Fuchs’ endothelial corneal dystrophy and RNA foci in patients with myotonic dystrophy

Venkateswara Mootha, Brock Hansen, Ziye Rong, Pradeep P Mammen, Zhengyang Zhou, Chao Xing, Xin Gong

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

PURPOSE. The most common cause of Fuchs’ endothelial corneal dystrophy (FECD) is an intronic CTG repeat expansion in TCF4. Expanded CUG repeat RNA colocalize with splicing factor, muscleblind-like 1 (MBNL1), in nuclear foci in endothelium as a molecular hallmark. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in the 30-untranslated region (UTR) of DMPK. In this study, we examine for RNAMBNL1 foci in endothelial cells of FECD subjects with DM1, test the hypothesis that DM1 patients are at risk for FECD, and determine prevalence of TCF4 and DMPK expansions in a FECD cohort. METHODS. Using FISH, we examined for nuclear RNA-MBNL1 foci in endothelial cells from FECD subjects with DM1. We examined 13 consecutive unrelated DM1 patients for FECD using slit-lamp and specular microscopy. We genotyped TCF4 and DMPK repeat polymorphisms in a FECD cohort of 317 probands using short-tandem repeat and triplet repeat-primed PCR assays. RESULTS. We detected abundant nuclear RNA foci colocalizing with MBNL1 in endothelial cells of FECD subjects with DM1. Six of thirteen DM1 patients (46%) had slit-lamp and specular microscopic findings of FECD, compared to 4% disease prevalence (P = 5:5310-6). As expected, 222 out of 317 (70%) FECD probands harbored TCF4 expansion, while one subject harbored DMPK expansion without prior diagnosis of DM1. CONCLUSIONS. Our work suggests that DM1 patients are at risk for FECD. DMPK mutations contribute to the genetic burden of FECD but are uncommon. We establish a connection between two repeat expansion disorders converging upon RNA-MBNL1 foci and FECD.

Original languageEnglish (US)
Pages (from-to)4579-4585
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume58
Issue number11
DOIs
StatePublished - Sep 1 2017

Fingerprint

Fuchs' Endothelial Dystrophy
Myotonic Dystrophy
RNA
Nuclear RNA
Endothelial Cells
Untranslated Regions
Trinucleotide Repeats
Microsatellite Repeats

Keywords

  • DMPK
  • Fuchs’ endothelial corneal dystrophy
  • Myotonic dystrophy
  • Nuclear RNA foci
  • Triplet repeat expansion

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Fuchs’ endothelial corneal dystrophy and RNA foci in patients with myotonic dystrophy. / Mootha, Venkateswara; Hansen, Brock; Rong, Ziye; Mammen, Pradeep P; Zhou, Zhengyang; Xing, Chao; Gong, Xin.

In: Investigative Ophthalmology and Visual Science, Vol. 58, No. 11, 01.09.2017, p. 4579-4585.

Research output: Contribution to journalArticle

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title = "Fuchs’ endothelial corneal dystrophy and RNA foci in patients with myotonic dystrophy",
abstract = "PURPOSE. The most common cause of Fuchs’ endothelial corneal dystrophy (FECD) is an intronic CTG repeat expansion in TCF4. Expanded CUG repeat RNA colocalize with splicing factor, muscleblind-like 1 (MBNL1), in nuclear foci in endothelium as a molecular hallmark. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in the 30-untranslated region (UTR) of DMPK. In this study, we examine for RNAMBNL1 foci in endothelial cells of FECD subjects with DM1, test the hypothesis that DM1 patients are at risk for FECD, and determine prevalence of TCF4 and DMPK expansions in a FECD cohort. METHODS. Using FISH, we examined for nuclear RNA-MBNL1 foci in endothelial cells from FECD subjects with DM1. We examined 13 consecutive unrelated DM1 patients for FECD using slit-lamp and specular microscopy. We genotyped TCF4 and DMPK repeat polymorphisms in a FECD cohort of 317 probands using short-tandem repeat and triplet repeat-primed PCR assays. RESULTS. We detected abundant nuclear RNA foci colocalizing with MBNL1 in endothelial cells of FECD subjects with DM1. Six of thirteen DM1 patients (46{\%}) had slit-lamp and specular microscopic findings of FECD, compared to 4{\%} disease prevalence (P = 5:5310-6). As expected, 222 out of 317 (70{\%}) FECD probands harbored TCF4 expansion, while one subject harbored DMPK expansion without prior diagnosis of DM1. CONCLUSIONS. Our work suggests that DM1 patients are at risk for FECD. DMPK mutations contribute to the genetic burden of FECD but are uncommon. We establish a connection between two repeat expansion disorders converging upon RNA-MBNL1 foci and FECD.",
keywords = "DMPK, Fuchs’ endothelial corneal dystrophy, Myotonic dystrophy, Nuclear RNA foci, Triplet repeat expansion",
author = "Venkateswara Mootha and Brock Hansen and Ziye Rong and Mammen, {Pradeep P} and Zhengyang Zhou and Chao Xing and Xin Gong",
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T1 - Fuchs’ endothelial corneal dystrophy and RNA foci in patients with myotonic dystrophy

AU - Mootha, Venkateswara

AU - Hansen, Brock

AU - Rong, Ziye

AU - Mammen, Pradeep P

AU - Zhou, Zhengyang

AU - Xing, Chao

AU - Gong, Xin

PY - 2017/9/1

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N2 - PURPOSE. The most common cause of Fuchs’ endothelial corneal dystrophy (FECD) is an intronic CTG repeat expansion in TCF4. Expanded CUG repeat RNA colocalize with splicing factor, muscleblind-like 1 (MBNL1), in nuclear foci in endothelium as a molecular hallmark. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in the 30-untranslated region (UTR) of DMPK. In this study, we examine for RNAMBNL1 foci in endothelial cells of FECD subjects with DM1, test the hypothesis that DM1 patients are at risk for FECD, and determine prevalence of TCF4 and DMPK expansions in a FECD cohort. METHODS. Using FISH, we examined for nuclear RNA-MBNL1 foci in endothelial cells from FECD subjects with DM1. We examined 13 consecutive unrelated DM1 patients for FECD using slit-lamp and specular microscopy. We genotyped TCF4 and DMPK repeat polymorphisms in a FECD cohort of 317 probands using short-tandem repeat and triplet repeat-primed PCR assays. RESULTS. We detected abundant nuclear RNA foci colocalizing with MBNL1 in endothelial cells of FECD subjects with DM1. Six of thirteen DM1 patients (46%) had slit-lamp and specular microscopic findings of FECD, compared to 4% disease prevalence (P = 5:5310-6). As expected, 222 out of 317 (70%) FECD probands harbored TCF4 expansion, while one subject harbored DMPK expansion without prior diagnosis of DM1. CONCLUSIONS. Our work suggests that DM1 patients are at risk for FECD. DMPK mutations contribute to the genetic burden of FECD but are uncommon. We establish a connection between two repeat expansion disorders converging upon RNA-MBNL1 foci and FECD.

AB - PURPOSE. The most common cause of Fuchs’ endothelial corneal dystrophy (FECD) is an intronic CTG repeat expansion in TCF4. Expanded CUG repeat RNA colocalize with splicing factor, muscleblind-like 1 (MBNL1), in nuclear foci in endothelium as a molecular hallmark. Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG repeat expansion in the 30-untranslated region (UTR) of DMPK. In this study, we examine for RNAMBNL1 foci in endothelial cells of FECD subjects with DM1, test the hypothesis that DM1 patients are at risk for FECD, and determine prevalence of TCF4 and DMPK expansions in a FECD cohort. METHODS. Using FISH, we examined for nuclear RNA-MBNL1 foci in endothelial cells from FECD subjects with DM1. We examined 13 consecutive unrelated DM1 patients for FECD using slit-lamp and specular microscopy. We genotyped TCF4 and DMPK repeat polymorphisms in a FECD cohort of 317 probands using short-tandem repeat and triplet repeat-primed PCR assays. RESULTS. We detected abundant nuclear RNA foci colocalizing with MBNL1 in endothelial cells of FECD subjects with DM1. Six of thirteen DM1 patients (46%) had slit-lamp and specular microscopic findings of FECD, compared to 4% disease prevalence (P = 5:5310-6). As expected, 222 out of 317 (70%) FECD probands harbored TCF4 expansion, while one subject harbored DMPK expansion without prior diagnosis of DM1. CONCLUSIONS. Our work suggests that DM1 patients are at risk for FECD. DMPK mutations contribute to the genetic burden of FECD but are uncommon. We establish a connection between two repeat expansion disorders converging upon RNA-MBNL1 foci and FECD.

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KW - Nuclear RNA foci

KW - Triplet repeat expansion

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