocal microscopy of a patient with FECD. Black areas (arrowheads) represent corneal guttae that are scattered in between corneal endothelial cells, disrupting a normally continuous layer of hexagonally shaped cells. B. Magnified view of one corneal gutta (arrowhead) with a center devoid of corneal endothelial cells. The remaining endothelial cells cluster around the gutta, staining positive for TUNEL (red), a marker of apoptosis, and positive for 8-OHdG (green), a marker of oxidative DNA damage.

Fig. 2

Fig. 2

Topology model for human SLC4All. Numbers indicate amino acid position. Predicted N-glycosylation sites are in black, and the branched structures represent oligosaccharide moieties. Black and gray arrowheads indicate trypsin cleavage sites identified through partial digestion of Myc-SLC4A11 and SLC4A11-Myc, respectively, as described in Vilas et al., 2011 (Vilas, G.L. et al., 2011). Identified point mutations causing CHED2 (blue filled), FECD (red filled), and Harboyan syndrome (orange filled) are indicated (see also Vilas et al. 2011, Refs. 4-6, 11,12,34,37,39,41,42). S213 was identified as mutated in both Harboyan syndrome and CHED2 and is shown in filled blue and orange, accordingly. Asterisks indicate residues where two different point mutations have been found to cause disease.

Fig. 3

Fig. 3

Diagram of the pathogenesis of FECD. Oxidative stress and genetic factors combined with endothelial cell post-mitotic arrest may lead to oxidant-antioxidant imbalance, oxidative mitochondrial DNA damage, endothelial morphological changes and apoptosis, and cause the corneal edema seen in FECD.

Fig. 4

Fig. 4

Specular photomicrographs of normal (A) and PPCD endothelium (B-E). PPCD endothelium displays pleomorphism, polymegethism, and vesicular lesions. Light microscopy detects oen layer of regular flat cells in normal endothelium (F). In PPCD, endothelium is composed of multilayered cells with prominent round nuclei and numerous projections (G,H). Red-propidium iodide. Courtesy of P. Liskova, M.D., Laboratory of the Biology and Pathology of the Eye, Charles University, Prague).

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