Germline and somatic loss of function of the mouse cpk gene causes biliaryductal pathology that is genetically modulated

The mouse cpk mutation is the most extensively characterized murine model o f polycystic kidney disease (PKD) and closely resembles human autosomal rec essive PKD (ARPKD), with the exception that B6-cpk/cpk homozygotes do not e xpress the biliary ductal plate malformation (DPM) lesion. However, homozyg ous 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 desi gned: (i) to characterize the cpk-associated biliary disease in affected F- 2 homozygotes from intercrosses with either CAST or D2; and (ii) to evaluat e focal biliary cysts identified in heterozygotes from a D2-cpkcongenic str ain. 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-quantitat ive histopathological analysis, was markedly variable in these F-2 progeny. We found no correlation between the severity of the DPM and the renal cyst ic disease in either F-2 cohort. In addition, we identified focal cysts, ap parently of biliary origin, in the livers of both aged D2-+/cpk and F-1 het erozygotes. Genetic analysis demonstrated loss of heterozygosity at the cpk interval and supports a loss-of-function model for biliary cysts. We concl ude that the cpk allele contains an inactivating mutation which disrupts tu bulo-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 gen e occurs as a germline or a somatic event.