Role of the TCF4 Gene Intronic Variant in Normal Variation of Corneal Endothelium

Mackey, David A.; Warrington, Nicole M.; Hewitt, Alex W.; Oates, Sandra K; Yazar, Seyhan; Soloshenko, Alla; Crawford, Gemma; Mountain, Jenny; Pennell, Craig E.

doi:10.1097/ico.0b013e318226155f

Cited by 7 publications

(6 citation statements)

References 18 publications

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“…This finding has been replicated by other groups, [23], [24], [25], [26] and variants in other genes within this region of the genome have been found in small numbers of patients with FECD. [8] Our data indicate that the expansion of the TGC repeat within the TCF 4 gene is found in a very high proportion of patients with FECD—over 79% of the 66 samples tested.…”

Section: Discussionsupporting

confidence: 68%

A Common Trinucleotide Repeat Expansion within the Transcription Factor 4 (TCF4, E2-2) Gene Predicts Fuchs Corneal Dystrophy

et al. 2012

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Fuchs endothelial corneal dystrophy (FECD) is a common, familial disease of the corneal endothelium and is the leading indication for corneal transplantation. Variation in the transcription factor 4 (TCF4) gene has been identified as a major contributor to the disease. We tested for an association between an intronic TGC trinucleotide repeat in TCF4 and FECD by determining repeat length in 66 affected participants with severe FECD and 63 participants with normal corneas in a 3-stage discovery/replication/validation study. PCR primers flanking the TGC repeat were used to amplify leukocyte-derived genomic DNA. Repeat length was determined by direct sequencing, short tandem repeat (STR) assay and Southern blotting. Genomic Southern blots were used to evaluate samples for which only a single allele was identified by STR analysis. Compiling data for 3 arms of the study, a TGC repeat length >50 was present in 79% of FECD cases and in 3% of normal controls cases (p<0.001). Among cases, 52 of 66 (79%) subjects had >50 TGC repeats, 13 (20%) had <40 repeats and 1 (2%) had an intermediate repeat length. In comparison, only 2 of 63 (3%) unaffected control subjects had >50 repeats, 60 (95%) had <40 repeats and 1 (2%) had an intermediate repeat length. The repeat length was greater than 1000 in 4 FECD cases. The sensitivity and specificity of >50 TGC repeats identifying FECD in this patient cohort was 79% and 96%, respectively Expanded TGC repeat was more specific for FECD cases than the previously identified, highly associated, single nucleotide polymorphism, rs613872 (specificity = 79%). The TGC trinucleotide repeat expansion in TCF4 is strongly associated with FECD, and a repeat length >50 is highly specific for the disease This association suggests that trinucleotide expansion may play a pathogenic role in the majority of FECD cases and is a predictor of disease risk.

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Section: Discussionsupporting

confidence: 68%

A Common Trinucleotide Repeat Expansion within the Transcription Factor 4 (TCF4, E2-2) Gene Predicts Fuchs Corneal Dystrophy

et al. 2012

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“…This finding was similar to that reported for Singaporean Chinese 6 and western Australians. 8 The minor G allele of SNP rs613872, which was strongly associated with FED development in Europeans and Australians, 5,7 was not detected in our samples.…”

Section: Discussioncontrasting

confidence: 77%

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

Wang

Jhanji

Chen

et al. 2013

Ophthalmic Genetics

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Fuchs' endothelial dystrophy is a common type of posterior CD characterized by the development of gutta in the Descemet membrane. Recently, TCF4 was considered as a major risk gene for European FED cases. However, another recent report has shown that rs613872 was not associated with Singaporean Chinese FEDs. Recent reports indicate the genotypic heterogeneity of FEDs in different ethnic populations. It is thus essential to understand whether these genes affect the occurrence of FEDs and non-Fuchs' CD in the local population. In the present study, we screened several reported SNPs (rs2286812, rs17595731 and rs613827 in TCF4; rs7640737 and rs2292245 in PTPRG) in FED and non-Fuchs' patients with corneal dystrophies of southern Chinese.

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“…Linkage to a broader region encompassing TCF4 has also been reported [16], [58], strengthening the case that the association signals reflect true linkage disequilibrium between this SNP and a causal variant, although the action of TCF4 may be independent of the FCD2 locus at chromosome 18q21.2–21.32 [17]. The gene product of TCF4, E2-2, is found in the developing corneal endothelium [15], but changes in the endothelial cell density associated with FECD are not apparent in carriers of the rs613872 G allele in early adulthood [59]. The precise mechanism by which E2-2 alters the structure of the cornea is unknown, but is likely to involve regulation of genes involved in cell growth and differentiation.…”

Section: Discussionmentioning

confidence: 92%

Differing Roles for TCF4 and COL8A2 in Central Corneal Thickness and Fuchs Endothelial Corneal Dystrophy

et al. 2012

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Fuchs endothelial corneal dystrophy (FECD) is the most common late-onset, vision-threatening corneal dystrophy in the United States, affecting about 4% of the population. Advanced FECD involves a thickening of the cornea from stromal edema and changes in Descemet membrane. 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. Other genes previously associated with FECD (PITX2, ZEB1, SLC4A11), and genes only known to affect CCT (COL5A1, FOXO1, AVGR8, ZNF469) were also interrogated. FECD probands, relatives and controls were recruited from 32 clinical sites; a total of 532 cases and 204 controls were genotyped and tested for association of FECD case/control status, a 7-step FECD severity scale and CCT, adjusting for age and sex. Association of FECD grade with TCF4 was highly significant (OR = 6.01 at rs613872; p = 4.8×10−25), and remained significant when adjusted for changes in CCT (OR = 4.84; p = 2.2×10−16). Association of CCT with TCF4 was also significant (p = 6.1×10−7), but was abolished with adjustment for FECD grade (p = 0.92). After adjusting for FECD grade, markers in other genes examined were modestly associated (p ∼ 0.001) with FECD and/or CCT. Thus, common variants in TCF4 appear to influence FECD directly, and CCT secondarily via FECD. Additionally, changes in corneal thickness due to the effect of other loci may modify disease severity, age-at-onset, or other biomechanical characteristics.

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Role of the TCF4 Gene Intronic Variant in Normal Variation of Corneal Endothelium

Cited by 7 publications

References 18 publications

A Common Trinucleotide Repeat Expansion within the Transcription Factor 4 (TCF4, E2-2) Gene Predicts Fuchs Corneal Dystrophy

A Common Trinucleotide Repeat Expansion within the Transcription Factor 4 (TCF4, E2-2) Gene Predicts Fuchs Corneal Dystrophy

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

Differing Roles for TCF4 and COL8A2 in Central Corneal Thickness and Fuchs Endothelial Corneal Dystrophy

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