Fuchs endothelial corneal dystrophy: The vicious cycle of Fuchs pathogenesis

The Fuchs corneal dystrophy-associated CTG repeat expansion in the TCF4 gene affects transcription from its alternative promoters

“…We have previously shown that TCF4 protein isoforms can be divided into longer and shorter isoforms which vary in their function and transactivation capability 4 , 8 . Currently FECD research focuses mainly on the CTG TNR and missplicing of longer TCF4 transcripts in FECD 17 , and little research has been done to analyze the expression of all the TCF4 transcripts in FECD. Our detailed analysis provides new insight into FECD as we show that the CTG TNR directly modulates the expression of TCF4 which may be among the underlying causes for the development of the disease.…”

“…FECD is an ocular disorder associated with corneal edema and vision disruption having a varying prevalence between different populations affecting about 4% of people over 40 in the United States 16 . Out of the many genetic mutations associated with FECD the CTG TNR expansion in TCF4 is thought to be one of the major factors in the development of the disease, as the presence of a TCF4 allele with 50 or more CTG TNR-s confers an increased risk of developing the disease 17 . BD is a psychiatric disorder that affects up to 1% of the global population, causing severe mood alterations in affected patients 18 .…”

Nrf2: A unifying transcription factor in the pathogenesis of Fuchs’ endothelial corneal dystrophy

“…Late onset FECD is the most common cause of CEC dysfunction. FECD was first described over 100 years ago [ 17 ]. Clinically, FECD is characterised by the progressive degeneration of CE with a visible decrease in CEC density and abnormal CEC morphology ( Fig.…”

“…Hence, it has been demonstrated that when normal CECs are seeded onto FECD-DM, the largest guttae induce cellular changes and result in apoptosis of the CEC [ 22 ]. However, it is not known if guttae directly trigger CEC stress and cell death or whether CEC stress stimulates guttae formation [ 17 ]. Ultimately, late stage FECD results in loss of CE function which leads to corneal edema, resulting in painful swelling of the cornea, loss of visual acuity and if left untreated blindness.…”

“…This was particularly evident from lenses isolated from donors above the age of 65 years and occurred at both mRNA and protein level and correlated with a demethylation in the keap1 promoter [ 49 ]. FECD is predominantly a disease of late onset and advanced age is a known risk factor for developing FECD [ 17 ]. However, it has not been determined if Keap1 levels in CEC increase with age and whether or not this proceeds loss of Nrf2 and phenotypic changes associated with FECD.…”