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dc.contributor.advisorJackson, Ianen
dc.contributor.advisorAbbott, Catherineen
dc.contributor.authorCarpanini, Sarah Marieen
dc.date.accessioned2014-10-27T14:09:55Z
dc.date.available2014-10-27T14:09:55Z
dc.date.issued2014-07-05
dc.identifier.urihttp://hdl.handle.net/1842/9611
dc.description.abstractWarburg Micro syndrome is a severe autosomal recessive condition characterised by abnormalities affecting the ocular, neurological and endocrine systems. Previous studies have identified causative loss-of-function mutations in four members of the RAB protein network; RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20, causing clinically indistinguishable phenotypes. RAB3GAP1 and RAB3GAP2 form a heterodimeric complex specifically regulating the RAB3 family of proteins in calcium mediated exocytosis of hormones and neurotransmitters. Rab3gap1 deficient mice have previously been generated and showed altered short term plasticity in the hippocampus and inhibition of Ca2+ mediated exocytosis of glutamate from cortical synaptosomes, but failed to recapitulate the characteristic ocular or neurological features of Warburg Micro syndrome. Mutations in TBC1D20, a GTPase activating protein (GAP) for the RAB1 family, have recently been identified in Warburg Micro syndrome patients and the bs (blind sterile) mouse model; although this model recapitulated many ocular and endocrine abnormalities of the disease any neurological abnormalities have yet to be reported. The function and localisation of RAB18 remains to be fully elucidated and its role in disease pathogenesis is still unclear. Initially, I have confirmed previous reports co-localising RAB18 with the cis-Golgi, ER and lipid droplets in mouse embryonic fibroblasts and identified a novel localisation in neuronal processes of primary hippocampal neurons. To examine the role of RAB18 in vivo a novel Rab18 genetrap mouse was generated by MRC Harwell as part of the EUMODIC screen. In this study I describe detailed histopathological and neurological characterisation of the Rab18-/- mouse model. Rab18-/- mice were viable and fertile. At eye opening they presented with dense nuclear congenital cataracts and atonic pupils recapitulating major ocular features of Warburg Micro syndrome. Analysis of embryonic eye development revealed a delay in lens development in Rab18-/- mice as early as embryonic day 12.5. From three weeks of age Rab18-/- mice developed progressive hind limb weakness indicative of neurological dysfunction. I have undertaken detailed neuropathological analysis of the observed hind limb weakness and identified no abnormalities in synaptic vesicle recycling and no atrophy of peripheral muscles or aberrant development or stability of neuromuscular connectivity. However, loss of RAB18 resulted in gross accumulations of neurofilament and microtubule proteins at the neuromuscular junction and disorganisation of the cytoskeleton in peripheral nerves. Investigation of global proteomic profiling in peripheral nerve of Rab18-/- mice identified alterations in core pathways regulating the axonal cytoskeleton in neurons. In summary this thesis describes a novel Rab18-/- mouse model recapitulating the characteristic ocular and neurological features of Warburg Micro syndrome. I highlight a novel mechanistic insight into Warburg Micro syndrome disease pathogenesis and a role for RAB18 in regulating cytoskeletal dynamics in neurons.en
dc.contributor.sponsorMedical Research Council (MRC)en
dc.language.isoen
dc.publisherThe University of Edinburghen
dc.relation.hasversionHandley MT, Morris-Rosendahl DJ, Brown S, Macdonald F, Hardy C, Bem D, Carpanini SM, Borck G, Martorell L, Izzi C, Faravelli F, Accorsi P, Pinelli L, Basel-Vanagaite L, Peretz G, Abdel-Salam GM, Zaki MS, Jansen A, Mowat D, Glass I, Stewart H, Mancini G, Lederer D, Roscioli T, Giuliano F, Plomp AS, Rolfs A, Graham JM, Seemanova E, Poo P, García-Cazorla A, Edery P, Jackson IJ, Maher ER, Aligianis IA. Muation Spectrum in RAB3GAP1, RAB3GAP2 and RAB18 and Genotype-Phenotype Correlations in Warburg Micro syndrome and Martsolf syndrome. Human Mutation 2013 May;34(5):686-96.en
dc.relation.hasversionGakovic M, Shu X, Kasioulis I, Carpanini S, Moraga I, Wright AF. The role of RPGR in cilia formation and actin stability. Human Molecular Genetics. 2011 Dec 15;20(24):4840-50.en
dc.subjectWarburg Micro syndromeen
dc.subjectRAB18en
dc.subjectneuropathological analysisen
dc.subjectmouse modelsen
dc.titleCharacterisation of a novel Rab18 mouse model for Warburg Micro syndromeen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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