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Shivakumar Vasanth, Nicolas F. Haller, Briana C. Gapsis, Allen O Eghrari, Jiangxia Wang, Walter J. Stark, Nicholas Katsanis, S Amer Riazuddin, John D Gottsch; Expansion of CTG18.1 Trinucleotide Repeat in TCF4 is a Potent Driver of Fuchs Corneal Dystrophy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4350.
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© ARVO (1962-2015); The Authors (2016-present)
To decipher the functional relevance of the expansion of CTG18.1 allele associated with Fuchs Corneal Dystrophy (FCD).
The (CTG) repeats within the CTG18.1 allele were estimated by STR and TPPCR assays in our cohort of 574 late-onset FCD cases and 354 controls. TCF4 isoforms were identified by 5’RACE of RNA from corneal endothelium. QRT-PCR assays were designed to distinguish the TCF4 isoforms that were subsequently tested in the RNA from corneal endothelium isolated from FCD cases who underwent Endothelial Keratoplasty (EK).
The expanded CTG18.1 for (CTG)n>40 showed a strong association (P=1.56X10-82) with FCD. Importantly, we found an expansion of >90 monomers [(CTG)n>90] in 32% of the FCD cases compared to 0.85% of controls, while regression analyses demonstrated a significant correlation of disease severity with age in individuals that harbor the expanded allele (P=1.54X10-5). Analysis of the expanded CTG18.1 in sporadic and large multi-generation familial cases suggested a biallelic expansion for (CTG)n>40 to be sufficient for FCD. Examination of the 11 isoforms of TCF4 identified by 5’RACE from the corneal endothelium in 17 FCD cases detected significant reduction of a specific TCF4 isoform (P = 0.04) in FCD cases who harbor at least one expanded allele.
A monoallelic expansion of CTG18.1 contributes to increased disease severity and is a significant driver of FCD at (CTG)n>90 whereas, a biallelic expansion for (CTG)n>40 is causal for FCD likely through its effect on the expression of TCF4 isoforms in the corneal endothelium.
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