Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

AbstractMutation of theCys1gene underlies the renal cystic disease in theCys1cpk/cpk(cpk)mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product ofCys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulatesMycexpression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of thecpkrenal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into theRosa26locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression ofMycincpkkidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a predicted deleterious splicing defect inCYS1. These findings suggest that mutations in theCys1mouse andCYS1human orthologues cause an ARPKD phenotype that is driven by overexpression of theMycproto-oncogene.Translational StatementThe cystin-deficientcpkmouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that thecpkmouse phenotype is associated with alteredMycexpression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated withCYS1mutations. We report the first case of ARPKD linked to aCYS1mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicateMycin disease initiation or progression, and validate thecpkmouse as a translationally relevant disease model.