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Human Molecular Genetics, 2001, Vol. 10, No. 21 2385-2396
© 2001 Oxford University Press

Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects

Weining Lu, Xiaohua Shen, Anna Pavlova, Montaha Lakkis, Christopher J. Ward3, Lynn Pritchard4, Peter C. Harris3, David R. Genest1, Antonio R. Perez-Atayde2 and Jing Zhou+

Renal Division, Department of Medicine, 1Department of Pathology, Brigham and Women’s Hospital, 2Department of Pathology, Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA, 3Division of Nephrology, Mayo Clinic, Rochester, MN, USA and 4Institute of Molecular Medicine, University of Oxford, Oxford, UK

A high level of polycystin-1 expression is detected in kidneys of all patients with autosomal dominant polycystic kidney disease (ADPKD). Mice that overexpress polycystin-1 also develop renal cysts. Whether overexpression of polycystin-1 is necessary for cyst formation is still unclear. Here, we report the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a ‘truncation mutation’ in Pkd1. We show that null homozygotes develop the same, but more aggressive, renal and pancreatic cystic disease as del34/del34. Moreover, we report that both homozygous mutants develop polyhydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. We show further that del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the two-hit model. Our data demonstrate for the first time that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and indicate that polycystin-1 is critical in both epithelium and chondrocyte development.

+ To whom correspondence ahould be addressed at: Harvard Institutes of Medicine, Room 522, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Tel: +1 617 525 5860; Fax: +1 617 525 5861; Email: zhou@rics.bwh.harvard.eduPresent address:Weining Lu, Genetics Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA


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