April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact With a Novel Locus on 9p
Author Affiliations & Notes
  • S. A. Riazuddin
    Center for Corneal Genetics, The Wilmer Eye Institute, Center for Human Genetics,
    McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology,
    Johns Hopkins University School of Medicine, Baltimore, Maryland
  • N. A. Zaghloul
    McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology,
    Johns Hopkins University School of Medicine, Baltimore, Maryland
  • A. Al-Saif
    McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology,
    Johns Hopkins University School of Medicine, Baltimore, Maryland
  • A. O. Eghrari
    Center for Corneal Genetics, The Wilmer Eye Institute, Center for Human Genetics,
    Johns Hopkins University School of Medicine, Baltimore, Maryland
  • M. A. Minear
    Center for Corneal Genetics, The Wilmer Eye Institute, Center for Human Genetics,
    Duke University Medical Center, Durham, North Carolina
  • Y. J. Li
    Center for Corneal Genetics, The Wilmer Eye Institute, Center for Human Genetics,
    Duke University Medical Center, Durham, North Carolina
  • G. K. Klintworth
    McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology,
    Duke University Medical Center, Durham, North Carolina
  • N. Afshari
    McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology,
    Duke University Medical Center, Durham, North Carolina
  • J. D. Gottsch
    Center for Corneal Genetics, The Wilmer Eye Institute, Center for Human Genetics,
    Johns Hopkins University School of Medicine, Baltimore, Maryland
  • N. Katsanis
    McKusick-Nathans Institute of Genetic Medicine, Department of Ophthalmology,
    Johns Hopkins University School of Medicine, Baltimore, Maryland
    Center for Human Disease Modeling, Department of Cell Biology, Duke University, Durham, North Carolina
  • Footnotes
    Commercial Relationships  S.A. Riazuddin, None; N.A. Zaghloul, None; A. Al-Saif, None; A.O. Eghrari, None; M.A. Minear, None; Y.J. Li, None; G.K. Klintworth, None; N. Afshari, None; J.D. Gottsch, None; N. Katsanis, None.
  • Footnotes
    Support  This study was supported in part by National Eye Institute Grants R01EY016835, R01EY016514, the Kwok Research Fund, and the National Institute of Child Health and Development Grant R01HD04260.
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 4296. doi:
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      S. A. Riazuddin, N. A. Zaghloul, A. Al-Saif, A. O. Eghrari, M. A. Minear, Y. J. Li, G. K. Klintworth, N. Afshari, J. D. Gottsch, N. Katsanis; Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact With a Novel Locus on 9p. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4296.

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Abstract

Purpose: : Fuchs corneal dystrophy (FCD) is a degenerative genetic disorder of the corneal endothelium that represents one of the most common causes of corneal transplantation in the United States. The following study was undertaken to investigate the association of TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), with late-onset FCD.

Methods: : We ascertained a cohort of 400 sporadic cases and small nuclear families of late-onset FCD patients and sequenced all coding exons and the exon-intron boundaries of TCF8. Upon identifying candidate pathogenic variations, we examined the functionality of the mutant proteins in a zebrafish in vivo rescue system. One of the mutations segregated in small nuclear family, where we were able to expand and collect enough additional family members to complete a genome-wide scan. We genotyped families with a 500K Affymetrix SNP array and calculated two-point LOD scores, which were further confirmed with closely spaced STR markers.

Results: : We report five missense mutations in TCF8, which affect highly conserved residues and were not present in ethnically matched controls. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggestive of loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree demonstrated that this allele is sufficient but not necessary to produce the disease phenotype. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified a novel FCD locus on chromosome 9p, while haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation.

Conclusions: : Our data suggest that PPCD and FCD are allelic variants of the same disease continuum and that genetic interaction between genes that cause corneal dystrophies can modulate the expressivity of the phenotype.

Keywords: cornea: endothelium • genetics 
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