Furthermore, we find that miR-199b-5p directly and negatively regulates Snai1 and ZEB1, two zinc finger transcription factors that lead to increased ECM deposition in FECD.
The CTG18.1 repeat expansion may reduce gene expression of TCF4 and ZEB1, suggesting that a mechanism triggering a loss of function may contribute to FECD.
While the early onset, and rarer, form of FECD has been linked to COL8A2 mutations, the more common, late onset form of FECD has genetic mutations linked to only a minority of cases.
This is the first report of genetic variations in ZEB1 and TCF4 SNP rs613872 in patients with FECD from northern India that suggests a possible role in disease pathogenesis and the regulation of endothelial cell density.
These findings suggest that increased expression levels of ZEB1 and Snail1 in FECD cells were responsible for an increased responsiveness to TGF-β present in the aqueous humor and excessive production of ECM.
Conversely, as the reported ZEB1 missense mutations do not significantly impact protein abundance or nuclear localization, the effect of these mutations on ZEB1 function and their relationship to FECD, if any, remain to be elucidated.
The coding regions of known FECD susceptibility genes collagen, type VIII, alpha 2 (COL8A2); solute carrier family 4, sodium borate transporter, member 11 (SLC4A11); and zinc finger E-box binding homeobox 1 (ZEB1 [also known as TCF8]) were Sanger sequenced in the 47 probands using DNA isolated from blood samples.
Variation in the COL8A2, SLC4A11, and ZEB1 genes is present in only a small fraction of our African American cases and as such does not appear to significantly contribute to the genetic risk of FECD in African Americans.
Mutations in several genes have been implicated as playing a pathogenic role in the corneal endothelial dystrophies: VSX1 mutations in PPCD1; COL8A2 mutations in PPCD2 and FECD; ZEB1 mutations in PPCD3 and FECD; and SLC4A11 mutations in CHED2 and FECD.
In the keratoconus cohort, a novel heterozygous pathogenic mutation in exon 7 (c.1920G > T; p.Gln640His) of ZEB1 was identified in a family affected with keratoconus and Fuchs' endothelial corneal dystrophy.
However, linkage, association and familial segregation analyses support a role of only one gene in each corneal endothelial dystrophy: ZEB1 in PPCD3, SLC4A11 in CHED2 and COL8A2 in FECD (early onset).
The present study used a transgenic Col8a2(Q455K/Q455K) knock-in mouse model of early-onset FECD to identify the endothelial expression profile of specific cellular stress response-related targets, which may be relevant to late-onset FECD.
To understand the relationship between FECD and central corneal thickness (CCT), we characterized common genetic variation in COL8A2 and TCF4, genes previously implicated in CCT and/or FECD.
This study confirms the Q455K substitution in the COL8A2 gene as being sufficient to cause FECD in the first mouse model of this disease and supports the role of the UPR and UPR-associated apoptosis in the pathogenesis of FECD caused by COL8A2 mutations.
To perform a genome-wide linkage screen with a single-nucleotide polymorphism (SNP) linkage panel to identify regions of genetic linkage in Fuchs endothelial corneal dystrophy (FECD) and to analyze affected individuals for mutations in the COL8A2 gene.