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Examining the role of the Prader-Willi syndrome critical interval in psychiatric illness and cognition

Zahova, Simona 2021. Examining the role of the Prader-Willi syndrome critical interval in psychiatric illness and cognition. PhD Thesis, Cardiff University.
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Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by loss of function mutations on chromosome 15q11.2-q13. It is characterized by hypotonia and hyperphagia, as well as impaired cognition and attention, maladaptive behaviour and increased prevalence of psychiatric illness including anxiety, depression, and psychosis. The hyperphagia and hypotonia observed in individuals with PWS are attributed mainly to the SNORD116 and IPW non-coding RNAs on chromosome 15, which are collectively known as the Prader-Willi syndrome critical interval (PWS-cr). However, the genetics underlying the cognitive and psychiatric disorders in PWS are still not well understood. The aim of this study is to assess the role, if any, of PWS-cr in cognition and psychiatric illness in three approaches: by investigating behaviours of relevance in a mouse model carrying a deletion of PWS-cr (Chapters 2, 3), by examining the transcriptomic effects of the deletion on the neonatal mouse brain (Chapter 4) and by analysing the effect of genetic variation in the PWS-cr interval in humans on phenotypes of relevance (Chapter 5). Previously, endophenotypes of relevance to ADHD and psychotic illness have been reported in a "full" mouse model of PWS (PWS-IC), in which expression of the entire PWS locus including PWS-cr is dysregulated. In comparison, the PWS-cr mouse model exhibited no behaviours of relevance to ADHD and psychotic illness, but exhibited a behaviour that could be indicative of depression. In order to investigate the molecular factors driving the behavioural phenotypes of PWS-IC and PWS-cr mouse models, RNA-sequencing study of neonatal brain of both models was performed. The results revealed transcriptomic changes relevant to psychosis in the PWS-IC mouse model, which were absent in the PWS-cr model. However, the PWS-cr mouse brain had increased expression of Necdin and differential isoform usage of Dyrk3, which are both linked with cognition and learning. Since the behavioural and transcriptomic studies provided evidence that PWS-cr might play a role in depression and cognition, the role of the interval in depression and cognition was examined by investigating whether genetic variants in the interval are associated with phenotypes of relevance. The results showed no evidence of genetic variants within PWS-cr having a role in depression, but gave an indication that PWS-cr might be involved in rate of processing visual figures. In conclusion, results from this study suggest that PWS-cr might play a subtle role in aspects of cognition, but its deletion does not induce most of the behavioural and molecular changes observed in individuals with PWS or in the PWS-IC mouse model.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 22 December 2021
Last Modified: 22 Dec 2021 10:38

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