Analysis of the Posterior Polymorphous Corneal Dystrophy 3 Gene,<i>TCF8</i>, in Late-Onset Fuchs Endothelial Corneal Dystrophy

Mehta, Jodhbir S.; Vithana, Eranga N.; Tan, Donald; Yong, Victor H. K.; Yam, Gary Hin‐Fai; Law, Ricky W.K.; Chong, Wesley; Pang, Calvin P.; Aung, Tin

doi:10.1167/iovs.07-0847

Cited by 73 publications

(51 citation statements)

References 30 publications

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“…6 Mutations in the ZEB1 (zinc-finger E-box binding homoebox 1) gene can cause both sporadic and familial late-onset FED. 6,14 ZEB1 is expressed in the CE. 15 It regulates cell proliferation and differentiation by inducing epithelial-mesenchymal transition.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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Fuchs' endothelial dystrophy (FED) is a disease affecting the corneal endothelium. Recent studies reported significant association of polymorphisms in the TCF4 (transcription factor 4) gene, and a borderline association of PTPRG (protein tyrosine phosphatase, receptor type, G) variants with late-onset FED in Caucasians from the United States. Association of TCF4 has also been reported in the Chinese population. We aimed to determine association of the reported polymorphisms in TCF4 and PTPRG, and association of polymorphisms in the candidate genes ZEB1 (zinc-finger E-box binding homoebox 1), COL8A2 (collagen, type VIII, alpha 2), TGFBI (transforming growth factor, b-induced) and CLU (clusterin) in Australian cases. We also compared the expression of TGFBI and CLU proteins between FED and normal whole corneas. In all, 30 single-nucleotide polymorphisms (SNPs) from the candidate genes were genotyped in 103 cases and 275 controls. Each SNP and haplotype was assessed for association with the disease. SNP analysis identified an association of TCF4 (rs613872 (P¼5.25Â10 À15 , OR¼4.05), rs9954153 (P¼3.37Â10 À7 , OR¼2.58), rs2286812 (P¼4.23Â10 À6 , OR¼2.55) and rs17595731 (P¼3.57Â10 À5 , OR¼3.79)), CLU (rs17466684; P¼0.003, OR¼1.85) and one haplotype of TGFBI SNPs (P¼0.011, OR¼2.29) with FED in Caucasian Australians. No evidence for genetic association of PTPRG, ZEB1 and COL8A2 was found. Immunohistochemistry showed differential expression of CLU and TGFBI proteins in FED-affected compared with normal corneas. In conclusion, variation in TCF4, CLU and TGFBI, but not PTPRG, ZEB1 and COL8A2 genes are associated with FED in Caucasian Australian cases. Differential expression of CLU and TGFBI proteins in FED-affected corneas provides novel insights into the disease mechanism.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…Late-onset classic FECD can either be familial or sporadic, with an onset typically occurring after the age of 40 years. Although mutations in the zinc-finger E-box binding homeobox 1 (ZEB1) gene 6,7 and the solute carrier family 4 member 11 (SLC4A11) gene 8,9 have been reported as causative of late-onset FECD, these mutations were only rarely observed in the patient population. On the other hand, Baratz et al 10 reported that a genome-wide association study (GWAS) revealed a highly significant association between single nucleotide polymorphisms in transcription factor 4 genes (TCF4) in classic late-onset FECD.…”

mentioning

confidence: 99%

Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy

Okumura

Minamiyama

et al. 2015

Laboratory Investigation

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Fuchs endothelial corneal dystrophy (FECD) due to corneal endothelial cell degeneration is a major cause of corneal transplantation. It is characterized by abnormal deposition of extracellular matrix (ECM), such as corneal guttae, accompanied by a loss of endothelial cells. Although recent studies have revealed several genomic factors, the molecular pathophysiology of FECD has not yet been revealed. In this study, we establish a cellular in vitro model by using immortalized corneal endothelial cells obtained from late-onset FECD and control patients and examined the involvement of epithelial mesenchymal transition (EMT) on excessive ECM production. We demonstrate that the EMT-inducing genes ZEB1 and SNAI1 were highly expressed in corneal endothelial cells in FECD and were involved in excessive production of ECM proteins, such as type I collagen and fibronectin through the transforming growth factor (TGF)-β signaling pathway. Furthermore, we found that SB431542, a specific inhibitor of TGF-β type I ALK receptors, suppressed the expression of ZEB1 and Snail1 followed by reduced production of ECM. 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. In addition, these results suggest that the regulation of EMT-related genes by blocking the TGF-β signaling pathway may be a feasible therapeutic strategy for FECD.

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“…Other candidates tested include the TCF8/ZEB1 (PPCD3) gene and the COL8A1 (collagen VIII, alpha-1 chain) gene. No significant role was found for either of these genes in FECD (Urquhart et al 2006;Mehta et al 2008;Vithana et al 2008). …”

Section: Genetics Of Fecdmentioning

confidence: 86%

Genetics of corneal endothelial dystrophies

Kannabiran

2009

J Genet

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The corneal endothelium maintains the level of hydration in the cornea. Dysfunction of the endothelium results in excess accumulation of water in the corneal stroma, leading to swelling of the stroma and loss of transparency. There are four different corneal endothelial dystrophies that are hereditary, progressive, non-inflammatory disorders involving dysfunction of the corneal endothelium. Each of the endothelial dystrophies is genetically heterogeneous with different modes of transmission and/or different genes involved in each subtype. Genes responsible for disease have been identified for only a subset of corneal endothelial dystrophies. Knowledge of genes involved and their function in the corneal endothelium can aid understanding the pathogenesis of the disorder as well as reveal pathways that are important for normal functioning of the endothelium.

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Analysis of the Posterior Polymorphous Corneal Dystrophy 3 Gene,TCF8, in Late-Onset Fuchs Endothelial Corneal Dystrophy

Abstract: The identification of a novel missense mutation in only one of the patients implied that TCF8 does not play a significant role in the pathogenesis of FECD in this Chinese population.

Cited by 73 publications

References 30 publications

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

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

Involvement of ZEB1 and Snail1 in excessive production of extracellular matrix in Fuchs endothelial corneal dystrophy

Genetics of corneal endothelial dystrophies

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