Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization.
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.
Cullinane
Andrew R
AR
Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
Straatman-Iwanowska
Anna
A
Zaucker
Andreas
A
Wakabayashi
Yoshiyuki
Y
Bruce
Christopher K
CK
Luo
Guanmei
G
Rahman
Fatimah
F
Gürakan
Figen
F
Utine
Eda
E
Ozkan
Tanju B
TB
Denecke
Jonas
J
Vukovic
Jurica
J
Di Rocco
Maja
M
Mandel
Hanna
H
Cangul
Hakan
H
Matthews
Randolph P
RP
Thomas
Steve G
SG
Rappoport
Joshua Z
JZ
Arias
Irwin M
IM
Wolburg
Hartwig
H
Knisely
A S
AS
Kelly
Deirdre A
DA
Müller
Ferenc
F
Maher
Eamonn R
ER
Gissen
Paul
P
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*
D015820:Cadherins; D002352:Carrier Proteins; D008565:Membrane Proteins; C539711:VIPAS39 protein, human; D033921:Vesicular Transport Proteins; C507730:Vps33b protein, zebrafish; D029961:Zebrafish Proteins