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S.M. Hosseini, F. Segev, E. Héon; Anticipation Like Phenomenon in Fuchs’ Endothelial Corneal Dystrophy . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4938.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Fuchs’ endothelial corneal dystrophy (FECD) (MIM 136800) is usually a late onset endothelial corneal dystrophy which commonly leads to corneal endothelium decompensation by the 6th decade of life. Mutations in COL8A2 have been reported in two families and sporadic cases with FECD. A recent study on sporadic FECD cases in Japan failed to show disease causing mutations in COL8A2. We studied the genetic and molecular characteristics of a family with FECD showing an anticipation–like phenomenon. Methods: Every participant had a comprehensive eye exam, including corneal pachymetry, specular microscopy and endothelial cell counts. Genotyping was performed using STRP markers. Data were analyzed using a combination of haplotype and linkage analysis. M–Link program (Cyrillic v2.1) was used for two point linkage analysis. Mutation analysis of COL8A2 was done by direct sequencing of the coding sequence. The observed sequence change was assessed in all family members using restriction enzyme digestion (BbvI). COL8A2 expression levels of fibroblast derived RNA were assessed by quantitative real time RT–PCR. Results: A large three generation family with autosomal dominant FECD (11 affected) were mapped to chromosome 1 by candidate loci haplotype analysis (Zmax = 3.31 at D1S2830, θ=0). Mutation analysis of COL8A2 showed a Q455K mutation which co–segregates with the disease status in the family. Variability in phenotype severity (age of onset and age of first penetrating keratoplasty) was observed between the successive generations, suggesting an anticipation–like phenomenon in this family (mean age of onset 43 vs. 25.4 in the first and second generations respectively and an 11 y/o affected individual in the 3rd generation; p–value < 0.05). No other change in the coding region of the gene was present in any of the three individuals sequenced from different generations. We did not identify any dynamic expanding repeat in the vicinity of COL8A2. Our preliminary expression analysis data suggest a decrease in the level of COL8A2 transcript in our patient sample versus unaffected controls. Conclusions: This report confirms the previously suggested role of COL8A2 in FECD. This first observation of an anticipation–like phenomenon in FECD warrants additional studies. Should this observation truly reflect anticipation, it may lead to an important modifying effect.
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