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Heterozygous Pkhd1C642* mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney
- Source :
- American Journal of Physiology-Renal Physiology. 316:F463-F472
- Publication Year :
- 2019
- Publisher :
- American Physiological Society, 2019.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Pathology
medicine.medical_specialty
Physiology
Radiography
030232 urology & nephrology
Receptors, Cell Surface
Disease
Medullary sponge kidney
Diagnosis, Differential
Kidney Tubules, Proximal
Loss of heterozygosity
Mice
03 medical and health sciences
0302 clinical medicine
Ectasia
Animals
Medicine
Cystic liver disease
Mice, Knockout
Medullary Sponge Kidney
Cysts
business.industry
Liver Diseases
Polycystic liver disease
Gene targeting
medicine.disease
Magnetic Resonance Imaging
Disease Models, Animal
030104 developmental biology
Kidney Diseases
business
Research Article
Dilatation, Pathologic
Subjects
Details
- ISSN :
- 15221466 and 1931857X
- Volume :
- 316
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Renal Physiology
- Accession number :
- edsair.doi.dedup.....fd3c733982ca2a3825bc247f19374cc8
- Full Text :
- https://doi.org/10.1152/ajprenal.00181.2018