RNA Toxicity and Missplicing in the Common Eye Disease Fuchs Endothelial Corneal Dystrophy

摘要: Fuchs endothelial corneal dystrophy (FECD) is an inherited degenerative disease that affects the internal cell monolayer of cornea and can result in edema vision loss severe cases. FECD ∼5% middle-aged Caucasians United States accounts for >14,000 transplantations annually. Among several genes loci associated with FECD, strongest association intronic (CTG·CAG)n trinucleotide repeat expansion TCF4 gene, which found majority affected patients. Corneal cells from patients harbor a poly(CUG)n RNA be visualized as foci containing this condensed proteins. Similar to myotonic type 1, co-localizes sequesters mRNA-splicing factor MBNL1, leading missplicing essential MBNL1-regulated mRNAs. Such are not observed similar who lack expansion. RNA-Seq splicing data endothelia controls reveal hundreds differential alternative events. These include events previously characterized context 1 epithelial-to-mesenchymal transition, well changes related proposed mechanisms pathogenesis. We report first instance toxicity common non-neurological/neuromuscular The patient population exceeds combined number all other microsatellite disorders.