Date of Award

Spring 2026

Language

English

Embargo Period

5-1-2026

Document Type

Master's Thesis

Degree Name

Master of Science (MS)

College/School/Department

Department of Biological Sciences

Program

Biology

First Advisor

J. Andrew Berglund

Committee Members

Dr. Morgan Sammons, Dr. Elise Vogt

Keywords

Trinucleotide Expansion, DM1, FECD, RNA Toxicity, Alternative Splicing, Bioinformatics

Subject Categories

Bioinformatics | Biology | Diseases

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant form of muscular dystrophy, and it is the most common form of adult-onset muscular dystrophy. The disease is the result of CTG trinucleotide repeats (TNR) in the 3’UTR of the dystrophia myotonica protein kinase (DMPK) gene. This produces toxic RNA hairpin structures by CUG repeat expansions that sequester proteins–most relevantly muscleblind-like 1 (MBNL)–that regulate alternative RNA splicing. The missplicing of a wide variety of genes results in the symptoms such as myotonia (rigidity of the muscles), atrophy, and cardiac failure.

Fuchs’ Endothelial Corneal Dystrophy (FECD) is characterized by progressive loss and dysfunction of corneal endothelial cells. There are two indistinguishable (relative to the clinical setting) subsets of the disease. One is caused by a CTG TNR within the transcription factor 4 (TCF4) gene or, less commonly, within the DMPK gene in the same 3’UTR as seen in DM1. The other subset of the disease lacks the CTG TNR. For our study we focused on the later-onset form of the disease caused by the CTG TNR.

Our study aimed to identify shared splicing abnormalities between DM1 and FECD on the grounds that they are both repeat expansion disorders. While several previous studies suggest downstream effects common in both diseases, none have directly performed a comparative analysis of the effects.

We performed an analysis of alternative splicing to identify shared molecular features between DM1 and FECD. Based on the known role of MBNL1 in both disorders, we hypothesized that dysregulated splicing would affect pathways related to development, cellular regeneration, and stress response; processes commonly implicated in dystrophic pathology.

We computationally analyzed tissue samples from two datasets of FECD corneas, tibialis anterior DM1 (TA DM1), and frontal cortex data from DM1. We identified a list of recurring v splicing events that appeared in all four of the datasets, performing gene ontology analysis to identify the shared cellular processes associated with the aberrantly spliced genes. We identified a set of recurring genes that appeared in all four datasets and three tissue types, suggesting common spliceopathic mechanisms and downstream effects in key cellular processes.

License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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