June 2013
Volume 54, Issue 15
Free
ARVO Annual Meeting Abstract  |   June 2013
An intronic TCF4 tri-nucleotide repeat expansion associated with Fuchs Corneal Dystrophy
Author Affiliations & Notes
  • S. Amer Riazuddin
    The Wilmer Eye Institute, Johns Hopkins Univ Sch of Med, Baltimore, MD
  • Briana Gapsis
    The Wilmer Eye Institute, Johns Hopkins Univ Sch of Med, Baltimore, MD
  • Nicholas Katsanis
    Center for Human Disease Modeling, Duke University Medical Center, Durham, NC
  • John Gottsch
    The Wilmer Eye Institute, Johns Hopkins Univ Sch of Med, Baltimore, MD
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 4724. doi:
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      S. Amer Riazuddin, Briana Gapsis, Nicholas Katsanis, John Gottsch; An intronic TCF4 tri-nucleotide repeat expansion associated with Fuchs Corneal Dystrophy. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4724.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: We previously localized three large familial cases to FCD2 on chromosome 18q. Subsequently, rs613872, an intronic SNP residing within the FCD2 critical interval was reported to be associated with FCD phenotype. Interestingly, the linkage disequilibrium region has been shown to harbor a tri-nucleotide repeat present just upstream of TCF4 isoform (NM_001243231). The following study was undertaken to examine the possibility that this trinucleotide repeat is associated with late-onset FCD.

Methods: Human ocular tissue was obtained from Tissue Bank International and the corneal endothelium was stripped of the Descemets membrane. Total RNA was extracted to synthesize cDNA and Taqman probes were used to examine the expression of TCF4 in corneal endothelium. We examined the repeat length in FCD patients using fluorescent labeled-STR markers that could detect repeat lengths up to 150 repeats using genomic DNAs of FCD affected individuals and unaffected controls. The tri-nucleotide repeat region was amplified, the PCR products were resolved on ABI 3100 genetic analyzer and analyzed using GeneMapper software. The distribution of the alleles and Fisher exact test were performed to test the allelic associations using Plink algorithms.

Results: We first examined the expression of TCF4 and our analyses suggest that the TCF4 is expressed in the corneal endothelium. We next examined the repeat length in FCD affected individuals and unaffected controls. Our results suggest that majority (212/288) of the FCD patients harbor a single allele within the normal physiological range of the polymorphic repeat with the second allele undetectable within our measurable range. In sharp contrast, the second allele was undetectable in only a small percentage (75/288) of controls subjects. We examined the distribution of these alleles in FCD affected individuals and unaffected controls and found that absence of the second allele is significantly associated with late-onset FCD. Interestingly, the absence of second allele segregated with disease phenotype in the two large familial cases of FCD.

Conclusions: The tri-nucleotide repeat expansion represents another marker that is significantly associated with FCD. We are currently investigating the possibility that a particular length and/or a specific range of the expansion may be responsible for the Fuchs Corneal Dystrophy.

Keywords: 481 cornea: endothelium • 539 genetics  
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