Trinucleotide Repeat Expansion in the Transcription Factor 4 (<i>TCF4</i>) Gene Leads to Widespread mRNA Splicing Changes in Fuchs' Endothelial Corneal Dystrophy

Wieben, Eric D.; Aleff, Ross A.; Tang, Xiaojia; Butz, Malinda L.; Kalari, Krishna R.; Highsmith, Edward W.; Jen, Jin; Vasmatzis, George; Patel, Sanjay V.; Maguire, Leo J.; Baratz, Keith H.; Fautsch, Michael P.

doi:10.1167/iovs.16-20900

Cited by 64 publications

(84 citation statements)

References 39 publications

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“…penetrance and different degree of correlation between ethnicities. 1,28,102,104,123,138 The second most frequent cause of endothelial decompensation is pseudophakic bullous keratopathy (PBK). Despite the major advances in cataract surgery and ophthalmic viscosurgical devices, phacoemulsification can damage the endothelial layer and result in corneal decompensation.…”

Section: Common Endothelial Diseasesmentioning

confidence: 99%

A review of the evidence for in vivo corneal endothelial regeneration

Bogerd

Dhubhghaill

Koppen

et al. 2018

Survey of Ophthalmology

107

104

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Human corneal endothelium has long been thought to be a nonmitotic cell layer with no endogenous reparative potential. Pathologies that damage endothelial function result in corneal decompensation and, if untreated, blindness. The mainstay of treatment involves partial or complete corneal replacement, amounting to 40% of all corneal transplants performed worldwide. We summarize the case reports describing complications postoperatively in the form of (sub)total graft detachment and those resulting in postoperative bare stroma. Complications during cataract and glaucoma surgeries leading to an uncovered posterior cornea are also included. We discuss the newer treatment strategies that are alternatives for current Descemet membrane endothelial keratoplasty and Descemet stripping automated endothelial keratoplasty, including partial grafts and stripping of the diseased cell layer. In more than half of the cases reviewed, corneal transparency returned despite incomplete or no corneal endothelial cell transplantation. We question the existing paradigm concerning corneal endothelial wound healing in vivo. The data support further clinical study to determine the safety of simple descemethorexis in central endothelial pathologies, such as Fuchs endothelial corneal dystrophy, where presence of healthy peripheral cells may allow successful corneal recompensation without the need for donor cells.

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Section: Common Endothelial Diseasesmentioning

confidence: 99%

A review of the evidence for in vivo corneal endothelial regeneration

Bogerd

Dhubhghaill

Koppen

et al. 2018

Survey of Ophthalmology

107

104

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“…Large repeats in or near a promoter can profoundly influence expression of the gene as illustrated with FXS above. Repeats within introns can influence alternative splicing of the disease gene, globally perturb splicing by sequestering splicing factors, or perturb transcription (13,148,151). Repeats within the 3’UTR likewise can have a toxic RNA effect by disrupting RNA homeostasis (151).…”

Section: Introductionmentioning

confidence: 99%

“…Normal CTG repeats are between 10 and 37, and pathogenic repeats are greater than 50. Little is known about how the expansion contributes to disease, but the current leading hypothesis is a toxic RNA effect (148). …”

Section: Introductionmentioning

confidence: 99%

Repeat expansion diseases

Paulson

2018

Handbook of Clinical Neurology

327

286

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More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.

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“…Overexpression of MBNL1 can reverse RNA missplicing and myotonia in a DM1 mouse model (31). MBNL is also associated with mutant CUG RNA in FECD cells and tissue (28)(29)(30). Blocking the CUG repeat region using antisense oligonucleotides can reverse missplicing in DM1 (caused by a CUG repeat within the DMPK gene) (48-51) and FECD (44,52) tissues.…”

Section: Discussionmentioning

confidence: 99%

“…CUG repeat RNA is known to bind the splicing factors muscleblind-like 1 and 2 (MBNL1 and MNBL2) (24)(25)(26)(27). Previous studies have proposed that sequestration of MBNL1 and MBNL2 reduces levels of available MBNL protein, causing the changes of splicing observed in tissue from FECD_REP patients (28)(29)(30) and in patients with myotonic dystrophy who possess expanded CUG repeats within 3'-untranslated region of the DMPK gene (24,25,31).…”

Section: Changes In Alternative Splicing Triggered By the Expanded Rementioning

confidence: 99%

Analyzing Presymptomatic Tissue to Gain Insights into the Molecular and Mechanistic Origins of Late-Onset Degenerative Trinucleotide Repeat Disease

Mootha

Corey

Chu

et al. 2020

Preprint

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How genetic defects trigger the molecular changes that cause late-onset disease is important for understanding disease progression and therapeutic development. Fuchs' endothelial corneal dystrophy (FECD) is an RNA-mediated disease caused by a trinucleotide CUG expansion in an intron within the TCF4 gene. The mutant intronic CUG RNA is present at 1-2 copies per cell, posing a challenge to understand how a rare RNA can cause disease. Late-onset FECD is a uniquely advantageous model for studying how RNA triggers disease because; 1) Affected tissue is routinely removed during surgery; 2) The expanded CUG mutation is one of the most prevalent disease-causing mutations, making it possible to obtain pre-symptomatic tissue from eye bank donors to probe how gene expression changes precede disease; and 3) The affected tissue is a homogeneous single cell monolayer, facilitating accurate transcriptome analysis. Here we use RNA sequencing (RNAseq) to compare tissue from individuals who are pre-symptomatic (Pre_S) to tissue from patients with late stage FECD (FECD_REP). The abundance of mutant repeat intronic RNA in Pre_S and FECD_REP tissue is elevated due to increased half-life in a corneal cell-specific manner. In Pre_S tissue, changes in splicing and extracellular matrix gene expression foreshadow the changes observed in advanced disease and predict the activation of the fibrosis pathway and immune system seen in late-stage patients. The absolute magnitude of splicing changes is similar in presymptomatic and late stage tissue. Our data identify gene candidates for early drivers of disease and biomarkers that may represent diagnostic and therapeutic targets for FECD. We conclude that changes in alternative splicing and gene expression are observable decades prior to the diagnosis of late-onset trinucleotide repeat disease. 3 3 6 6

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Trinucleotide Repeat Expansion in the Transcription Factor 4 (TCF4) Gene Leads to Widespread mRNA Splicing Changes in Fuchs' Endothelial Corneal Dystrophy

Cited by 64 publications

References 39 publications

A review of the evidence for in vivo corneal endothelial regeneration

A review of the evidence for in vivo corneal endothelial regeneration

Repeat expansion diseases

Analyzing Presymptomatic Tissue to Gain Insights into the Molecular and Mechanistic Origins of Late-Onset Degenerative Trinucleotide Repeat Disease

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