Linkage of a Mild Late-Onset Phenotype of Fuchs Corneal Dystrophy to a Novel Locus at 5q33.1-q35.2

Abstract

Late-onset FCD is linked to a novel locus on 5q33.1-q35.2 and is associated with a milder severity in age at onset and rate of progression than the FCD1 and FCD2 loci. Correlation of individual genotypes with unique rates of disease progression will provide important tools for disease management, as well as for identifying the underlying genetic lesion, offer insight into the pathomechanism of FCD.

Fuchs Corneal Dystrophy

“…This interval was localized to chromosome 5 using an SNP array, followed by refinement of the region with an STR marker panel to 5q33.1-5q35.2. 21 The FCD4 locus was identified in the region 9p22.1-9p24.1 and was the first to demonstrate interaction between two pathologic alleles in this disease. After mutations in TCF8 were identified among some affected members of this family, linkage analyses were performed conditioned to the presence of the TCF8 mutation, and refined using STR markers, with maximum LOD scores of 3.09 at D9S168 and 3.20 at D9S256, and a linkage interval spanning 14.3 Mb between recombinations at D91681 and D9S1684.…”

Genetics of corneal endothelial dystrophies

“…The features of disease mapped to the FCD3 locus were found to be milder with slower progression as compared with FCD1 and FCD2 phenotypes (Riazuddin et al 2009). Different approaches have been used to identify the underlying genes in cases of the more common, complex forms of late-onset FECD.…”

“…Late-onset AD-FECD in large multiplex families has been mapped to three separate loci at chromosomes 13pTel-q12 (FCD1), 18q21.2-21.3 (FCD2), and 5q33-35 (FCD3) (Sundin et al 2006a,b;Riazuddin et al 2009). The features of disease mapped to the FCD3 locus were found to be milder with slower progression as compared with FCD1 and FCD2 phenotypes (Riazuddin et al 2009).…”

What does the future hold for the treatment of Fuchs endothelial dystrophy; will ‘keratoplasty’ still be a valid procedure?

“…28 These mutations, however, are not identified in every cohort of FECD patients. 29,30 In addition to mutations in known genes, linkage studies have identified mutations in chromosomal loci such as in chromosome 5 (FCD3), 31 9 (FCD4), 27 13 (FCD1), 32 18 (FCD 2), 33 and potential linkages at chromosome 1, 7, 15, 17, and X, 20 of which the specific mutated genes have not been identified yet. Some of these mutations have also been identified in other types of endothelial dystrophy; the SLC4A11 mutation has also been identified in congenital hereditary endothelial dystrophy 34,35 and perceptive deafness (Harboyan syndrome), 36 and Figure 1 Wound healing response and regenerative potential of recipient endothelial cells of normal and FECD corneas.…”

“…Other examples include loss-of-function mutations in TCF8, that can interact with FCD4 to modulate FECD severity, 27 and FCD3 mutations presenting clinically with milder phenotypes than FCD1 and FCD2. 31 This implies that genetic mutations, whether alone or in concert with other factors, may be used to identify risk of developing disease or act as prognostic factors to determine disease severity and progression. 58 Another important question is whether in the different FECD variants, all endothelial cells are affected by the disorder or whether in some a mosaic of non-affected and affected cells exists?…”