Adult Inactivation of the Recessive Polycystic Kidney Disease Gene Causes Polycystic Liver Disease.

BACKGROUND

A major difference between autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) lies in the pattern of inheritance, and the resultant timing and focality of cyst formation. In both diseases, cysts form in the kidney and liver as a consequence of the cellular recessive genotype of the respective disease gene, but this occurs by germline inheritance in ARPKD and somatic second hit mutations to the one normal allele in ADPKD. The fibrocystic liver phenotype in ARPKD is attributed to abnormal ductal plate formation because of the absence of expression during embryogenesis and organ development. The finding of polycystic liver disease in a subset of adult heterozygous carriers raises the question of whether somatic second hit mutations in in adults may also result in bile duct-derived cyst formation.

METHODS

We used an adult-inducible mouse model to examine whether has a functional role in maintaining bile duct homeostasis after normal liver development.

RESULTS

Inactivation of beginning at 4 weeks of age resulted in a polycystic liver phenotype with minimal fibrosis at 17 weeks. Increased biliary epithelium, which lines these liver cysts, was most pronounced in female mice. We assessed genetic interaction of this phenotype with either reduced or increased copies of , and found no significant effects on the phenotype in the liver or kidney from altered expression.

CONCLUSIONS

Somatic adult inactivation of results in a polycystic liver phenotype. is a required gene in adulthood for biliary structural homeostasis independent of . This suggests that heterozygous carrier patients can develop liver cysts after somatic mutations in their normal copy of .