Praschberger, Roman; (2018) Expanding the mutational spectrum and investigating the pathophysiology of GOSR2 mediated progressive myoclonus epilepsy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In this PhD thesis I summarize my research into the genetics and pathophysiology of progressive myoclonus epilepsy (PME) associated with mutations in GOSR2. This disorder is characterized by early disease onset with ataxia around 3 years of age, followed by development of cortical myoclonus, generalized epilepsy and a rapid deterioration of motor function. Upon beginning my PhD, only one homozygous GOSR2 mutation – c.430G>T (p.G144W) – had been shown to cause PME. Furthermore, because GOSR2 encodes a Golgi SNARE protein (termed Membrin) that mediates ER-to-Golgi trafficking in every cell of the human body, it was an unresolved mystery how this mutation gives rise to a largely selective neuronal disorder. I first describe my discovery of the novel c.491-493delAGA (p.K164del) GOSR2 mutation in a PME patient who also carried the previously described c.430G>T variant in the compound heterozygous state. Overall, the clinical phenotype of this patient was remarkably consistent with previous cases, although her disease course appeared milder. My finding thus expanded the phenotypes and genotypes linked to this disorder, thus providing an additional tool to investigate the underlying disease mechanisms. In the subsequent chapters I summarize our attempts to unravel why the nervous system is selectively affected in GOSR2-PME. To this end I examined how pathogenic Membrin mutations impacted ER-to-Golgi trafficking in patient-derived fibroblasts, and developed novel Drosophila models of GOSR2-PME to study neuronal pathophysiology. Intriguingly, while ER-to-Golgi trafficking was remarkably preserved in G144W mutant Membrin fibroblasts, neuronal integrity was severely disturbed in GOSR2- PME model Drosophila, where dendrites were significantly shorter. Neurons have special secretory demands owing to their very large surface area, and hence appear selectively vulnerable to partial loss of function mutations in Membrin. Thus, the results presented in this thesis provide a possible explanation for the nervous system specificity of GOSR2-PME.

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