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Heterozygous Pkhd1C642* mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney.

Authors: Shan, Dan  Rezonzew, Gabriel  Mullen, Sean  Roye, Ronald  Zhou, Juling  Chumley, Phillip  Revell, Dustin Z  Challa, Anil  Kim, Harrison  Lockhart, Mark E  Schoeb, Trenton R  Croyle, Mandy J  Kesterson, Robert A  Yoder, Bradley K  Guay-Woodford, Lisa M  Mrug, Michal 
Citation: Shan D, etal., Am J Physiol Renal Physiol. 2019 Mar 1;316(3):F463-F472. doi: 10.1152/ajprenal.00181.2018. Epub 2019 Jan 2.
Pubmed: (View Article at PubMed) PMID:30600684
DOI: Full-text: DOI:10.1152/ajprenal.00181.2018

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 Pkhd1C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1G617fs and PKHD1G644*). Mouse heterozygotes or homozygotes for the Pkhd1C642* 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 Pkhd1C642* 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 Pkhd1C642* homozygotes. Interestingly, aged female Pkhd1C642* 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 Pkhd1C642* 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.

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RGD Object Information
RGD ID: 14700919
Created: 2019-08-27
Species: All species
Last Modified: 2019-08-27
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.