| First Author | Shan D | Year | 2019 |
| Journal | Am J Physiol Renal Physiol | Volume | 316 |
| Issue | 3 | Pages | F463-F472 |
| PubMed ID | 30600684 | Mgi Jnum | J:281464 |
| Mgi Id | MGI:6368440 | Doi | 10.1152/ajprenal.00181.2018 |
| Citation | Shan D, et al. (2019) Heterozygous Pkhd1(C642*) mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney. Am J Physiol Renal Physiol 316(3):F463-F472 |
| abstractText | 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 ~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. |
