Effect of Trinucleotide Repeat Expansion on the Expression of TCF4 mRNA in Fuchs' Endothelial Corneal Dystrophy

Naoki Okumura, Ryosuke Hayashi, Masakazu Nakano, Kengo Yoshii, Kei Tashiro, Takahiko Sato, Derek J. Blake, Ross Aleff, Malinda Butz, W Edward Jr. Highsmith, Eric D Wieben, Michael P Fautsch, Keith Baratz, Yuya Komori, Makiko Nakahara, Theofilos Tourtas, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Noriko Koizumi

Research output: Contribution to journalArticle

Abstract

Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.

Original languageEnglish (US)
Pages (from-to)779-786
Number of pages8
JournalInvestigative ophthalmology & visual science
Volume60
Issue number2
DOIs
StatePublished - Feb 1 2019

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Fuchs' Endothelial Dystrophy
Trinucleotide Repeat Expansion
Transcription Factors
Messenger RNA
Corneal Endothelium
Trinucleotide Repeats
Southern Blotting
Microsatellite Repeats
Polymerase Chain Reaction
Descemet Membrane
DNA
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Effect of Trinucleotide Repeat Expansion on the Expression of TCF4 mRNA in Fuchs' Endothelial Corneal Dystrophy. / Okumura, Naoki; Hayashi, Ryosuke; Nakano, Masakazu; Yoshii, Kengo; Tashiro, Kei; Sato, Takahiko; Blake, Derek J.; Aleff, Ross; Butz, Malinda; Highsmith, W Edward Jr.; Wieben, Eric D; Fautsch, Michael P; Baratz, Keith; Komori, Yuya; Nakahara, Makiko; Tourtas, Theofilos; Schlötzer-Schrehardt, Ursula; Kruse, Friedrich; Koizumi, Noriko.

In: Investigative ophthalmology & visual science, Vol. 60, No. 2, 01.02.2019, p. 779-786.

Research output: Contribution to journalArticle

Okumura, N, Hayashi, R, Nakano, M, Yoshii, K, Tashiro, K, Sato, T, Blake, DJ, Aleff, R, Butz, M, Highsmith, WEJ, Wieben, ED, Fautsch, MP, Baratz, K, Komori, Y, Nakahara, M, Tourtas, T, Schlötzer-Schrehardt, U, Kruse, F & Koizumi, N 2019, 'Effect of Trinucleotide Repeat Expansion on the Expression of TCF4 mRNA in Fuchs' Endothelial Corneal Dystrophy', Investigative ophthalmology & visual science, vol. 60, no. 2, pp. 779-786. https://doi.org/10.1167/iovs.18-25760
Okumura, Naoki ; Hayashi, Ryosuke ; Nakano, Masakazu ; Yoshii, Kengo ; Tashiro, Kei ; Sato, Takahiko ; Blake, Derek J. ; Aleff, Ross ; Butz, Malinda ; Highsmith, W Edward Jr. ; Wieben, Eric D ; Fautsch, Michael P ; Baratz, Keith ; Komori, Yuya ; Nakahara, Makiko ; Tourtas, Theofilos ; Schlötzer-Schrehardt, Ursula ; Kruse, Friedrich ; Koizumi, Noriko. / Effect of Trinucleotide Repeat Expansion on the Expression of TCF4 mRNA in Fuchs' Endothelial Corneal Dystrophy. In: Investigative ophthalmology & visual science. 2019 ; Vol. 60, No. 2. pp. 779-786.
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abstract = "Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80{\%}) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.",
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T1 - Effect of Trinucleotide Repeat Expansion on the Expression of TCF4 mRNA in Fuchs' Endothelial Corneal Dystrophy

AU - Okumura, Naoki

AU - Hayashi, Ryosuke

AU - Nakano, Masakazu

AU - Yoshii, Kengo

AU - Tashiro, Kei

AU - Sato, Takahiko

AU - Blake, Derek J.

AU - Aleff, Ross

AU - Butz, Malinda

AU - Highsmith, W Edward Jr.

AU - Wieben, Eric D

AU - Fautsch, Michael P

AU - Baratz, Keith

AU - Komori, Yuya

AU - Nakahara, Makiko

AU - Tourtas, Theofilos

AU - Schlötzer-Schrehardt, Ursula

AU - Kruse, Friedrich

AU - Koizumi, Noriko

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.

AB - Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.

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