Medical and Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
Nat Genet. 2010 Apr;42(4):303-12. doi: 10.1038/ng.538. Epub 2010 Feb 28.
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.
关节挛缩、肾功能障碍和胆汁淤积综合征（ARC）是一种与极化肝和肾细胞异常相关的多系统疾病。VPS33B 的突变导致大多数 ARC 病例。我们在没有 VPS33B 缺陷的 ARC 个体中发现了 VIPAR（也称为 C14ORF133）的突变。我们表明 VIPAR 与 VPS33B 形成功能性复合物，与 RAB11A 相互作用。在斑马鱼中敲低 vipar 导致胆汁排泄和 E-钙粘蛋白缺陷类似于 ARC 个体。Vipar 和 Vps33b 缺陷型小鼠内髓集合管（mIMDC-3）细胞异常表达膜蛋白，并有结构和功能紧密连接缺陷。异常的 Ceacam5 表达是由于错误分拣到溶酶体降解，但 E-钙粘蛋白水平降低与转录下调有关。因此，VPS33B-VIPAR 复合物在调节肝和肾顶底极性的途径中具有多种功能。
