@article{abf45812f5114cf2b4f1b14ab4eef3eb,
title = "Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization",
abstract = "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.",
author = "Cullinane, {Andrew R.} and Anna Straatman-Iwanowska and Andreas Zaucker and Yoshiyuki Wakabayashi and Bruce, {Christopher K.} and Guanmei Luo and Fatimah Rahman and Figen G{\"u}rakan and Eda Utine and Zkan, {Tanju B.} and Jonas Denecke and Jurica Vukovic and {Di Rocco}, Maja and Hanna Mandel and Hakan Cangul and Matthews, {Randolph P.} and Thomas, {Steve G.} and Rappoport, {Joshua Z.} and Arias, {Irwin M.} and Hartwig Wolburg and Knisely, {A. S.} and Kelly, {Deirdre A.} and Ferenc M{\"u}ller and Maher, {Eamonn R.} and Paul Gissen",
note = "Funding Information: help with the E-cadherin luciferase assay, G. Reynolds for help with E-cadherin immunostaining and R. Knittel for her help with freeze fracture experiments. The authors also wish to thank all the families and clinicians who contributed to this research and thank the ARC syndrome association; Children Living with Inherited Metabolic Diseases (CLIMB); Birmingham Children{\textquoteright}s Hospital Research Foundation (BCHRF); WellChild; the Wellcome Trust; and the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, US National Institutes of Health, for their generous financial support. Funding Information: A.R.C. holds the Children Liver Disease Foundation PhD Studentship and P.G. is a GlaxoSmithKline Clinician Scientist. A.Z. and F.M. are supported by Framework 6 IP EUTRACC, LSGH CT 2006037445. H.C. is supported by grants from the European Molecular Biology Organization (ASTF 121:2007) and European Science Foundation (Exchange Grant 2008). J.Z.R. is supported by the Biotechnology and Biosciences Research Council (BB/H002308/1). Thanks to F. Lock for her",
year = "2010",
month = apr,
doi = "10.1038/ng.538",
language = "English (US)",
volume = "42",
pages = "303--312",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",
}