Skip to main content
Article thumbnail
Location of Repository

Characterisation of the role of VPS33B in Vesicular trafficking in polarised Epithelial cells.

By Andrew Robert Cullinane

Abstract

Arthrogryposis, Renal dysfunction, and Cholestasis (ARC) syndrome is a multisystem disorder associated with abnormal localisation of some polarised membrane transporter proteins. Distinct apical and basolateral poles are essential for epithelial function and organ development but the molecular pathways determining the biogenesis of polarised membranes are not fully characterised. Mutations in VPS33B, a Sec1-Munc18 protein, account for 75% of ARC patients. Reduced expression of VPS33B at both the RNA and protein level was demonstrated in all ARC syndrome patients, even if mutations were not identified in VPS33B. A novel protein POLARIN (PLRN) was identified that interacts with VPS33B, and is crucial for VPS33B function. Pathogenic mutations in PLRN occur in ARC patients without VPS33B mutations. Decreased Polarin and Vps33b expression in mouse renal collecting duct cells led to abnormal localisation of specific apical membrane proteins and to disordered apical junction complex formation. In an in vivo model, knockdown of polarin in zebrafish resulted in defects in biliary tract development. These findings establish that a VPS33B-POLARINRab11a intracellular trafficking pathway is functionally distinct from another VPS33-related pathway (VPS33A/VPS16) and is required for (a) normal epithelial polarisation and apical junction complex formation, and (b) normal liver and kidney development and function

Topics: RJ Pediatrics, RJ101 Child Health. Child health services
Year: 2009
OAI identifier: oai:etheses.bham.ac.uk:344

Suggested articles

Citations

  1. (1999). A role for the deep orange and carnation eye color genes in lysosomal delivery in Drosophila. Mol Cell doi
  2. (2005). Arthrogryposis, renal tubular acidosis and cholestasis (ARC) syndrome: two new cases and review. Clin Dysmorphol doi
  3. (2006). Clinical and molecular genetic features of ARC syndrome. Human Genetics doi
  4. Cloning, mapping and expression analysis of VPS33B, the human orthologue of rat Vps33b. doi
  5. (2005). Comparative evolutionary analysis of VPS33 homologues: genetic and functional insights. Human Molecular Genetics doi
  6. (2003). deep-orange and carnation define distinct stages in late endosomal biogenesis in Drosophila melanogaster. doi
  7. (2009). Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome. Hum Mutat doi
  8. (2004). Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nature Genetics doi
  9. (2001). The class C Vps complex functions at multiple stages of the vacuolar transport pathway. Traffic doi
  10. (2003). The riddle of the Sec1/Munc-18 proteins - new twists added to their interactions with SNAREs. Trends Biochem Sci doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.