Abstract

Fuchs Endothelial Corneal Dystrophy (FECD) is a late onset, autosomal dominant eye disease that can lead to loss of vision. Expansion of a CTG trinucleotide repeat in the third intron of the transcription factor 4 (TCF4) gene is highly associated with FECD. However, only about 75% of FECD patients in the northern European population possess an expansion of this repeat. The remaining FECD cases appear to be associated with variants in other genes. To better understand the pathophysiology of this disease, we compared gene expression profiles of corneal endothelium from FECD patients with an expanded trinucleotide repeat (RE+) to those that do not have a repeat expansion (RE-). Comparative analysis of these two cohorts showed widespread RNA mis-splicing in RE+, but not in RE- samples. Quantitatively, we identified 39 genes in which expression was significantly different between RE+ and RE- samples. Examination of the mutation profiles in the RE- samples did not find any mutations in genes previously associated with FECD, but did reveal one sample with a rare variant of laminin subunit gamma 1 (LAMC1) and three samples with rare variants in the gene coding for the mitochondrial protein peripheral-type benzodiazepine receptor-associated protein 1 (TSPOAP1).

Highlights

  • Fuchs endothelial corneal dystrophy (FECD) is a common, heritable degeneration of the corneal endothelium with considerable locus heterogeneity

  • In this study we examined corneal endothelial tissue from eyes with FECD to analyze for differences in RNA splicing patterns and gene expression between subjects with transcription factor 4 (TCF4) trinucleotide repeat expansion (RE+) and those without this expansion (RE-)

  • An expansion of a CTG repeat sequence in the TCF4 gene is by far the most common genetic anomaly found in FECD patients in the United States [1, 11, 12]

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Summary

Introduction

Fuchs endothelial corneal dystrophy (FECD) is a common, heritable degeneration of the corneal endothelium with considerable locus heterogeneity. Mutations in 7 genes (AGBL1, COL8A2, LOXHD1, SLC4A11, TCF4, ZEB1, DMPK) have been shown to be either causal or highly associated with the disease [1,2,3,4,5,6,7,8,9]. A recent large genome-wide association study of FECD added an additional 3 genes to the candidate list (KANK4, LAMC1 and LINC00970/ ATP1B1) and re-confirmed the strongest genetic signal for FECD in a predominantly. Gene expression in FECD patients with and without expansion of a trinucleotide repeat in TCF4 had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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