Identifying changes in stress regulation and organisation within the messenger RNA metabolism in myotonic dystrophy type 1 disease models

  • Selma Gulyurtlu

Student thesis: Doctoral Thesis (PhD)


Myotonic dystrophy is an RNA-mediated multi-systemic disease, and the most common form of muscular dystrophy in adults. This project focussed on type 1 (DM1), characterised by a CTG trinucleotide repeat expansion on the 3’UTR of the DMPK gene. This expansion when transcribed forms an elongated metastable stem loop structure, with mutant transcripts accumulating into nuclear foci resulting in toxic gain-of-effects. This causes a shift in activities of antagonistic alternative splicing regulators MBNL1 and CUGBP1. MBNL1 is attracted to and believed to sequester in the foci, whereas CUGBP1 experiences an increase of activity. It is deemed that the shift in splicing patterns caused by their altered activities, gives rise to the DM1 phenotype. Cataracts are the most prevalent DM1 symptom. The human eye lens epithelium contains the majority of nucleated cells. The foci in these epithelial cells in vitro are smaller than in other tissues, with little MBNL1 recruitment. It was suggested that other mechanisms apart from MBNL1 sequestration are likely to be contributing to the DM1 phenotype. Here, the RNA metabolism was investigated, observing different RNA-rich bodies and MBNL1/CUGBP1’s relationship to them in human lens epithelial cells (HLECs). Importantly, it was investigated whether these bodies or MBNL1/CUGBP1’s relationship to them changed in DM1 HLECs. It was found that altered intracellular bodies in DM1 HLECs had a common theme of stress sensing and regulation. This implies that these cells may be experiencing an impairment in responding to stress. It was suggested that these changes may be attributed to altered autophagy levels. This is important because lens epithelial cells differentiate into fiber cells, a process involving denucleation and organelle loss and regulated partly by autophagy. Additionally, changes in MBNL1 expression patterns and increased formation of solid bodies were also observed. Hence, additional contributions to the cellular DM1 phenotype were suggested in HLECs, apart from altered splicing patterns.
Date of Award30 Jun 2021
Original languageEnglish
Awarding Institution
  • University of St Andrews
SupervisorJudith Elizabeth Sleeman (Supervisor) & Alan R. Prescott (Supervisor)

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  • Full text embargoed until
  • 9 April 2023

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