ZFIN ID: ZDB-PUB-100302-23
Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization
Cullinane, A.R., Straatman-Iwanowska, A., Zaucker, A., Wakabayashi, Y., Bruce, C.K., Luo, G., Rahman, F., Gürakan, F., Utine, E., Ozkan, T.B., Denecke, J., Vukovic, J., Di Rocco, M., Mandel, H., Cangul, H., Matthews, R.P., Thomas, S.G., Rappoport, J.Z., Arias, I.M., Wolburg, H., Knisely, A.S., Kelly, D.A., Muller, F., Maher, E.R., and Gissen, P.
Date: 2010
Source: Nature Genetics   42(4): 303-312 (Journal)
Registered Authors: Matthews, Randy, Müller, Ferenc, Zaucker, Andreas
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Arthrogryposis/genetics*
  • Cadherins/metabolism
  • Carrier Proteins/genetics*
  • Cell Polarity
  • Cholestasis/genetics*
  • Epithelium/physiology
  • Humans
  • Kidney Diseases/genetics*
  • Membrane Proteins/genetics*
  • Mice
  • Mutation
  • Phenotype
  • Syndrome
  • Tight Junctions/pathology
  • Vesicular Transport Proteins
  • Zebrafish
  • Zebrafish Proteins/genetics*
PubMed: 20190753 Full text @ Nat. Genet.
Arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) is a multisystem disorder associated with abnormalities in polarized liver and kidney cells. Mutations in VPS33B account for most cases of ARC. We identified mutations in VIPAR (also called C14ORF133) in individuals with ARC without VPS33B defects. We show that VIPAR forms a functional complex with VPS33B that interacts with RAB11A. Knockdown of vipar in zebrafish resulted in biliary excretion and E-cadherin defects similar to those in individuals with ARC. Vipar- and Vps33b-deficient mouse inner medullary collecting duct (mIMDC-3) cells expressed membrane proteins abnormally and had structural and functional tight junction defects. Abnormal Ceacam5 expression was due to mis-sorting toward lysosomal degradation, but reduced E-cadherin levels were associated with transcriptional downregulation. The VPS33B-VIPAR complex thus has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney.