Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization.
Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization.
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DOI：
10.1038/ng.538
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发表时间：
2010-04
期刊：
影响因子：
30.8
通讯作者：
Gissen P
中科院分区：
文献类型：
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作者：
Cullinane AR;Straatman-Iwanowska A;Zaucker A;Wakabayashi Y;Bruce CK;Luo G;Rahman F;Gürakan F;Utine E;Ozkan TB;Denecke J;Vukovic J;Di Rocco M;Mandel H;Cangul H;Matthews RP;Thomas SG;Rappoport JZ;Arias IM;Wolburg H;Knisely AS;Kelly DA;Müller F;Maher ER;Gissen P
关节挛缩、肾功能障碍和胆汁淤积综合征（ARC）是一种与肝脏和肾脏极化细胞异常相关的多系统疾病。VPS33B突变是大多数ARC病例的原因。我们在无VPS33B缺陷的ARC患者中鉴定出VIPAR（也称为C14ORF133）的突变。我们表明VIPAR与VPS33B形成一个功能性复合物，该复合物与RAB11A相互作用。在斑马鱼中敲低vipar导致胆汁排泄和E - 钙黏蛋白缺陷，与ARC患者的情况相似。Vipar和Vps33b缺陷的小鼠内髓集合管（mIMDC - 3）细胞异常表达膜蛋白，并且存在结构和功能上的紧密连接缺陷。Ceacam5异常表达是由于向溶酶体降解的错误分选，但E - 钙黏蛋白水平降低与转录下调有关。因此，VPS33B - VIPAR复合物在调节肝脏和肾脏顶 - 基底外侧极性的途径中具有多种功能。
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 withVPS33B that interacts with RAB11 A. 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.