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Keith H Baratz, Michael P Fautsch, Ross A. Aleff, Xiaojia Tang, Krishna R. Kalari, Sanjay V Patel, Leo J. Maguire, Eric Wieben; CTG Repeat Expansion in TCF4 without Phenotypic Fuchs Dystrophy: a Genetic Analysis. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3876.
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© ARVO (1962-2015); The Authors (2016-present)
Fuchs Endothelial Corneal Dystrophy (FECD) is associated with a CTG trinucleotide repeat expansion (RE+) situated in an intron of the TCF4 gene (RE+/FECD+) in 70-80% of Caucasian cohorts. However, a few elderly individuals with repeat expansions in the pathogenic range (>40 CTG repeats) fail to develop the disease (RE+/FECD-). To understand why these rare RE+/FECD- individuals have escaped the disease phenotype, we performed DNA and RNA sequencing studies in a small cohort.
RNASeq analysis was performed on corneal endothelial (CE) specimens from RE+/FECD- patients (n=3; age range = 81 – 86 years) following keratoplasty for corneal edema due to pseudophakia +/- glaucoma surgery. Whole transcriptomic sequencing data were analyzed using MAP-RSeq and MISO statistical packages. Splicing patterns in RE+/FECD- CE were compared to previously-described patterns of mis-splicing in 18 RE+/FECD+ corneas. Whole exome sequencing from peripheral blood leukocyte DNA was performed on 5 RE+/FECD- samples (age range = 66 - 86 years) using Agilent exome capture reagents and Illumina sequencers.
The patterns of gene expression in RE+/FECD- tissue differed from RE+/FECD+ CE tissue. Specifically, characteristic MBNL1, KIF13A and AKAP13 mis-splicing events seen in RE+/FECD+ samples were absent in all 3 RE+/FECD- samples. RE+/FECD- samples demonstrated significantly lower expression of genes involved in generation of precursor metabolites and energy (including many mitochondrial genes) and increased expression of genes required for negative regulation of apoptotic processes. Exome sequencing of leukocyte DNA did not reveal variants in any gene common to all 5 RE+/FECD- subjects. Rare variants in ATF6 or ATF6B, genes involved in the activation of the unfolded protein response, were found in 3 of these subjects.
Absence of RNA mis-splicing in MBNL1, KIF13A and AKAP13 in the corneal endothelium of RE+/FECD- patients, but present in RE+/FECD+ patients, implicates these genes as potential molecules of interest in FECD pathogenesis. Gene expression differences and variants in ATF6 or ATF6B lend further insights into genes that may be protective against FECD disease.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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