<i>TCF4</i>Triplet Repeat Expansion and Nuclear RNA Foci in Fuchs' Endothelial Corneal Dystrophy

Mootha, Venkateswara; Hussain, Imran; Cunnusamy, Khrishen; Graham, Eric; Gong, Xin; Neelam, Sudha; Xing, Chao; Kittler, Ralf; Petroll, Walter M

doi:10.1167/iovs.14-16222

Cited by 89 publications

(87 citation statements)

References 46 publications

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“…Both SNPs are in moderate disequilibrium with the expanded form of the CTG18.1 trinucleotide repeat in intron 2 of TCF4 ( r 2 =0.47), consistent with the previously reported values of 0.65 and 0.31 between the triplet repeat and rs613872 in FECD cases and controls, respectively21. The CTG18.1 repeat expansion is a strongly influential variant with good biologic plausibility2223, but does not fully explain disease occurrence in all patients because of the lack of penetrance in some families21.…”

Section: Resultssupporting

confidence: 89%

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

et al. 2017

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The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10−8): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.

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Section: Resultssupporting

confidence: 89%

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

et al. 2017

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“…Furthermore, transcription of CTG repeats resulted in nuclear foci containing condensed poly (CUG) n RNA and muscleblind-like1 (MBNL1) protein, an mRNA-splicing factor. 25,26 As MBNL1 is known to have a role in EMT in other types of cells, 27,28 the possibility that CTG repeats in TCF4 are related to the activation of EMT inducer genes in FECD needs to be further investigated to elucidate the pathophysiology of FECD. The cellular models of FECD were established from three different patients in our current experiments, but whether patients possess CTG repeats in TCF4 was not investigated.…”

Section: Zeb1 and Snail1 Regulate Ecm In Fecd N Okumura Et Almentioning

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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“…Southern blot analysis was performed to measure large triplet repeat expansions using digoxigenin-labeled probes as previously described. 21 …”

Section: Ctg181 Polymorphism Genotypingmentioning

confidence: 99%

“…20 Simultaneous reports in early 2015 documented the presence of CUG RNA nuclear foci in the corneal endothelium of patients with FECD with the CTG18.1 triplet repeat expansion, implicating toxic RNA as the mechanism of disease in this common disorder. 21,22 The RNA nuclear foci, a hallmark of toxic gain-of-function RNA, had been previously seen only in rare, neurodegenerative disorders caused by simple repeat expansions. 23 Rather than a primary mechanism of haploinsufficiency of TCF4, 21 the triplet repeat expansion at the CTG18.1 locus may mediate endothelial dysfunction via aberrant gene splicing as a result of the mutant CUG RNA transcripts sequestering the splicing factor muscleblind-like 1.…”

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Correlation of Severity of Fuchs Endothelial Corneal Dystrophy With Triplet Repeat Expansion inTCF4

et al. 2015

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IMPORTANCEThe CTG18.1 triplet repeat expansion in TCF4 has recently been found to be a common functional variant contributing significant risk to the development of Fuchs endothelial corneal dystrophy (FECD) in Eurasian populations.OBJECTIVES To determine the effect of the expanded CTG18.1 allele of TCF4 on FECD severity and to correlate CTG triplet repeat allele length to the severity of FECD. DESIGN, SETTING, AND PARTICIPANTSIn a cross-sectional analysis, we studied 139 index cases (probands and unrelated individuals) with FECD recruited from a cornea referral practice at the University of Texas Southwestern Medical Center, Dallas, from April 2010 through February 2015. The triplet repeat polymorphism CTG18.1 was genotyped using a combination of short tandem repeat analysis, triplet repeat-primed polymerase chain reaction assay, and Southern blot analysis. Severity of FECD was graded using a modified Krachmer grading system (severity scale of 0-6 based on extent of confluent guttae). MAIN OUTCOMES AND MEASURESThe CTG triplet repeat length of the largest allele was compared with the Krachmer grade of FECD severity, keratoplasty proportion, and central corneal thickness in the white subset.RESULTS Eighty-five of 122 white index cases with FECD (69.7%) harbored the triplet repeat expansion. The mean (SD) Krachmer grade was 5.61 (0.76) in the group with the repeat expansion compared with 5.11 (1.05) in the group without the expanded repeats (P = .01). Forty-seven participants with the repeat expansion (55.3%) had undergone keratoplasty at the time of recruitment, compared with 13 (35.1%) of those without the expansion (P = .0497). There was a positive correlation of Krachmer grade to triplet repeat number (P = .002) and a nominal association of the keratoplasty proportion with triplet repeat number (P = .04). The mean (SD) central corneal thickness was 605.9 (50.5) μm in the group with the expanded repeats compared with 581.3 (50.5) μm in the group without the expansion (P = .04). CONCLUSIONS AND RELEVANCEThe Krachmer grade of disease severity was greater in FECD cases with the CTG18.1 triplet repeat expansion in TCF4 than in those without the expansion. The CTG triplet repeat allele length was positively correlated with the Krachmer grade of severity. The TCF4 triplet repeat expansion resulted in a more severe form of FECD, with clinical and surgical therapeutic implications.

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TCF4Triplet Repeat Expansion and Nuclear RNA Foci in Fuchs' Endothelial Corneal Dystrophy

Cited by 89 publications

References 46 publications

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

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

Correlation of Severity of Fuchs Endothelial Corneal Dystrophy With Triplet Repeat Expansion inTCF4

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