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Abstract
Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells down-regulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a deleterious splicing variant in CYS1. These findings suggest that mutations in Cys1/CYS1 cause an ARPKD phenotype in mouse and human, respectively, and that the renal cystic phenotype in the mouse is driven by overexpression of the Myc proto-oncogene.
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1 Children’s National Research Institute, Center for Translational Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586)
2 University of Alabama at Birmingham, Department of Genetics, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
3 Children’s National Research Institute, Center for Translational Research, Washington, USA (GRID:grid.239560.b) (ISNI:0000 0004 0482 1586); University of Alabama at Birmingham, Department of Genetics, Birmingham, USA (GRID:grid.265892.2) (ISNI:0000000106344187)
4 Boston Children’s Hospital, Harvard Medical School, Department of Medicine, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X)
5 Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34)
6 University of Alexandria, Alexandria Faculty of Medicine, Alexandria, Egypt (GRID:grid.7155.6) (ISNI:0000 0001 2260 6941)
7 Yale University School of Medicine, Department of Genetics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710); Yale University School of Medicine, Yale Center for Mendelian Genomics, New Haven, USA (GRID:grid.47100.32) (ISNI:0000000419368710)