A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD).

Moser M; Matthiesen S; Kirfel J; Schorle H; Bergmann C; Senderek J; Rudnik-Schöneborn S; Zerres K; Buettner R

doi:10.1002/hep.20655

A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD).

Rudnik-Schöneborn S ,

Zerres K ,

Buettner R

Affiliations

1. Max-Planck-Institute of Biochemistry, Martinsried, Germany.
Authors
Moser M¹
(1 author)

ORCIDs linked to this article

Hepatology (Baltimore, Md.), 01 May 2005, 41(5):1113-1121
https://doi.org/10.1002/hep.20655 PMID: 15830394

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of liver- and renal-related morbidity and mortality in childhood. Recently, PKHD1, the gene encoding the transmembrane protein polyductin, was shown to be mutated in ARPKD patients. We here describe the first mouse strain, generated by targeted mutation of Pkhd1. Due to exon skipping, Pkhd1ex40 mice express a modified Pkhd1 transcript and develop severe malformations of intrahepatic bile ducts. Cholangiocytes maintain a proliferative phenotype and continuously synthesize TGF-beta1. Subsequently, mesenchymal cells within the hepatic portal tracts continue to synthesize collagen, resulting in progressive portal fibrosis and portal hypertension. Fibrosis did not involve the hepatic lobules, and we did not observe any pathological changes in morphology or function of hepatocytes. Surprisingly and in contrast to human ARPKD individuals, Pkhd1ex40 mice develop morphologically and functionally normal kidneys. In conclusion,our data indicate that subsequent to formation of the embryonic ductal plate, dysgenesis of terminally differentiated bile ducts occurs in response to the Pkhd1ex40 mutation. The role of polyductin in liver and kidney may be functionally divergent, because protein domains essential for bile duct development do not affect nephrogenesis in our mouse model.

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References

Articles referenced by this article (19)

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Proteins in UniProt (10)

Fibrocystin(UniProt - E9PZ36)
Uncharacterized protein(UniProt - Q3UNU5)
IPT/TIG domain-containing protein(UniProt - Q8K3J6)
PKHD1(UniProt - Q6T3A5)
Polyductin(UniProt - Q8CIS7)

Mouse Genome Informatics (MGI)

http://www.informatics.jax.org/reference/15830394

The Rat Genome Database (RGD) was established in 1999 and rapidly became the premier site for genetic, genomic, phenotype, and disease-related data generated from rat research. In addition, RGD has expanded to include a large body of structured and standardized data for eight species (rat, mouse, human, chinchilla, bonobo, 13-lined ground squirrel, dog and pig). Much of this data is the result of manual curation work by RGD curators. In other instances, it has been imported into RGD from other databases through custom ELT (Extract, Load and Transform) pipelines giving RGD users integrated access to a wide variety of data to support their research efforts. RGD also offers a growing suite of innovative tools for querying, analyzing and visualizing this data making it a valuable resource for researchers worldwide. (4)

Search life-sciences literature (45,103,589 articles, preprints and more)

A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD).

Affiliations

Authors

ORCIDs linked to this article

Abstract

Full text links

References

Title not supplied

Autosomal recessive polycystic kidney disease.

Mapping of the gene for autosomal recessive polycystic kidney disease (ARPKD) to chromosome 6p21-cen.

Autosomal recessive polycystic kidney disease: long-term outcome of neonatal survivors.

The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein.

Enhanced apoptotic cell death of renal epithelial cells in mice lacking transcription factor AP-2beta.

Fine mapping of the autosomal recessive polycystic kidney disease locus (PKHD1) and the genes MUT, RDS, CSNK2 beta, and GSTA1 at 6p21.1-p12.

PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats.

Identification and characterization of Pkhd1, the mouse orthologue of the human ARPKD gene.

Ultrastructural cartilage abnormalities in MIA/CD-RAP-deficient mice.

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Smart citations by scite.ai
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.1002/hep.20655

Article citations

Fibrocystin/Polyductin releases a C-terminal fragment that translocates into mitochondria and suppresses cystogenesis.

Differential regulation of MYC expression by PKHD1/Pkhd1 in human and mouse kidneys: phenotypic implications for recessive polycystic kidney disease.

Pkhd1^cyli/cyli mice have altered renal Pkhd1 mRNA processing and hormonally sensitive liver disease.

Mitigation of portal fibrosis and cholestatic liver disease in ANKS6-deficient livers by macrophage depletion.

Cystin genetic variants cause autosomal recessive polycystic kidney disease associated with altered Myc expression.

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Proteins in UniProt (10)

Mouse Genome Informatics (MGI)

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A mouse model for cystic biliary dysgenesis in autosomal recessive polycystic kidney disease (ARPKD).

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