Missense Mutations in TCF8 Cause Late-Onset Fuchs Corneal Dystrophy and Interact with FCD4 on Chromosome 9p

Abstract

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. Despite its high prevalence (4% over the age of 40), the underlying genetic basis of FCD is largely unknown. Here we report missense mutations in TCF8, a transcription factor whose haploinsufficiency causes posterior polymorphous corneal dystrophy (PPCD), in a cohort of late-onset FCD patients. In contrast to PPCD-causing mutations, all of which are null, FCD-associated mutations encode rare missense changes suggested to cause loss of function by an in vivo complementation assay. Importantly, segregation of a recurring p.Q840P mutation in a large, multigenerational FCD pedigree showed this allele to be sufficient but not necessary for pathogenesis. Execution of a genome-wide scan conditioned for the presence of the 840P allele identified an additional late-onset FCD locus on chromosome 9p, whereas haplotype analysis indicated that the presence of the TCF8 allele and the disease haplotype on 9p leads to a severe FCD manifestation with poor prognosis. 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.

Association of TCF4 and CLU polymorphisms with Fuchs’ endothelial dystrophy and implication of CLU and TGFBI proteins in the disease process

“…5 The prevalence of FED varies markedly across the world. It affects B4% of the USA population over the age of 40 years, 6 but is less frequent in Asian 7 and Middle-Eastern populations. 8 In Australia, corneal grafting for FED accounts for B6% of all corneal grafts performed annually.…”

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

“…37,38 This suggests that corneal endothelial dystrophies may not be separate diseases, but may represent a phenotypic continuum with a significant genetic overlap, despite discrete clinical manifestations. 27 However, in most cases, FECD is not associated with a specific genetic mutation, but may rather be due to an impaired defense to environmental factors, such as oxidative stress. 39 The major inducers of oxidative stress in the cornea are ultraviolet radiation, temperature changes, and aqueous humor soluble factors (Figure 1).…”

“…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.…”

“…For instance, although the prevalence of the TCF4 mutation is low, it is associated with a very high risk of developing FECD. 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.…”

“…When we take a look at what is currently known about the genetic background of FECD, mutated genes have only been found in inherited cases and some sporadic cases. For instance, FECD has been associated with rare mutations in SLC4A11 (solute carrier family 4, sodium borate transporter, member 11), 18,19 TCF4 (transcription factor 4), [20][21][22][23][24][25] TCF8 (transcription factor 8), 26,27 CLU (clusterin), 24 and LOXHD1 (lipoxygenase homology domains 1). 28 These mutations, however, are not identified in every cohort of FECD patients.…”