A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype

Lynn Pritchard, Jackie A. Sloane-Stanley, Jackie A. Sharpe, Richard Aspinwall, Weining Lu, Veronica Buckle, Lana Strmecki, Denise Walker, Christopher J. Ward, Charles E. Alpers, Jing Zhou, William G. Wood, Peter C Harris

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Abstract

Three founder transgenic mice were generated with a 108 kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease (ADPKD) gene, PKD1, plus the tuberous sclerosis gene, TSC2. Two lines were established (TPK1 and TPK3) each with ~30 copies of the transgene. Both lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life, markedly reduced at the conclusion of renal development. Tuberin expression was limited to the brain. Transgenic animals from both lines (and the TPK2 founder animal) often displayed a renal cystic phenotype, typically consisting of multiple microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. All animals with two copies of the transgenic chromosome developed cysts and, in total, 48 of the 100 transgenic animals displayed a cystic phenotype. To test the functionality of the transgene, animals were bred with the Pkd1(del34) knockout mouse. Both transgenic lines rescued the embryonically lethal Pkd1(del34/del34) phenotype, demonstrating that human polycystin-1 can complement for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1(del34)/+ animals. The TPK mice have defined a minimal area that appropriately expresses human PKD1. Furthermore, this model indicates that over-expression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease.

Original languageEnglish (US)
Pages (from-to)2617-2627
Number of pages11
JournalHuman Molecular Genetics
Volume9
Issue number18
StatePublished - Nov 1 2000

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Transgenes
Phenotype
Autosomal Dominant Polycystic Kidney
Genetically Modified Animals
Kidney
Cysts
Common Hepatic Duct
Tuberous Sclerosis
Knockout Mice
Bile
Transgenic Mice
Genes
Embryonic Development
Proteins
Chromosomes
polycystic kidney disease 1 protein
Messenger RNA
Liver
Brain

ASJC Scopus subject areas

  • Genetics

Cite this

Pritchard, L., Sloane-Stanley, J. A., Sharpe, J. A., Aspinwall, R., Lu, W., Buckle, V., ... Harris, P. C. (2000). A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Human Molecular Genetics, 9(18), 2617-2627.

A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. / Pritchard, Lynn; Sloane-Stanley, Jackie A.; Sharpe, Jackie A.; Aspinwall, Richard; Lu, Weining; Buckle, Veronica; Strmecki, Lana; Walker, Denise; Ward, Christopher J.; Alpers, Charles E.; Zhou, Jing; Wood, William G.; Harris, Peter C.

In: Human Molecular Genetics, Vol. 9, No. 18, 01.11.2000, p. 2617-2627.

Research output: Contribution to journalArticle

Pritchard, L, Sloane-Stanley, JA, Sharpe, JA, Aspinwall, R, Lu, W, Buckle, V, Strmecki, L, Walker, D, Ward, CJ, Alpers, CE, Zhou, J, Wood, WG & Harris, PC 2000, 'A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype', Human Molecular Genetics, vol. 9, no. 18, pp. 2617-2627.
Pritchard L, Sloane-Stanley JA, Sharpe JA, Aspinwall R, Lu W, Buckle V et al. A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Human Molecular Genetics. 2000 Nov 1;9(18):2617-2627.
Pritchard, Lynn ; Sloane-Stanley, Jackie A. ; Sharpe, Jackie A. ; Aspinwall, Richard ; Lu, Weining ; Buckle, Veronica ; Strmecki, Lana ; Walker, Denise ; Ward, Christopher J. ; Alpers, Charles E. ; Zhou, Jing ; Wood, William G. ; Harris, Peter C. / A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. In: Human Molecular Genetics. 2000 ; Vol. 9, No. 18. pp. 2617-2627.
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abstract = "Three founder transgenic mice were generated with a 108 kb human genomic fragment containing the entire autosomal dominant polycystic kidney disease (ADPKD) gene, PKD1, plus the tuberous sclerosis gene, TSC2. Two lines were established (TPK1 and TPK3) each with ~30 copies of the transgene. Both lines produced full-length PKD1 mRNA and polycystin-1 protein that was developmentally regulated, similar to the endogenous pattern, with expression during renal embryogenesis and neonatal life, markedly reduced at the conclusion of renal development. Tuberin expression was limited to the brain. Transgenic animals from both lines (and the TPK2 founder animal) often displayed a renal cystic phenotype, typically consisting of multiple microcysts, mainly of glomerular origin. Hepatic cysts and bile duct proliferation, characteristic of ADPKD, were also seen. All animals with two copies of the transgenic chromosome developed cysts and, in total, 48 of the 100 transgenic animals displayed a cystic phenotype. To test the functionality of the transgene, animals were bred with the Pkd1(del34) knockout mouse. Both transgenic lines rescued the embryonically lethal Pkd1(del34/del34) phenotype, demonstrating that human polycystin-1 can complement for loss of the endogenous protein. The rescued animals were viable into adulthood, although more than half developed hepatic cystic disease in later life, similar to the phenotype of older Pkd1(del34)/+ animals. The TPK mice have defined a minimal area that appropriately expresses human PKD1. Furthermore, this model indicates that over-expression of normal PKD1 can elicit a disease phenotype, suggesting that the level of polycystin-1 expression may be relevant in the human disease.",
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AU - Buckle, Veronica

AU - Strmecki, Lana

AU - Walker, Denise

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AU - Zhou, Jing

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