Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene in Thai patients with Fuchs endothelial corneal dystrophy

Okumura, Naoki; Puangsricharern, Vilavun; **dasak, Raina; Koizumi, Noriko; Komori, Yuya; Ryousuke, Hayashi; Nakahara, Makiko; Nakano, Masakazu; Adachi, Hiroko; Tashiro, Kei; Yoshii, Kengo; Chantaren, Patchima; Ittiwut, Rungnapa; Shotelersuk, Vorasuk; Suphapeetiporn, Kanya

doi:10.1038/s41433-019-0595-8

Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene in Thai patients with Fuchs endothelial corneal dystrophy

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Published: 25 September 2019

Volume 34, pages 880–885, (2020)
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Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene in Thai patients with Fuchs endothelial corneal dystrophy

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Naoki Okumura¹,
Vilavun Puangsricharern^2,3,
Raina **dasak²,
Noriko Koizumi¹,
Yuya Komori¹,
Hayashi Ryousuke¹,
Makiko Nakahara¹,
Masakazu Nakano⁴,
Hiroko Adachi⁴,
Kei Tashiro⁴,
Kengo Yoshii⁵,
Patchima Chantaren³,
Rungnapa Ittiwut^6,7,
Vorasuk Shotelersuk^6,7 &
…
Kanya Suphapeetiporn^6,7

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Abstract

Purpose

To evaluate the association of single nucleotide polymorphisms (SNPs) and the intronic expansion of a trinucleotide repeat (TNR) in the TCF4 gene with Fuchs endothelial corneal dystrophy (FECD) in a Thai population.

Methods

In total, 54 Thai FECD patients and 54 controls were recruited for the study. Five SNPs (rs613872, rs2123392, rs17089887, rs1452787, and rs1348047), previously reported to be associated with FECD, were genotyped by direct sequencing. The repeat length was determined by direct sequencing of PCR-amplified DNA (a short tandem repeat; STR assay) and by triplet repeat primed PCR (TP-PCR).

Results

Only one of the 54 patients with FECD harboured rs613872 (1.9%). Four SNPs (rs2123392, rs17089887, rs1452787, and rs1348047), which are not rare polymorphisms in the Thai population, were found in approximately half of the patients. Of the 54 patients, 21 (1 homozygous and 20 heterozygous patients; 39%) harboured a TNR ≥ 40, while 33 patients (61%) harboured a TNR < 40.

Conclusions

The association of TNR expansion in TCF4 with FECD is shown for the first time in the Thai population. The intronic TNR expansion identified in various ethnic groups underlines the importance of expansion as a potent pathophysiological cause of FECD.

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Introduction

Fuchs endothelial corneal dystrophy (FECD) is a bilateral corneal disease characterised by a progressive loss of corneal endothelial cells that typically begins after the age of 40 [1, 2]. The corneal endothelium is responsible for maintaining corneal transparency by regulating the amount of water in the corneal stroma; therefore, a severe loss of corneal endothelial cells results in vision loss due to corneal haziness.

FECD initially showed an autosomal dominant inheritance pattern with variable penetrance and expressivity in investigations of large families conducted in the 1970s and 1980s [3,4,5]. Early screening studies for functional candidate genes and investigations of causal genes of other corneal endothelial dystrophies identified four genes (SLCA411, TCF8, LOXHD1, and AGBL1) that were associated with late-onset FECD (the typical form of FECD) [6,7,8,9,10,11]. However, these genes were not frequently encountered in the general population of FECD patients; therefore, researchers have continued searching for a more common genetic cause.

In 2010, a genome-wide association study (GWAS) reported a significant association between the intronic single nucleotide polymorphism (SNP) in the transcription factor 4 (TCF4) and late-onset FECD [12]. Subsequently, Wieben et al. reported a strong association between FECD and a cytosine–thymine–guanine (CTG) repeat expansion in the non-coding region of TCF4 and found a sensitivity and specificity of ≥50 repeats of 79% and 96%, respectively, for identifying FECD patients in their cohort [13]. Subsequent studies have replicated these novel findings in various populations, although the frequency of the repeat expansion in FECD tends to be lower in non-Caucasian (i.e., Chinese, Indian, and Japanese) cohorts [Full size table

Direct sequencing and TP-PCR demonstrated that no control subjects harboured a CTG trinucleotide repeat (TNR) higher than 40 repeats. Conversely, 21 of the 54 patients (39%; 1 homozygous and 20 heterozygous) harboured CTG TNR lengths greater than 40, while 33 patients of the 54 patients (61%) did not harbour TNR lengths greater than 40 (P < 0.001). The mean age of the 5 male and 16 female patients harbouring ≥40 CTG TNR was 65.3 ± 9.6 years (range, 39–78 years), while the mean age of the 5 male and 28 female patients harbouring <40 CTG TNR was 61.1 ± 15.6 years (range, 21–85 years). No statistically significant difference was observed in either age or gender among control subjects, patients with or without CTG TNR expansion higher than 40 repeats (Table 2). In agreement with the previous study, the distribution of the TNR length was bimodal, and fourteen patients harboured ≥100 CTG TNR (Fig. 1). One patient with FECD (a 66-year-old female) was homozygous for the CTG TNR expansion, and she was considered to be a Krachmer grade 2 and exhibited a transparent cornea. Clinical manifestations of the representative Thai patients with FECD harbouring CTG TNR < 40 and ≥40 are shown in Supplementary Fig. 1.

Table 2 Demographic data of subjects with Fuchs endothelial corneal dystrophy (FECD) with or without cytosine-thymine-guanine (CTG) trinucleotide repeat (TNR) expansion

Full size table

Discussion

Baratz et al. used GWAS to investigate 280 FECD cases and 410 controls and identified the minor allele (G) in rs613872 more frequently in the FECD cases (G = 0.40) than in non-FECD controls (G = 0.15); the odds ratios for this minor allele were 5.5 and 30 for being heterozygous and homozygous, respectively [12]. Subsequent reports in independent cohorts replicated the association between rs613872 and FECD. In addition to rs613872, other SNPs were identified in some populations, especially from non-Caucasian cohorts, indicating ethnic variation of SNPs in TCF4 [16, 20,21,22,23]. No previous study has examined SNPs in TCF4 in FECD in Thailand; therefore, we first looked for the reported SNPs in our Thai cohort. We found that only two among the 54 FECD subjects were polymorphic with regard to rs613872. Four other reported SNPs (rs2123392, rs17089887, rs1452787, and rs1348047) were found in our cases, but these SNPs are not rare polymorphisms, according to our findings in the controls and the 1000 Genomes Project database. We found that none of the reported SNPs in TCF4 showed an association with FECD in the Thai population.

The first report showing TNR expansion in TCF4, conducted in a Caucasian population, revealed that 52 of 66 (79%) FECD cases harboured CTG TNR ≥ 50, whereas only 2 of 63 (3%) controls had CTG TNR ≥ 50 [13]. Replication studies in an independent Caucasian cohort showed that 73% of the patients with FECD and 7% of the control subjects had CTG TNR expansion [14]. In a large hospital-based study in US, 62% of 574 FECD cases and 3.7% of 354 controls harboured TNR length >40 [18]. This association between TNR and FECD was also replicated in non-Caucasian cohorts, but the proportion of the patients harbouring TNR was lower than that observed in Caucasians. For example, in a Chinese cohort, 25 of 57 (44%) cases and 2 of 121 (1.7%) control subjects harboured CTG TNR lengths >50 [15], whereas these numbers were 15 of 44 (34%) cases and 5 of 97 (5.2%) control subjects in an Indian cohort [16], and 12 of 47 (26%) cases and 0 of 96 (0%) control subjects in a Japanese cohort [17]. In the current study, 21 of 54 patients (39%) and 0 of 54 controls (0%) in our Thai cohort harboured CTG TNR lengths ≥40. Our study in the Thai population provided further evidence that the harbouring of a CTG TNR expansion in TCF4 patients with FECD is a global finding, although the proportion was again lower in our Thai population when compared with the previously reported proportion in Caucasians.

In the current study, we utilised TP-PCR to determine very large TNR expansions, as these large expansions were difficult to detect by direct sequencing of PCR products. However, measuring very large repeats is challenging, and mosaicism within the leucocyte population further complicates these measurements. Therefore, the possibility of underestimation of patients harbouring TNR length ≥40 should be kept in mind due to the difficulty of obtaining accurate measurements of very large repeats.

TCF4 is a member of the basic helix-loop-helix (bHLH) family of transcription factors that are expressed in various tissues, such as brain, muscle, liver, lung, testis, and cornea [24]. Associations with TCF4 have been identified for primary sclerosing cholangitis and Pitt-Hopkins syndrome, as well as FECD [25]. However, probably because of the varied roles played by TCF4 in fundamental cellular events, the mechanistic cascade that determines the contribution of TCF4 to the phenotypes of these diseases remains unclear. Du and colleagues reported that poly(CUG)n RNA accumulated as RNA foci in the corneal endothelial cells of patients with FECD, and induced RNA toxicity and missplicing [26]. The involvement of repeat-associated non-ATG translation, a protein translation mechanism that has no requirement for an initiating ATG, was also suggested to explain TNR expansion in TCF4 as part of the pathophysiology of FECD [27]. A recent study has shown that antisense oligonucleotide targeting (CAG)₇ could reduce the gain-of-function RNA toxicity caused by TNR in TCF4, supporting TNR as a potent therapeutic target [28]. Our investigations of the pathophysiology of FECD have resulted in the establishment of a cellular model for the corneal endothelium of patients with FECD. We have also demonstrated that the genes that induce the epithelial–mesenchymal transition (EMT) play an important role in the production of extracellular matrix materials, such as type 1 collagen and fibronectin, which are components of guttae [29]. Sobrado et al. have also reported that overexpression of TCF4 in Madin–Darby canine kidney cells generated motile and highly invasive phenotypes that acquired EMT-related markers, and they proposed that TCF4 was an important regulator of the EMT [30]. Pathway analysis also showed that knockdown of TCF4 in neuroblastoma cells altered the expression of EMT-related genes [31]. However, the possibility that TCF4 plays a role in regulating the EMT has not been clearly elucidated in the corneal endothelium. Therefore, further studies of TCF4 function, focusing on the possible connection with the regulation of the EMT, are anticipated to elucidate the pathophysiology of FECD.

In conclusion, the findings of an association between SNPs in TCF4 and FECD differed depending on the ethnic background of the patients. The CTG repeat in intron 3 of TCF4 was always identified in all ethnic groups studied thus far, but with some variations in frequency. Here, we provide additional evidence that the CTG TNR in TCF4 is associated with FECD in the Thai population. To the best of our knowledge, this is the first genetic analysis of FECD in Thailand.

Summary

What was known before

A significant association between the SNP in the TCF4 and late-onset FECD was shown in the Caucasian population.
FECD cases frequently harbour intronic TNR expansion in TCF4 with CTG repeat ≥50 in the Caucasian population, but the proportion of the patients harbouring TNR was lower in non-Caucasians.
Ethnic variation of SNPs and TNR expansion in TCF4 is indicated, and the genetic analysis of FECD in Thai cases has not yet reported.

What this study adds

Only 2 among the 54 FECD subjects in the Thai cohort were polymorphic with regard to rs613872.
Twenty-one of 54 patients with FECD (39%) and 0 of 54 non-FECD controls (0%) in the Thai cohort harboured CTG TNR length ≥40.
This study is the first genetic analysis of FECD in Thailand which provided additional evidence that CTG repeat in TCF4 was present in all ethnic groups studied thus far with some variations in frequency.

Change history

03 October 2019
The original version of this Article contained an incorrect affiliation for Rungnapa Ittiwut. This has now been corrected in both the PDF and HTML versions of the Article.
21 February 2020
The original HTML version of this Article was updated shortly after publication to acknowledge funding from the Ratchadapiseksompotch Fund.

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Acknowledgements

The authors wish to thank Ms. Emi Ueda and Ms. Kyoko Watanabe for technical support.

Funding

This work was supported by the Programme for the Strategic Research Foundation at Private Universities from MEXT (NK and NO), Chulalongkorn Academic Advancement into Its 2nd Century Project and the Thailand Research Fund (BRG5980001 and DPG6180001) and Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University, (Grant number RA56/027).

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Authors and Affiliations

Department of Biomedical Engineering, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan
Naoki Okumura, Noriko Koizumi, Yuya Komori, Hayashi Ryousuke & Makiko Nakahara
Department of Ophthalmology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
Vilavun Puangsricharern & Raina **dasak
Excellence Center for Cornea and Limbal Stem Cell Transplantation, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, 10330, Thailand
Vilavun Puangsricharern & Patchima Chantaren
Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
Masakazu Nakano, Hiroko Adachi & Kei Tashiro
Department of Mathematics and Statistics in Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan
Kengo Yoshii
Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
Rungnapa Ittiwut, Vorasuk Shotelersuk & Kanya Suphapeetiporn
Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, 10330, Thailand
Rungnapa Ittiwut, Vorasuk Shotelersuk & Kanya Suphapeetiporn

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Naoki Okumura
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Vilavun Puangsricharern
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Raina **dasak
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Noriko Koizumi
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Yuya Komori
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Hayashi Ryousuke
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Masakazu Nakano
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Hiroko Adachi
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Kei Tashiro
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Kengo Yoshii
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Patchima Chantaren
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Rungnapa Ittiwut
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Vorasuk Shotelersuk
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Kanya Suphapeetiporn
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Correspondence to Vilavun Puangsricharern.

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Supplementary information

ST1: Oligonucleotide sequences

SF1: Clinical manifestation of Thai patients with FECD

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Okumura, N., Puangsricharern, V., **dasak, R. et al. Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene in Thai patients with Fuchs endothelial corneal dystrophy. Eye 34, 880–885 (2020). https://doi.org/10.1038/s41433-019-0595-8

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Received: 27 November 2018
Revised: 10 June 2019
Accepted: 22 August 2019
Published: 25 September 2019
Issue Date: May 2020
DOI: https://doi.org/10.1038/s41433-019-0595-8
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Trinucleotide repeat expansion in the transcription factor 4 (TCF4) gene in Thai patients with Fuchs endothelial corneal dystrophy