CTG18.1 Expansion in TCF4 Increases Likelihood of Transplantation in Fuchs Corneal Dystrophy

Self Cite

PurposeStudies of Fuchs' dystrophy have largely focused on individuals of European origin. Characterization of disease among African Americans is required to ensure prognostic factors and therapeutic approaches are applicable across diverse patient populations.MethodsWe assessed all self-reported black and white patients aged older than 40 years at a tertiary care institution with a diagnosis of cataract over a 3-year period for concurrent diagnosis of Fuchs' dystrophy. Affected patients in a longitudinal cohort were invited to provide a blood sample from which we extracted genomic DNA. The CTG18.1 trinucleotide repeat length was determined using a two-step, triplet repeat primed PCR protocol. Expansion was defined as >40 CTG repeats. Demographic information, including race, was documented.ResultsOf 59,365 self-reported black and white adults who presented for cataract evaluation, the odds ratio of presenting with Fuchs' dystrophy among black compared to white patients was 0.6992 (95% confidence interval [CI], 0.6210–0.7872). A total of 60 black and 549 white patients with Fuchs' corneal dystrophy enrolled in the longitudinal study, of which 21 (35.0%) black and 343 (62.5%) white patients demonstrated trinucleotide repeat expansion, a significant difference (P = 7.7 × 10−5). In a multivariable linear regression model, repeat expansion but not race was significantly associated with mean clinical grading of severity.ConclusionsBlack patients with Fuchs' dystrophy were less likely than white patients to demonstrate CTG18.1 allele expansion. The data contribute to our understanding of population differences in clinical presentation, and highlight the need for considering diversity of patient populations in clinical research.

Section: Discussionmentioning

confidence: 57%

CTG18.1 Expansion in TCF4 Among African Americans With Fuchs' Corneal Dystrophy

Eghrari

Vahedi

Afshari

et al. 2017

Self Cite

“…We evaluated the association of the CTG18.1 repeat status (expanded or nonexpanded) with the type of surgical procedure (whether it involved corneal endothelium), as the CTG trinucleotide repeat expansion status in patients with FECD can increase the likelihood of corneal transplantation. 33,34 We found a tendency between the involvement of corneal endothelium in the surgical procedure and the CTG trinucleotide repeat expansion status in our FECD cohort, but it did not reach the level of significance (Table 6). We did not find an association between the FECD grade and CTG trinucleotide repeat expansion status.…”

Section: Diagnostic Performance Of Tcf4 Gene Variantsmentioning

confidence: 72%

CTG18.1 Expansion is the Best Classifier of Late-Onset Fuchs' Corneal Dystrophy Among 10 Biomarkers in a Cohort From the European Part of Russia

Skorodumova

Belodedova

Antonova

et al. 2018

PURPOSE. To assess the occurrence and diagnostic performance of nine single-nucleotide variants (SNVs) in the TCF4, SLC4A11, LOXHD1, and AGBL1 genes and the CTG18.1 trinucleotide repeat expansion in a Russian cohort of Fuchs' endothelial corneal dystrophy (FECD) patients. METHODS. This retrospective case-control study included 100 patients diagnosed with FECD (cases) and 100 patients with cataracts (controls). Blood DNA was used to perform PCR and subsequent Sanger sequencing of rs613872 and rs17595731 in TCF4, c.99-100delTC, rs267607065, rs267607064, and rs267607066 in SLC4A11, rs113444922 in LOXHD1, and rs181958589 and rs185919705 in AGBL1. The number of CTG18.1 trinucleotide repeats was determined by a combination of conventional PCR or triplet primed PCR with fragment analysis. RESULTS. At least one rs613872 marker allele was found in 78% of FECD patients and 21% of controls, and at least one rs17595731 marker allele was found in 14% and 2%, respectively. CTG18.1 trinucleotide expansion (>40 repeats) was detected in 72% of FECD patients and 5% of controls. Marker alleles of the tested SNVs in SLC4A11, LOXHD1, and rs185919705 in AGBL1 were not found in our FECD cohort. One FECD patient carried the marker allele of the rs181958589 SNV. Analysis of the diagnostic performance of individual markers in TCF4 and their combinations showed that the CTG18.1 repeat expansion was the best classifier for FECD (AUC ¼ 0.84). CONCLUSIONS. Patients carrying CTG18.1 repeat expansion constituted a high proportion of the Russian FECD cohort; therefore, this marker is suitable for development of diagnostic and therapeutic approaches.

“…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.…”

mentioning

confidence: 99%

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

Soragni

Petrosyan

Rinkoski

et al. 2018

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.