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Waugh, Christopher (2025) Synthesis of Muscleblind-Like Splicing Regulator 1 (MBNL1) protein and CUGexp toxic RNA biomolecules in Myotonic Dystrophy Type 1 disease. MSc(Res) thesis, University of Nottingham.

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Abstract

Myotonic Dystrophy type 1 (dystrophia myotonica type 1 (DM1)) is a debilitating form of Muscular Dystrophy disease, and the most common form of DM affecting ~1 in 8000 individuals. The disease presents an array of multisystemic, typically neuromuscular symptoms, where complications vary considerably between patients, manifesting in an age-onset manner in adult DM1, or earlier in childhood and congenital DM1. Symptomatic relief of DM1 symptoms is the current treatment route under medical consortium guidelines, with no approved available treatments to cure DM1 disease, although promising novel therapeutics are at various stages of clinical trials.

The cause of DM1 is a trinucleotide repeat CTG (n=50 - >3000) sequence located within the 3’-UTR ends of the dystrophia myotonica protein kinase (DMPK) gene, with disease severity directly correlated to repeat length. The transcribed mRNA forms highly structured hairpin conformations, preferentially binding splicing factor Muscleblind-Like Splicing Regulator 1 (MBNL1) protein, and other co-factors, forming large RNA-Protein “foci” located typically in the cell nucleus, or cytoplasm. These complexes sequester MBNL1 from its normal function, leading to DM1 symptoms.

Here, the aim of the study presented is to synthesise DM1 representative mRNA and MBNL1 protein constructs for downstream structural analysis of the RNA-MBNL1 complexes. Current structure data depositions relating to MBNL1 domains with toxic RNA are few, and none on intact DM1 disease complexes. Therefore, the ability to do biophysical investigations into DM1 disease complexes in this detail would allow for future Structure-Based Drug Design (SBDD), an approach widely adopted to increase success of novel treatment compound development.

Item Type:	Thesis (University of Nottingham only) (MSc(Res))
Supervisors:	Borkar, Aditi Brook, David
Keywords:	Myotonic Dystrophy type 1; MBNL1 protein constructs; RNA structural analysis; RNA-MBNL1 complexes
Subjects:	R Medicine > RC Internal medicine
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID:	83046
Depositing User:	Blore, Mrs Kathryn
Date Deposited:	19 Dec 2025 09:15
Last Modified:	19 Dec 2025 09:15
URI:	https://eprints.nottingham.ac.uk/id/eprint/83046

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