Browsing by Author "Wakabayashi, Yoshiyuki"
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Item Molecular investigations to improve diagnostic accuracy in patients with ARC syndrome.(Wiley, 2009-02) Cullinane, Andrew R.; Straatman, Anna Iwanowska; Seo, Jeong K.; Ko, Jae S.; Song, Kyung S.; Gizewska, Maria; Gruszfeld, Dariusz; Gliwicz, Dorota; Tüysüz, Beyhan; Sougrat, Rachid; Wakabayashi, Yoshiyuki; Hinds, Rupert; Barnicoat, Angela; Mandel, Hanna; Chitayat, David; Fischler, Bjorn; Garcia, Angels Cazorla; Knisely, A. S.; Kelly, Deirdre A.; Maher, Eamonn R.; Gissen, Paul; Erdemir, Gülin; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı/Çocuk Gastroenteroloji Hepatoloji ve Beslenme Bilim Dalı.; 0000-0002-9726-8219; 36015044400Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a multi-system autosomal recessive disorder caused by germline mutations in VPS33B. The detection of germline VPS33B mutations removes the need for diagnostic organ biopsies (these carry a >50% risk of life-threatening haemorrhage due to platelet dysfunction); however, VPS33B mutations are not detectable in similar to 25% of patients. In order further to define the molecular basis of ARC we performed mutation analysis and mRNA and protein studies in patients with a clinical diagnosis of ARC. Here we report novel mutations in VPS33B in patients from Eastern Europe and South East Asia. One of the mutations was present in 7 unrelated Korean patients. Reduced expression of VPS33B and cellular phenotype was detected in fibroblasts from patients clinically diagnosed with ARC with and without known VPS33B mutations. One mutation-negative patient was found to have normal mRNA and protein levels. This patient's clinical condition improved and he is alive at the age of 2.5 years. Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC.Item Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization(Nature Portfolio, 2010-04) Cullilane, Andrew Robert; Straatman-Iwanowska, Anna A.; Zaucker, Andreas; Wakabayashi, Yoshiyuki; Bruce, Christopher K.; Luo, Guanmei; Rahman, Fatimah; Gürakan, Figen; Ütine, Gülen Eda; Denecke, Jonas; Vukovic, Jurica; Di Rocco, Maja; Mandel, Hanna; Matthews, Randolph P.; Thomas, Steven G.; Rappoport, Joshua Zachary; Arias, Irwin M.; Wolburg, Hartwig; Knisely, Alexander S.; Kelly, Deirdre Anne K.; Ferenc Müller, Ferenc; Mäher, Eamonn Richard; Gissen, Paul; Özkan, Tanju Başarır; Cangül, Hakan; Uludağ Üniversitesi/Tıp Fakültesi/Çocuk Sağlığı ve Hastalıkları Anabilim Dalı.; Uludağ Üniversitesi/Tıp Fakültesi/Tıbbi Genetik Anabilim Dalı.; 35772174800; 8911611600Arthrogryposis, 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.