Investigation of VPS33B deficiency in mouse and man

Smith, Holly (2012). Investigation of VPS33B deficiency in mouse and man. University of Birmingham. Ph.D.

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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.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine, Department of Medical and Molecular Genetics
Funders: None/not applicable
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine


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