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.
authors.affiliation: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
authors.forename: Anna
authors.initials: A
authors.lastname: Straatman-Iwanowska
authors.forename: Andreas
authors.initials: A
authors.lastname: Zaucker
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Wakabayashi
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Bruce
authors.forename: Guanmei
authors.initials: G
authors.lastname: Luo
authors.forename: Fatimah
authors.initials: F
authors.lastname: Rahman
authors.forename: Figen
authors.initials: F
authors.lastname: Gürakan
authors.forename: Eda
authors.initials: E
authors.lastname: Utine
authors.forename: Tanju B
authors.initials: TB
authors.lastname: Ozkan
authors.forename: Jonas
authors.initials: J
authors.lastname: Denecke
authors.forename: Jurica
authors.initials: J
authors.lastname: Vukovic
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.forename: Hakan
authors.initials: H
authors.lastname: Cangul
authors.forename: Randolph P
authors.initials: RP
authors.lastname: Matthews
authors.forename: Steve G
authors.initials: SG
authors.lastname: Thomas
authors.forename: Joshua Z
authors.initials: JZ
authors.lastname: Rappoport
authors.forename: Irwin M
authors.initials: IM
authors.lastname: Arias
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Kelly
authors.forename: Ferenc
authors.initials: F
authors.lastname: Müller
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001176:Arthrogryposis / Q000235:genetics*; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics*; D016764:Cell Polarity; D002779:Cholestasis / Q000235:genetics*; D004848:Epithelium / Q000502:physiology; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010641:Phenotype; D013577:Syndrome; D019108:Tight Junctions / Q000473:pathology; D033921:Vesicular Transport Proteins; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D015820:Cadherins; D002352:Carrier Proteins; D008565:Membrane Proteins; C539711:VIPAS39 protein, human; D033921:Vesicular Transport Proteins; C507730:Vps33b protein, zebrafish; D029961:Zebrafish Proteins