Human Molecular Genetics, 2000, Vol. 9, No. 5 769-778
© 2000 Oxford University Press
Germline and somatic loss of function of the mouse cpk gene causes biliary ductal pathology that is genetically modulated
Departments of 1Medicine, 2Pediatrics and 3Comparative Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA and 4Genetics Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
The mouse cpk mutation is the most extensively characterized murine model of polycystic kidney disease (PKD) and closely resembles human autosomal recessive PKD (ARPKD), with the exception that B6-cpk/cpk homozygotes do not express the biliary ductal plate malformation (DPM) lesion. However, homozygous mutants from outcrosses to other strains, e.g. DBA/2J (D2), CD-1, BALB/c and Mus mus castaneus (CAST), express the DPM. The current study was designed: (i) to characterize the cpk-associated biliary disease in affected F2 homozygotes from intercrosses with either CAST or D2; and (ii) to evaluate focal biliary cysts identified in heterozygotes from a D2-cpk congenic strain. We found that all F2 cpk/cpk pups expressed both the typical renal cystic disease and the DPM. The DPM severity, assessed using semi-quantitative histopathological analysis, was markedly variable in these F2 progeny. We found no correlation between the severity of the DPM and the renal cystic disease in either F2 cohort. In addition, we identified focal cysts, apparently of biliary origin, in the livers of both aged D2-+/cpk and F1 heterozygotes. Genetic analysis demonstrated loss of heterozygosity at the cpk interval and supports a loss-of-function model for biliary cysts. We conclude that the cpk allele contains an inactivating mutation which disrupts tubulo-epithelial differentiation in the kidney and biliary tract. Expression of the biliary lesion is modulated by genetic background, and the specific biliary phenotype is determined by whether loss of function of the cpk gene occurs as a germline or a somatic event.
+ To whom correspondence should be addressed. Tel: +1 205 934 7308; Fax: +1 205 975 5689; Email: lgw@uab.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. N. Muchatuta, V. H. Gattone II, F. A. Witzmann, and B. L. Blazer-Yost Structural and Functional Analyses of Liver Cysts from the BALB/c-cpk Mouse Model of Polycystic Kidney Disease Experimental Biology and Medicine, January 1, 2009; 234(1): 17 - 27. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. Schrick, P. Vogel, A. Abuin, B. Hampton, and D. S. Rice ADP-Ribosylation Factor-Like 3 Is Involved in Kidney and Photoreceptor Development Am. J. Pathol., April 1, 2006; 168(4): 1288 - 1298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yamaguchi, S. J. Hempson, G. A. Reif, A.-M. Hedge, and D. P. Wallace Calcium Restores a Normal Proliferation Phenotype in Human Polycystic Kidney Disease Epithelial Cells J. Am. Soc. Nephrol., January 1, 2006; 17(1): 178 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mrug, R. Li, X. Cui, T. R. Schoeb, G. A. Churchill, and L. M. Guay-Woodford Kinesin Family Member 12 Is a Candidate Polycystic Kidney Disease Modifier in the cpk Mouse J. Am. Soc. Nephrol., April 1, 2005; 16(4): 905 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Fischer, L. Gresh, A. Reimann, and M. Pontoglio Cystic kidney diseases: learning from animal models Nephrol. Dial. Transplant., November 1, 2004; 19(11): 2700 - 2702. [Full Text] [PDF]
|
|
|
|
|
|
T. V. Masyuk, B. Q. Huang, A. I. Masyuk, E. L. Ritman, V. E. Torres, X. Wang, P. C. Harris, and N. F. LaRusso Biliary Dysgenesis in the PCK Rat, an Orthologous Model of Autosomal Recessive Polycystic Kidney Disease Am. J. Pathol., November 1, 2004; 165(5): 1719 - 1730. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Guay-Woodford Murine models of polycystic kidney disease: molecular and therapeutic insights Am J Physiol Renal Physiol, December 1, 2003; 285(6): F1034 - F1049. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. K. Yoder, A. Tousson, L. Millican, J. H. Wu, C. E. Bugg Jr., J. A. Schafer, and D. F. Balkovetz Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium Am J Physiol Renal Physiol, March 1, 2002; 282(3): F541 - F552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sanzen, K. Harada, M. Yasoshima, Y. Kawamura, M. Ishibashi, and Y. Nakanuma Polycystic Kidney Rat Is a Novel Animal Model of Caroli's Disease Associated with Congenital Hepatic Fibrosis Am. J. Pathol., May 1, 2001; 158(5): 1605 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. NAUTA, M. A. GOEDBLOED, H. V. HERCK, D. A. HESSELINK, P. VISSER, R. WILLEMSEN, R. P. E. V. DOKKUM, C. J. WRIGHT, and L. M. GUAY-WOODFORD New Rat Model that Phenotypically Resembles Autosomal Recessive Polycystic Kidney Disease J. Am. Soc. Nephrol., December 1, 2000; 11(12): 2272 - 2284. [Abstract] [Full Text]
|
|