Arthrogryposis, Renal dysfunction, and Cholestasis (ARC) syndrome is a multisystem disorder associated with abnormal localisation of some polarised membrane transporter proteins. Distinct apical and basolateral poles are essential for epithelial function and organ development but the molecular pathways determining the biogenesis of polarised membranes are not fully characterised. Mutations in VPS33B, a Sec1-Munc18 protein, account for 75% of ARC patients. Reduced expression of VPS33B at both the RNA and protein level was demonstrated in all ARC syndrome patients, even if mutations were not identified in VPS33B. A novel protein POLARIN (PLRN) was identified that interacts with VPS33B, and is crucial for VPS33B function. Pathogenic mutations in PLRN occur in ARC patients without VPS33B mutations. Decreased Polarin and Vps33b expression in mouse renal collecting duct cells led to abnormal localisation of specific apical membrane proteins and to disordered apical junction complex formation. In an in vivo model, knockdown of polarin in zebrafish resulted in defects in biliary tract development. These findings establish that a VPS33B-POLARINRab11a intracellular trafficking pathway is functionally distinct from another VPS33-related pathway (VPS33A/VPS16) and is required for (a) normal epithelial polarisation and apical junction complex formation, and (b) normal liver and kidney development and function
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