Investigation of VPS33B deficiency in mouse and man

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http://eprints.org/relation/isVersionOf http://etheses.bham.ac.uk/id/document/27341 http://eprints.org/relation/isVolatileVersionOf http://etheses.bham.ac.uk/id/document/27341 http://eprints.org/relation/isIndexCodesVersionOf http://etheses.bham.ac.uk/id/document/27341 archive 4031 disk0/00/00/35/69 2013-03-05 11:06:06 2019-01-23 09:56:35 2013-03-05 11:06:06 thesis show 0 Smith Holly Gissen Paul Watson Steve P. University of Birmingham Investigation of VPS33B deficiency in mouse and man unpub QH426 RC 10col_mede Work related to this thesis is published in: 1. Smith, H. et al. Associations among genotype, clinical phenotype and intracellular localization of trafficking proteins in ARC syndrome. Human Mutation (2012) doi:10.1002/humu.22155 2. Unsworth, A. J., Smith, H., Gissen, P., Watson, S. P. & Pears, C. J. Submaximal inhibition of protein kinase C restores ADP-induced dense granule secretion in platelets in the presence of Ca2+. J. Biol. Chem. 286, 21073–21082 (2011). Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a severe multisystem disorder caused by mutations in VPS33B and VIPAR. A splice site mutation, VPS33B c.1225+5 G>C, was identified in a patient with attenuated ARC phenotype. Modelling of this mutation and missense mutations indicated that VPS33B-VIPAR interaction and co-localisation at recycling-endosome like structures is necessary for their function. Development of a murine ARC model began with ubiquitous removal of Vps33b, and in parallel, its homologue Vps33a. Both resulted in embryonic lethality between E7.5 and E8.5. A good ARC phenocopy was obtained the liver specific Vps33b knockout, Vps33b\(^{fl/fl}\)- AlpfCre. Bile acid levels were increased in comparison to control and the apical proteins CEA and BSEP were mislocalised, with the distribution similar to that in ARC livers. In contrast, a Vps33b\(^{fl/fl}\)-Pf4Cre mouse did not result in a good ARC platelet phenocopy, with α-granules found present. They did however present with a mild platelet phenotype, with defects in stable aggregate formation under shear conditions and deficiencies in the α- granule proteins VWF and PF4, giving possible insights into the bleeding diathesis in patients. In conclusion, this work has produced suitable ARC models for further study of Vps33b function and provides a platform for the future development of gene therapy and drug treatments. 2012-12 2012-03 graduation eng author unchecked This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. public 225 University of Birmingham School of Clinical and Experimental Medicine, Department of Medical and Molecular Genetics d_ph na 2012-12 graduation