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Yelena Bykhovskaya, Helen P Makarenkova, Yaron S Rabinowitz; Expression studies of keratoconus corneal buttons reveal abnormalities in the regulation of extracellular matrix and adhesion molecules. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1010.
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Keratoconus (KC) is a non-inflammatory corneal disorder of complex genetic inheritance characterized by progressive corneal thinning. Genes encoding proteins of extracellular matrix (ECM), including collagens, and adhesion molecules have been proposed to contribute to normal variation of central corneal thickness and a number of corneal diseases, including KC. In this study we performed expression study to identify changes in the expression of these genes in KC patients, patients with corneal opacities, and controls.
We analyzed 20 corneal tissue samples from 13 KC patients, 2 patients with corneal opacities and 5controls. We used Human Extracellular Matrix & Adhesion Molecules Profiler PCR Array (SABiosciences) to measure expression levels of 84 genes using total RNA extracted from the corneal tissue. To identify statistically significant changes in gene expression, Ct values were analyzed using the Data Analysis software v.3.5 (SABiosciences).
Unsupervised clustering analysis revealed several distinct expression signatures between KC patients, patients with corneal opacities, and normal controls. Comparison of KC and control corneas with thresholds of fold change of 1.5 or greater and p-value of 0.05 or lower, revealed 25 differentially expressed genes, 17 genes were significantly downregulated and 8 upregulated. Among transcripts downregulated in KC patients we identified several collagens, integrins, metalloproteinases, as well as tissue inhibitors of metalloproteinases, THBS1, and FN1. Among upregulated genes, we identified TGFBI (p=0.0009), which plays a role in cell-collagen interactions, and was previously identified in the KC library constructed by our group. TGFBI mutations have been linked to several corneal dystrophies and its overexpression in the transgenic mice results in the abnormal corneas.
Based on the results of our study we find that change of the expression of multiple collagens and related proteins (i.e. TGFBI) may be largely responsible for the thinning of the corneal stroma whereas decrease in FN1 and THBS1 may potentially affect corneal repair. These expression results provide further support to the potential deregulation of ECM and adhesion proteins as contributors to the development of KC.
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