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dc.contributor.advisorShoubridge, Cheryl-
dc.contributor.authorMattiske, Tessa-
dc.description.abstractIntellectual disability (ID) is a highly prevalent disorder that affects 1-3% of the population, with ~ 100 causative genes mapped to the X-chromosome. The Aristaless-related homeobox gene (ARX) is an important transcription factor with critical roles in development, particularly in the developing brain. Variants are not well tolerated within ARX, with missense mutations resulting in phenotypes that always involve ID with frequent comorbidities of epilepsy, infantile spasms, hand dystonia, autism or dysarthria. Historically, it was thought that only males were affected by mutations in ARX due to their single X-chromosome. In this thesis, we describe a family with multiple affected individuals, including two females with a novel insertion mutation within ARX. We furthermore review the reported phenotype of females with mutations in ARX and highlight the importance of screening ARX in both male and female patients with ID and seizures. The majority of patients with ARX mutations are affected by expansion mutations in polyalanine tract 1 and 2 within the protein, giving rise to ID with or without epilepsy and movement disorders of varying severity. Mice modelling the two most frequent polyalanine expansion mutations (Arx(GCG)7 referred to as PA1 and Arx432-455dup24 referred to as PA2) recapitulate many of the clinical features seen in humans (Kitamura et al. 2009, Jackson et al. Submitted 2017). To dissect the molecular basis of different polyalanine expansions in vivo, we used 12.5 dpc brain samples from PA1 and PA2 mice to analyse disruptions in gene expression in the developing forebrain to capture the primary disruption leading to the developmental phenotypes caused by these mutations. A greater number of genes deregulated in the more severe PA1 mice was shown, with the majority of genes also perturbed in the milder PA2 mice, but failed to reach significance compared to WT at this early stage of development. We saw a significant overlap with a number of known direct targets of ARX (5%) and genes implicated in ID, epilepsy and autism (12%). From my analysis, I predict a core pathway of transcription regulators as potential drivers of the ID and infantile spasms in patients with ARX polyalanine expansion mutations. Next, I investigated the mechanisms driving the partial loss of function. My data indicates this reduced function does not occur through disruptions of binding to DNA or protein interactors in relation to the region of ARX spanning both polyalanine tract 1 and 2. However, in this thesis, I demonstrate a marked reduction in polyalanine mutant protein may be the contributing factor to disease manifestation. Transcription activity assays indicated ARX responds in a dose-depend manner, and greater reduction in protein leads to an increased severity of the disease. Investigations into the molecular mechanism contributing to this reduction in protein level show no significant change in protein stability (in vitro). Instead, initial studies indicate inefficiency of translation resulting in reduced protein abundance. From my data and other previous studies, I discuss the likelihood of a multiple hit model contributing to the partial loss of function and leading to the variability of clinical presentations.en
dc.subjectpolyalanine tract mutationsen
dc.subjectintellectual disabilityen
dc.titleInvestigating the Pathogenic Mechanism of Expanded Polyalanine Tract Mutations in the ARX Homeobox Transcription Factor causing Intellectual Disabilityen
dc.contributor.schoolAdelaide Medical Schoolen
dc.provenanceThis electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at:
dc.description.dissertationThesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2017en
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