{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T02:28:35Z","timestamp":1784773715463,"version":"3.55.0"},"reference-count":18,"publisher":"American Physiological Society","issue":"3","funder":[{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["P30-DK-074038"],"award-info":[{"award-number":["P30-DK-074038"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["DK097423"],"award-info":[{"award-number":["DK097423"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","doi-asserted-by":"publisher","award":["P30-DK-079337"],"award-info":[{"award-number":["P30-DK-079337"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs (VA)","doi-asserted-by":"publisher","award":["1-I01-BX002298"],"award-info":[{"award-number":["1-I01-BX002298"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Detraz Endowed Research Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2019,3,1]]},"abstract":"<jats:p> 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<jats:sup>C642*<\/jats:sup> mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1<jats:sup>G617fs<\/jats:sup> and PKHD1<jats:sup>G644*<\/jats:sup>). Mouse heterozygotes or homozygotes for the Pkhd1<jats:sup>C642*<\/jats:sup> 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<jats:sup>C642*<\/jats:sup> 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<jats:sup>C642*<\/jats:sup> homozygotes. Interestingly, aged female Pkhd1<jats:sup>C642*<\/jats:sup> 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<jats:sup>C642*<\/jats:sup> 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. <\/jats:p>","DOI":"10.1152\/ajprenal.00181.2018","type":"journal-article","created":{"date-parts":[[2019,1,2]],"date-time":"2019-01-02T08:12:27Z","timestamp":1546416747000},"page":"F463-F472","source":"Crossref","is-referenced-by-count":24,"title":["Heterozygous <i>Pkhd1<\/i><sup>C642*<\/sup> mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney"],"prefix":"10.1152","volume":"316","author":[{"given":"Dan","family":"Shan","sequence":"first","affiliation":[{"name":"Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Rezonzew","sequence":"additional","affiliation":[{"name":"Department 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