Fuchs’ endothelial corneal dystrophy in patients with myotonic dystrophy, Type 1

Nelson S. Winkler, Margherita Milone, Jennifer Martinez-Thompson, Harish Raja, Ross A. Aleff, Sanjay V. Patel, Michael P Fautsch, Eric D Wieben, Keith Baratz

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

PURPOSE. RNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs’ endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium. METHODS. FECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA. RESULTS. FECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P <0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients. CONCLUSIONS. FECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.

Original languageEnglish (US)
Pages (from-to)3053-3057
Number of pages5
JournalInvestigative Ophthalmology and Visual Science
Volume59
Issue number7
DOIs
StatePublished - Jun 1 2018

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Fuchs' Endothelial Dystrophy
Myotonic Dystrophy
Trinucleotide Repeat Expansion
Transcription Factors
Protein Kinases
Trinucleotide Repeats
DNA
Corneal Endothelium
Southern Blotting
Genes

Keywords

  • Cornea
  • Corneal dystrophies
  • Corneal genetics
  • Fuchs’ endothelial corneal dystrophy
  • Myotonic dystrophy

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Fuchs’ endothelial corneal dystrophy in patients with myotonic dystrophy, Type 1. / Winkler, Nelson S.; Milone, Margherita; Martinez-Thompson, Jennifer; Raja, Harish; Aleff, Ross A.; Patel, Sanjay V.; Fautsch, Michael P; Wieben, Eric D; Baratz, Keith.

In: Investigative Ophthalmology and Visual Science, Vol. 59, No. 7, 01.06.2018, p. 3053-3057.

Research output: Contribution to journalArticle

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abstract = "PURPOSE. RNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs’ endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium. METHODS. FECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA. RESULTS. FECD grade was 2 or higher in 5 (36{\%}) of 14 probands, significantly greater than the general population (5{\%}) (P <0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75{\%} prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4{\%}. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients. CONCLUSIONS. FECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.",
keywords = "Cornea, Corneal dystrophies, Corneal genetics, Fuchs’ endothelial corneal dystrophy, Myotonic dystrophy",
author = "Winkler, {Nelson S.} and Margherita Milone and Jennifer Martinez-Thompson and Harish Raja and Aleff, {Ross A.} and Patel, {Sanjay V.} and Fautsch, {Michael P} and Wieben, {Eric D} and Keith Baratz",
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T1 - Fuchs’ endothelial corneal dystrophy in patients with myotonic dystrophy, Type 1

AU - Winkler, Nelson S.

AU - Milone, Margherita

AU - Martinez-Thompson, Jennifer

AU - Raja, Harish

AU - Aleff, Ross A.

AU - Patel, Sanjay V.

AU - Fautsch, Michael P

AU - Wieben, Eric D

AU - Baratz, Keith

PY - 2018/6/1

Y1 - 2018/6/1

N2 - PURPOSE. RNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs’ endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium. METHODS. FECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA. RESULTS. FECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P <0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients. CONCLUSIONS. FECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.

AB - PURPOSE. RNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs’ endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium. METHODS. FECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA. RESULTS. FECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P <0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients. CONCLUSIONS. FECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.

KW - Cornea

KW - Corneal dystrophies

KW - Corneal genetics

KW - Fuchs’ endothelial corneal dystrophy

KW - Myotonic dystrophy

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