The Genetic Underpinnings of Gordon Holmes Syndrome

Abstract

Recently, whole exome sequencing linked mutations in the E3 ligase RNF216 to the pathogenesis of the Gordon Holmes Syndrom. Though a molecular basis has been identified, the biological mechanism remains elusive and has yet to be well characterized. Since the cerebellum is an area in the brain involved in motor control, we selected it as our main target for experiments to study mechanisms underlying disease inflicted ataxia. In addition, the hypothalamus, a small, but powerful brain region controlling various neuroendocrine physiologies, was targeted for experiments due to symptoms of neuroendocrine dysfunction. Our objective was to determine mechanisms leading to ataxia and neuroendocrine failure with focus on the cerebellum and hypothalamus in a zebrafish model of Holmes Syndrome. We hypothesized that loss of rnf216 leads to a dysregulation in development, specifically in the brain regions of the cerebellum and hypothalamus. Thus, immunohistochemistry and in situ hybridization assays were used to analyze various cellular markers throughout development and hence further characterize a mutant phenotype.