TCF4 trinucleotide repeat expansion in Swedish cases with Fuchs' endothelial corneal dystrophy

Abstract

Purpose: Fuchs' endothelial corneal dystrophy (FECD) has been considered a genetically heterogeneous disease but is increasingly associated with the transcription factor 4 (TCF4) gene. This study investigates the prevalence of the cytosine-thymine-guanine (CTG) n repeat expansion in TCF4 among FECD patients in northern Sweden coupled to the phenotype. Methods: Blood samples were collected from 85 FECD cases at different stages. Short tandem repeat PCR and triplet repeat-primed PCR were applied in order to determine TCF4 (CTG) n genotype. Results: A (CTG) n repeat expansion (n > 50) in TCF4 was identified in 76 of 85 FECD cases (89.4%) and in four of 102 controls (3.9%). The median (CTG) n repeat length was 81 (IQR 39.3) in mild FECD and 87 (IQR 13.0) in severe FECD (p = 0.01). A higher number of (CTG) n repeats in an expanded TCF4 allele increased the probability of severe FECD. Other ocular surgery was overrepresented in FECD cases without a (CTG) n repeat expansion (44.4%, n = 4) compared with 3.9% (n = 3) in FECD cases with an (CTG) n repeat expansion (p < 0.001). Conclusion:In northern Sweden, the FECD phenotype is associated with (CTG) n expansion in the TCF4 gene, with nearly 90% of patients being heteroor homozygous for (CTG) n expansion over 50 repeats. Furthermore, the severity of FECD was associated with the repeat length in the TCF4 gene. Ocular surgery might act as an environmental factor explaining the clinical disease in FECD without a repeat expansion in TCF4.

DNA methylation changes and increased mRNA expression of coagulation proteins, Factor V and Thrombomodulin in Fuchs endothelial corneal dystrophy

“…The assay to determine the TCF4 CTG18.1 repeat lengths for all samples included in this study (except two samples of CE with corneal stroma) was performed as described earlier [17].…”

“…Later, an even stronger association was found to a cytosine-thymine-guanine (CTG)n repeat expansion in an intron of TCF4, denoted as the CTG18.1 locus, 43 kb from the original SNP [8]. Today, multiple studies on the TCF4 repeat expansion and FECD have been conducted in several populations, all showing convincing association to FECD with repeat lengths over 40-50 [9][10][11][12][13][14][15][16][17]. Expansion of the CTG18.1 locus in the TCF4 gene makes FECD one of the most common tri-nucleotide repeat disorders along with myotonic dystrophy (DM), Huntington disease (HD), Spinocerebellar ataxia (SCA), Friedreich ataxia (FA) and Fragile X syndrome (FRAXA) [18].…”

“…These diseases are characterized by large expansions (>100 repeats) in non-coding sequences and their hypermethylation affects gene expression [26][27][28][29][30][31]. The CTG18.1 locus in TCF4 is also located in non-coding sequence within intron 2 (NM_001083962.2), and the median TCF4 repeat length is close to 100 repeats in the Swedish FECD cohort [17]. A well-known consequence of DNA methylation at gene promoter regions is gene silencing, whereas gene body methylation may be involved in the regulation of gene splicing [32,33].…”

DNA methylation changes and increased mRNA expression of coagulation proteins, Factor V and Thrombomodulin in Fuchs endothelial corneal dystrophy

“…These diseases are characterized by large expansions (>100 repeats) in non-coding sequences and their hypermethylation affects gene expression [26][27][28][29][30][31]. The CTG18.1 locus in TCF4 is also located in non-coding sequence within intron 2 (NM_001083962.2), and the median TCF4 repeat length is close to 100 repeats in the Swedish FECD cohort [17]. A well-known consequence of DNA methylation at gene promoter regions is gene silencing, whereas gene body methylation may be involved in the regulation of gene splicing [32,33] and affect gene expression through i.a.…”

Lower Fractions of TCF4 Transcripts Spanning over the CTG18.1 Trinucleotide Repeat in Human Corneal Endothelium

“…However later, a much stronger association was found to an expansion of cytosine-thymine-guanine (CTG) n repeat, known as CTG18.1 [ 5 ], in intron 3 of the TCF4 gene [ 6 ]. Currently, association of the TCF4 repeat expansion ( n > 50) and FECD has been reported in several populations [ 7 , 8 , 9 , 10 , 11 ]. In other studies, association of FECD and (CTG) n repeat length over 40 has also been shown [ 12 , 13 , 14 , 15 ].…”