title: RNA toxicity and missplicing in the common eye disease fuchs endothelial corneal dystrophy.
abstract: Fuchs endothelial corneal dystrophy (FECD) is an inherited degenerative disease that affects the internal endothelial cell monolayer of the cornea and can result in corneal edema and vision loss in severe cases. FECD affects ∼5% of middle-aged Caucasians in the United States and accounts for >14,000 corneal transplantations annually. Among the several genes and loci associated with FECD, the strongest association is with an intronic (CTG·CAG)n trinucleotide repeat expansion in the TCF4 gene, which is found in the majority of affected patients. Corneal endothelial cells from FECD patients harbor a poly(CUG)n RNA that can be visualized as RNA foci containing this condensed RNA and associated proteins. Similar to myotonic dystrophy type 1, the poly(CUG)n RNA co-localizes with and sequesters the mRNA-splicing factor MBNL1, leading to missplicing of essential MBNL1-regulated mRNAs. Such foci and missplicing are not observed in similar cells from FECD patients who lack the repeat expansion. RNA-Seq splicing data from the corneal endothelia of FECD patients and controls reveal hundreds of differential alternative splicing events. These include events previously characterized in the context of myotonic dystrophy type 1 and epithelial-to-mesenchymal transition, as well as splicing changes in genes related to proposed mechanisms of FECD pathogenesis. We report the first instance of RNA toxicity and missplicing in a common non-neurological/neuromuscular disease associated with a repeat expansion. The FECD patient population with this (CTG·CAG)n trinucleotide repeat expansion exceeds that of the combined number of patients in all other microsatellite expansion disorders.
authors.affiliation: From the Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 and.
authors.forename: Jintang
authors.initials: J
authors.lastname: Du
authors.affiliation: the Departments of Biochemistry and Molecular Biology.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Aleff
authors.affiliation: From the Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 and.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Soragni
authors.affiliation: Health Science Research, and.
authors.forename: Krishna
authors.initials: K
authors.lastname: Kalari
authors.affiliation: Health Science Research, and.
authors.forename: Jinfu
authors.initials: J
authors.lastname: Nie
authors.affiliation: Health Science Research, and.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Tang
authors.affiliation: Health Science Research, and.
authors.forename: Jaime
authors.initials: J
authors.lastname: Davila
authors.affiliation: Health Science Research, and.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kocher
authors.affiliation: Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Sanjay V
authors.initials: SV
authors.lastname: Patel
authors.affiliation: From the Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 and.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gottesfeld
authors.affiliation: Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Keith H
authors.initials: KH
authors.lastname: Baratz
authors.affiliation: the Departments of Biochemistry and Molecular Biology, wieben.eric@mayo.edu.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Wieben
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D003315:Cornea / Q000378:metabolism / Q000473:pathology; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D012326:RNA Splicing / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C493663:MBNL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors
keywords: Alternative Splicing; Cornea; Eye; Fuchs Corneal Dystrophy; RNA Foci; RNA Splicing; RNA Toxicity; Trinucleotide Repeat Disease