Development of congenital stromal corneal dystrophy is dependent on export and extracellular deposition of truncated decorin.

PURPOSE: Congenital stromal corneal dystrophy (CSCD) is an autosomal dominant condition with clouding of the cornea due to stromal opacities. It is caused by mutations in the decorin gene (DCN) leading to the expression of a truncated form of decorin. In an attempt to replicate this condition in mice, a knock-in mouse strain, 952delT Dcn, was created.

METHODS: Mice were constructed by targeted mutation. Sequencing of genomic DNA confirmed correct genotype. Mouse and human corneas, including corneas from patients with CSCD, and primary keratocyte cultures were subjected to Western blot analysis, transmission electron microscopy, and immunofluorescence microscopy.

RESULTS: Histologically, the mice did not show any organ pathology. Corneas were clear, and the electron-lucent deposits observed in CSCD were not present. Furthermore, while nearly equivalent amounts of normal and truncated decorin are present in CSCD corneas, truncated decorin was hardly detectable in the mouse corneas. By immunofluorescence analysis of corneas from 952delT Dcn homozygous mice, decorin was found only in keratocytes. In primary cultures of mouse corneal explants, truncated decorin was retained intracellularly in contrast with human corneal explants where truncated decorin was exported into the culture medium. Immunofluorescence analysis revealed that native mouse decorin localized to the Golgi complex, whereas the truncated decorin accumulated in the endoplasmic reticulum (ER).

CONCLUSIONS: The ER retention of truncated decorin may explain why the mouse corneas remained clear. The consequences of the decorin mutation are different in mice and humans, and 952delT Dcn knock-in mice are therefore not a suitable model for CSCD.