Association of<i>Transcription Factor 4 (TCF4</i>) and<i>Protein Tyrosine Phosphatase, Receptor Type G (PTPRG</i>) with Corneal Dystrophies in Southern Chinese

Wang, Kai Jie; Jhanji, Vishal; Chen, Jian‐Huan; Law, Ricky W.K.; Leung, Alfred Tai-Shing; Zhang, Mingzhi; Wang, Ke; Pang, Chi‐Pui; Yam, Gary Hin‐Fai

doi:10.3109/13816810.2013.804098

Cited by 15 publications

(11 citation statements)

References 9 publications

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“…Indian FECD patients do not show a distinct association with this TCF4 variant, which may be explained by a small sample size studied [ 17 ]. In Chinese FECD patients no association could be observed as the population is not polymorphic at this genomic position [ 18 – 20 ]. In these FECD patients, TCF4 genetic variants adjacent to rs613872 (e.g., rs17089887 in both Indian and Chinese subjects) were strongly associated with FECD, which suggested the presence of significant disease-causing changes in the nearby regions of these alleles [ 17 , 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

Fuchs Endothelial Corneal Dystrophy: Strong Association with rs613872 Not Paralleled by Changes in Corneal EndothelialTCF4mRNA Level

Ołdak

Ruszkowska

Udziela

et al. 2015

BioMed Research International

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Fuchs endothelial corneal dystrophy (FECD) is a common corneal endotheliopathy with a complex and heterogeneous genetic background. Different variants in the TCF4 gene have been strongly associated with the development of FECD. TCF4 encodes the E2-2 transcription factor but the link between the strong susceptibility locus and disease mechanism remains elusive. Here, we confirm a strong positive association between TCF4 single nucleotide polymorphism rs613872 and FECD in Polish patients (OR = 12.95, 95% CI: 8.63–19.42, χ 2 = 189.5, p < 0.0001). We show that TCF4 expression at the mRNA level in corneal endothelium (n = 63) does not differ significantly between individuals with a particular TCF4 genotype. It is also not altered in FECD patients as compared to control samples. The data suggest that changes in the transcript level containing constitutive TCF4 exon encoding the amino-terminal part of the protein seem not to contribute to disease pathogenesis. However, considering the strong association of TCF4 allelic variants with FECD, genotyping of TCF4 risk alleles may be important in the clinical practice.

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Section: Discussionmentioning

confidence: 99%

Fuchs Endothelial Corneal Dystrophy: Strong Association with rs613872 Not Paralleled by Changes in Corneal EndothelialTCF4mRNA Level

Ołdak

Ruszkowska

Udziela

et al. 2015

BioMed Research International

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“…The strongest genetic association with FECD is with an intronic (CTG·CAG) n trinucleotide repeat (TNR) expansion in the third intron of the transcription factor 4 ( TCF4 ) gene. 1 – 8 Unaffected individuals typically have 12 to 18 TNR repeats, but up to 79% of individuals with FECD have an unstable CTG·CAG repeat length greater than 50. 1 While nearly all TNR expansion diseases to date are directly linked to rare neurologic or neuromuscular disorders, FECD is the first eye disease associated with a TNR expansion.…”

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confidence: 99%

Repeat-Associated Non-ATG (RAN) Translation in Fuchs' Endothelial Corneal Dystrophy

Soragni

Petrosyan

Rinkoski

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeThe strongest genetic association with Fuchs' endothelial corneal dystrophy (FECD) is the presence of an intronic (CTG·CAG)n trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene. Repeat-associated non-ATG (RAN) translation, an unconventional protein translation mechanism that does not require an initiating ATG, has been described in many TNR expansion diseases, including myotonic dystrophy type 1 (DM1). Given the similarities between DM1 and FECD, we wished to determine whether RAN translation occurs in FECD.MethodsAntibodies against peptides in the C-terminus of putative RAN translation products from TCF4 were raised and validated by Western blotting and immunofluorescence (IF). CTG·CAG repeats of various lengths in the context of the TCF4 gene were cloned in frame with a 3× FLAG tag and transfected in human cells. IF with antipeptide and anti-FLAG antibodies, as well as cytotoxicity and cell proliferation assays, were performed in these transfected cells. Corneal endothelium derived from patients with FECD was probed with validated antibodies by IF.ResultsCTG·CAG repeats in the context of the TCF4 gene are transcribed and translated via non-ATG initiation in transfected cells and confer toxicity to an immortalized corneal endothelial cell line. An antipeptide antibody raised against the C-terminus of the TCF4 poly-cysteine frame recognized RAN translation products by IF in cells transfected with CTG·CAG repeats and in FECD corneal endothelium.ConclusionsExpanded CTG·CAG repeats in the context of the third intron of TCF4 are transcribed and translated via non-ATG initiation, providing evidence for RAN translation in corneal endothelium of patients with FECD.

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“…We performed the sensitivity analysis by exclusion of one individual study each time and we found that the study by Nanda et al [ 17 ] might be the source of heterogeneity, as heterogeneity was significantly decreased after excluding that study. For rs2286812, substantial heterogeneity was also observed in the additive model and the sensitivity analysis also showed that Wang’s [ 35 ] study is the source of the heterogeneity.…”

Section: Discussionmentioning

confidence: 89%

“…Of these, six articles were excluded for the following reasons: the article was a review (n = 1) [ 28 ]; the articles lacked controls (n = 3) [ 29 – 31 ]; and the articles did not focus on the relative polymorphism (n = 2) [ 32 , 33 ]. Finally, 12 articles met the inclusion criteria and were included in this meta-analysis [ 8 , 13 – 17 , 22 – 25 , 34 , 35 ]. One trial [ 8 ], reported the allele and the genotype of the discovery group and the replication group, respectively.…”

Section: Resultsmentioning

confidence: 99%

Association of TCF4 polymorphisms and fuchs’ endothelial dystrophy: a meta-analysis

Peng

Sun

2015

BMC Ophthalmol

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BackgroundStudies investigating the associations between transcription factor 4 (TCF4) genetic polymorphisms and Fuchs’ endothelial dystrophy (FED) have reported controversial results. Therefore, this meta-analysis aims to clarify the effects of TCF4 polymorphisms on FED risk.MethodsA meta-analysis was conducted to assess the association between four single nucleotide polymorphisms (SNPs) inTCF4 and the risk of FED. Relevant studies were selected through an extensive search of PubMed, EMBASE, and the Web of Science databases. Pooled odds ratio (OR) and 95 % confidence interval (CI) were calculated using the random-effects model.ResultsThirteen studies were included in this systematic review and meta-analysis. The pooled results showed that there was a strong positive association between the TCF4 rs613872 polymorphism and FED risk in all the genetic models tested (G allele vs. T allele: OR = 4.19, 95 % CI = 3.53–4.97; GG vs. GT/TT: OR = 4.27, 95 % CI = 2.54–7.19; GG/GT vs. TT: OR = 6.29, 95 % CI = 4.23–8.93; GG VS. TT: OR = 10.64, 95 % CI = 5.28–21.41; GT VS. TT: OR = 6.08, 95 % CI = 4.28–8.64). Statistic evidence was also detected for a significant association between three other SNPs and the risk of FED.ConclusionsThis meta-analysis suggested a genetic association between four TCF4 polymorphisms (rs613872, rs2286812, rs17595731, and rs9954153) and the risk of FED.

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Association ofTranscription Factor 4 (TCF4) andProtein Tyrosine Phosphatase, Receptor Type G (PTPRG) with Corneal Dystrophies in Southern Chinese

Cited by 15 publications

References 9 publications

Fuchs Endothelial Corneal Dystrophy: Strong Association with rs613872 Not Paralleled by Changes in Corneal EndothelialTCF4mRNA Level

Fuchs Endothelial Corneal Dystrophy: Strong Association with rs613872 Not Paralleled by Changes in Corneal EndothelialTCF4mRNA Level

Repeat-Associated Non-ATG (RAN) Translation in Fuchs' Endothelial Corneal Dystrophy

Association of TCF4 polymorphisms and fuchs’ endothelial dystrophy: a meta-analysis

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