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 PKHD1 expression during embryogenesis and organ development. The finding of polycystic liver disease in a subset of adult PKHD1 heterozygous carriers raises the question of whether somatic second hit mutations in PKHD1 in adults may also result in bile duct-derived cyst formation. Methods We used an adult-inducible Pkhd1 mouse model to examine whether Pkhd1 has a functional role in maintaining bile duct homeostasis after normal liver development. Results Inactivation of Pkhd1 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 Pkd1 , and found no significant effects on the Pkhd1 phenotype in the liver or kidney from altered Pkd1 expression. Conclusions Somatic adult inactivation of Pkhd1 results in a polycystic liver phenotype. Pkhd1 is a required gene in adulthood for biliary structural homeostasis independent of Pkd1 . This suggests that PKHD1 heterozygous carrier patients can develop liver cysts after somatic mutations in their normal copy of PKHD1 .