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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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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.
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.
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.
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.
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