Variations in the TCF8 Gene Are Associated With a Posterior Polymorphous Corneal Dystrophy Phenotype

Abstract

Purpose:: Posterior polymorphous corneal dystrophy (PPCD) is a rare disease characterized by metaplasia and overgrowth of the corneal endothelium. Mutations in the VSX1 and COL8A2 genes have been identified in some patients with PPCD. Another PPCD gene, TCF8, was recently discovered. Krafchak et al (2005) found mutations in this gene in 5/11 unrelated patients with PPCD. We sought to characterize the relationship between mutations in TCF8 and PPCD by screening a cohort of patients from Iowa for TCF8 mutations.

Methods:: DNA samples were obtained from 29 unrelated probands with features of PPCD. Bidirectional DNA sequencing was used to screen the coding sequence of the TCF8 gene for disease-causing mutations. When a TCF8 mutation was detected in a proband, a single strand conformation polymorphism (SSCP) assay was then developed to allow a control panel of normal subjects to be screened for this variation. The frequency of mutations in patients and controls were evaluated by Fisher's exact test.

Results:: None of the previously reported mutations were found in our cohort but a total of 3 novel, non-synonymous coding sequence changes in TCF8 were detected: Pro336del1C, Asn365Ser, and Thr751Ala. These variations were each detected in a single patient proband and were absent from a cohort of 115 normal control subjects. As a group, the TCF8 sequence variations were present in patient probands at a statistically higher frequency than controls (p=0.0075).

Conclusions:: Novel TCF8 mutations Pro336del1C, Asn365Ser, and Thr751Ala were found in 3 of 29 (10.3%) cases in a cohort drawn from Iowa. This report confirms the association between mutations in the TCF8 gene and PPCD and suggests that this gene may be responsible for a smaller proportion of PPCD cases in some patient populations.

Keywords: cornea: endothelium • degenerations/dystrophies • genetics