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

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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
StatePublished - Nov 1 2001

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Bone and Bones
Cysts
Autosomal Dominant Polycystic Kidney
Pancreatic Diseases
Homozygote
Kidney
Epithelium
Spina Bifida Occulta
Osteochondrodysplasias
Polyhydramnios
Hydrops Fetalis
Mutation
Heterozygote
Chondrocytes
polycystic kidney disease 1 protein

ASJC Scopus subject areas

  • Genetics

Cite this

Lu, W., Shen, X., Pavlova, A., Lakkis, M., Ward, C. J., Pritchard, L., ... 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.

Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. / Lu, Weining; Shen, Xiaohua; Pavlova, Anna; Lakkis, Montaha; Ward, Christopher J.; Pritchard, Lynn; Harris, Peter C; Genest, David R.; Perez-Atayde, Antonio R.; Zhou, Jing.

In: Human Molecular Genetics, Vol. 10, No. 21, 01.11.2001, p. 2385-2396.

Research output: Contribution to journalArticle

Lu, W, Shen, X, Pavlova, A, Lakkis, M, Ward, CJ, Pritchard, L, Harris, PC, Genest, DR, Perez-Atayde, AR & Zhou, J 2001, 'Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects', Human Molecular Genetics, vol. 10, no. 21, pp. 2385-2396.
Lu W, Shen X, Pavlova A, Lakkis M, Ward CJ, Pritchard L et al. Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Human Molecular Genetics. 2001 Nov 1;10(21):2385-2396.
Lu, Weining ; Shen, Xiaohua ; Pavlova, Anna ; Lakkis, Montaha ; Ward, Christopher J. ; Pritchard, Lynn ; Harris, Peter C ; Genest, David R. ; Perez-Atayde, Antonio R. ; Zhou, Jing. / Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. In: Human Molecular Genetics. 2001 ; Vol. 10, No. 21. pp. 2385-2396.
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