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Keith H. Baratz, Ross A. Aleff, Nirubol Tosakulwong, Laura A. Hecker, Michael P. Fautsch, Albert O. Edwards, Eric D. Wieben; An Association between an Expanded Trinucleotide Repeat in Transcription Factor 4 (TCF4, E2-2) and Fuchs Corneal Dystrophy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1740.
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Genetic variation across the transcription factor 4 gene (TCF4) encoding the basic-helix-loop helix DNA-binding protein E2-2 is a major contributor to Fuchs corneal dystrophy (FCD). We aimed to determine whether a known region of nucleotide triplet repeat expansion could explain the association between TCF4 and FCD.
Corneas of 67 patients (FCD=35; normal=32) were examined by slit lamp biomicroscopy and graded for FCD severity by using the Krachmer scale. FCD cases were grade 6 (n=27), grade 5 (n=4), grade 3 (n=2), and grade 2 (n=2). Controls had no detectable guttae. Primers designed to specifically amplify the CTG repeat in intron 2 of the TCF4 gene were used in PCR reactions and subjected to agarose gels. Amplified DNA for all samples was sized by GeneScan (Applied Biosystems) analysis. Genotypes for the most highly associated single nucleotide polymorphism (rs613872) across TCF4 were determined for most subjects.
The mean age of FCD (72 years, range = 58-86) and control (76 years, range = 60-85) subjects were similar. Women comprised 80% (n=28) of FCD subjects and 62% (n=20) of control subjects. Amplification of the CTG repeat revealed well-defined bands containing 17-30 repeats or large ill-defined bands consistent with repeat expansion. GeneScan analysis confirmed CTG expansion of the ill-defined bands. Expansion of at least one allele was present in 28 of 35 (80%) FCD subjects and in 2 of 32 (6%) control subjects (p<0.001). Homozygous expansion was observed in 5 FCD and no control subjects. The triplet repeat was in linkage disequilibrium with previously established SNPs (rs613872) tagging disease risk across TCF4.
Expansion of a CTG trinucleotide short tandem repeat in intron 2 of the TCF4 gene was associated with FCD with a positive predictive value of 93%. The CTG repeat was highly correlated with a previous genetic marker (rs613872) established for this locus and was located within a haplotype region associated with disease risk. Expansion of trinucleotide repeats, which have been well-established as a genetic basis for disease, should be explored as a frequent functional cause of FCD and as a possible target for identifying at-risk individuals.
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