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Germline and somatic loss of function of the mouse cpk gene causes biliary ductal pathology that is genetically
L M Guay-Woodford1, W J Green, J R Lindsey
1Department of Medicine, University of Alabama at Birmingham, 35294, USA. lgw@uab.edu
Abstract:
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 F(2) 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 F(2) 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 F(2) progeny. We found no correlation between the severity of the DPM and the renal cystic disease in either F(2) cohort. In addition, we identified focal cysts, apparently of biliary origin, in the livers of both aged D2-+/cpk and F(1) 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.
Insights
The cpk mutation in mice models human polycystic kidney disease (PKD). Genetic background influences the severity of biliary ductal plate malformation (DPM) and can lead to biliary cysts in heterozygotes.
Area of Science:
- Genetics
- Developmental Biology
- Pathology
Background:
- The mouse cpk mutation is a model for autosomal recessive polycystic kidney disease (ARPKD).
- Biliary ductal plate malformation (DPM) is typically absent in B6-cpk/cpk homozygotes but present in other strains.
- Genetic background significantly influences the expression of DPM in cpk mutants.
Purpose of the Study:
- To characterize cpk-associated biliary disease in F2 homozygotes from crosses with CAST or D2 strains.
- To investigate focal biliary cysts found in heterozygotes of a D2-cpk congenic strain.
- To explore the genetic basis of biliary cyst formation in cpk mutants.
Main Methods:
- Histopathological analysis of F2 cpk/cpk progeny.
- Semi-quantitative assessment of DPM severity.
- Genetic analysis to evaluate loss of heterozygosity in the cpk interval.
- Examination of livers from D2-+/cpk and F1 heterozygotes.
Main Results:
- All F2 cpk/cpk pups exhibited renal cystic disease and DPM, with variable DPM severity.
- No correlation was found between DPM severity and renal cystic disease.
- Focal biliary cysts were identified in livers of aged D2-+/cpk and F1 heterozygotes.
- Genetic analysis supported a loss-of-function model for biliary cysts.
Conclusions:
- The cpk allele harbors an inactivating mutation affecting kidney and biliary tract tubulo-epithelial differentiation.
- Genetic background modulates the expression of biliary lesions in cpk mutants.
- Biliary phenotype is determined by germline versus somatic loss of cpk gene function.