April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
L450W and Q455K Knock-In Mutations in the Col8a2 Gene Cause Fuchs Endothelial Corneal Dystrophy in the Mouse
Huan Meng; Mario Matthaei; Rhonda Grebe; Shukti Chakravarti; Albert Jun
Author Affiliations & Notes
  • Huan Meng
    Ophthalmology, Anterior Segment, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
  • Mario Matthaei
    Ophthalmology, Anterior Segment, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
  • Rhonda Grebe
    Ophthalmology, Anterior Segment, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
  • Shukti Chakravarti
    Ophthalmology, Anterior Segment, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
  • Albert Jun
    Ophthalmology, Anterior Segment, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland
  • Footnotes
    Commercial Relationships  Huan Meng, None; Mario Matthaei, None; Rhonda Grebe, None; Shukti Chakravarti, None; Albert Jun, None
  • Footnotes
    Support  National Eye Institute Grant RO1EY019874 (AJ), EY01765 (Wilmer Core Module for Microscopy and Imaging), Research to Prevent Blindness Career Development and Special Scholar Awards (AJ)
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 6600. doi:
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      Huan Meng, Mario Matthaei, Rhonda Grebe, Shukti Chakravarti, Albert Jun; L450W and Q455K Knock-In Mutations in the Col8a2 Gene Cause Fuchs Endothelial Corneal Dystrophy in the Mouse. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6600.

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Abstract

Purpose: : Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal vision loss. The L450W and Q455K missense mutations in the alpha-2 collagen VIII encoding gene COL8A2 result in highly penetrant, early-onset disease. Here, we report two transgenic knock-in mouse lines, Col8a2L450W and Col8a2Q455K that closely recapitulate the corneal pathology of FECD.

Methods: : In vivo endothelial cell counts, morphology, and Descemet membrane features were imaged and analyzed via confocal microscopy using the NIDEK Confocal Microscope. Ultrastructural analysis of endothelial cells and Descemets membrane was performed using transmission electron microscopy (TEM), and endothelial cell apoptosis was detected by TUNEL assay.

Results: : Col8a2 mutant mice showed enlarged, irregularly-shaped endothelial cells with excrescences of Descemet membrane (guttae) characteristic of FECD. In vivo confocal microscopy at 20 weeks revealed a 13% (p<.05) and 29% (p<.0001) decrease in endothelial cell counts in Col8a2L450W and Col8a2Q455K, respectively, compared to age-matched wild-type mice. 40-week-old mice demonstrated even greater cell loss, with Col8a2L450W and Col8a2Q455K having 30% (p<.0001) and 41% (p<.0001) fewer cells, respectively, than age-matched wild-type mice. Furthermore, we observed 20-week-old Col8a2 transgenic mice to have an average of 2.3±0.3 (n=26) TUNEL-positive cells per central corneal cross-section compared to 0.3±0.1 (n=19) in age-matched controls (p<.0001). TEM of corneas from transgenic mice revealed redundant, dilated endoplasmic reticulum consistent with the ultrastructural hallmarks of explanted FECD corneal tissues.

Conclusions: : Taken together, these results suggest that missense mutations in murine Col8a2 lead to apoptosis, endothelial cell loss, and basement membrane alterations strikingly similar to human FECD. We conclude that Col8a2L450W and Col8a2Q455K transgenic mice represent important model systems in which future studies of the pathophysiology and potential therapies for FECD can be undertaken.

Keywords: cornea: endothelium • transgenics/knock-outs • apoptosis/cell death 
© 2011, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2024 Association for Research in Vision and Ophthalmology.
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