Heterozygous Pkhd1 C642* mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney.

Heterozygosity for human polycystic kidney and hepatic disease 1 (PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1(C642*). mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1(G617fs )and PKHD1(G644*)). Mouse heterozygotes or homozygotes for the Pkhd1(C642*) mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to similar to 1.5 yr, the Pkhd1(C642*). heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1(C642*) homozygotes. Interestingly, aged female Pkhd1(C642*). heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1(C642*) mutation, we provide important validation for relevant human association studies. Together. these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.