Published online before print January 17, 2008

This Article Full Text (Rapid PDF) Supplemental Material All Versions of this Article: ajpath.2008.070381v1 172/2/417    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gallagher, A.-R. Articles by Somlo, S. PubMed PubMed Citation Articles by Gallagher, A.-R. Articles by Somlo, S.

Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070381

Accepted for publication November 21, 2007.

Article

Biliary and Pancreatic Dysgenesis in Mice Harboring a Mutation in Pkhd1

Anna-Rachel Gallagher^*, Ernie L. Esquivel^*, Tiffany S. Briere, Xin Tian^*, Michihiro Mitobe^*, Luis F. Menezes, Glen S. Markowitz, Dhanpat Jain^¶, Luiz F. Onuchic, and Stefan Somlo^*@

From the Departments of Internal Medicine,* Genetics, and Pathology,^¶ Yale University School of Medicine, New Haven, Connecticut; the Department of Pathology, Columbia University Medical Center, New York, New York; and the Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil

^@ To whom correspondence should be addressed. E-mail: stefan.somlo{at}yale.edu.

	Abstract

Autosomal recessive polycystic kidney disease is a hereditary fibrocystic disease that involves the kidneys and the biliary tract. Mutations in the PKHD1 gene are responsible for typical forms of autosomal recessive polycystic kidney disease. We have generated a mouse model with targeted mutation of Pkhd1 by disrupting exon 4, resulting in a mutant transcript with deletion of 66 codons and expression at 30% of wild-type levels. Pkhd1^del4/del4 mice develop intrahepatic bile duct proliferation with progressive cyst formation and associated periportal fibrosis. In addition, these mice exhibit extrahepatic manifestations, including pancreatic cysts, splenomegaly, and common bile duct dilation. The kidneys are unaffected both histologically and functionally. Fibrocystin is expressed in the apical membranes and cilia of bile ducts and distal nephron segments but is absent from the proximal tubule. This pattern is unchanged in orthologous models of autosomal dominant polycystic kidney disease due to mutation in Pkd1 or Pkd2. Mutant fibrocystin in Pkhd1^del4/del4 mice also retains this expression pattern. The hypomorphic Pkhd1^del4/del4 mouse model provides evidence that reduced functional levels of fibrocystin are sufficient for cystogenesis and fibrosis in the liver and pancreas, but not the kidney, and supports the hypothesis of species-dependent differences in susceptibility of tissues to Pkhd1 mutations.