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. Ward, Lynn Pritchard, Peter C. Harris, David R. Genest, Antonio R. Perez-Atayde, Jing Zhou

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2385-2396
Number of pages12
JournalHuman molecular genetics
Volume10
Issue number21
DOIs
StatePublished - Nov 1 2001

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Lu, W., Shen, X., Pavlova, A., Lakkis, M., Ward, C. J., Pritchard, L., Harris, P. C., Genest, D. R., Perez-Atayde, A. R., & Zhou, J. (2001). Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Human molecular genetics, 10(21), 2385-2396. https://doi.org/10.1093/hmg/10.21.2385