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

Nature Genetics volume 30, pages 259–269 (2002)Cite this article

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of collecting ducts and by biliary dysgenesis and is an important cause of renal- and liver-related morbidity and mortality. Genetic analysis of a rat with recessive polycystic kidney disease revealed an orthologous relationship between the rat locus and the ARPKD region in humans; a candidate gene was identified. A mutation was characterized in the rat and screening the 66 coding exons of the human ortholog (PKHD1) in 14 probands with ARPKD revealed 6 truncating and 12 missense mutations; 8 of the affected individuals were compound heterozygotes. The PKHD1 transcript, approximately 16 kb long, is expressed in adult and fetal kidney, liver and pancreas and is predicted to encode a large novel protein, fibrocystin, with multiple copies of a domain shared with plexins and transcription factors. Fibrocystin may be a receptor protein that acts in collecting-duct and biliary differentiation.

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Figure 1: Map of the rat PCK and human ARPKD candidate regions, and expression analysis of PKHD1.
Figure 2: Mutation analysis of the PCK rat and individuals with ARPKD.
Figure 3: Analysis of fibrocystin homologies.
Figure 4: Model of fibrocystin.

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Acknowledgements

We thank the patients and their families for taking part in the study, M. El Youssef, J. Gloor, E.N. Haugen, P.S. Kamath and B.Z. Morgenstern for referring patients, and P. Fraught, M. de Andrade and E.J. Atkinson for assistance. Charles River Japan are thanked for the gift of the breeding pairs of PCK rats. The work was supported by grants from the National Institutes of Health, the PKD Foundation (to S.R. and M.H.), the Mayo Graduate School and Foundation, Mayo Cancer Center and the Wellcome Trust.

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Authors and Affiliations

  1. Division of Nephrology, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Christopher J. Ward, Marie C. Hogan, Sandro Rossetti, Denise Walker, Tam Sneddon, Xiaofang Wang, Vicky Kubly, Dawn S. Milliner, Vicente E. Torres & Peter C. Harris

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Julie M. Cunningham

  3. Department of Medicine, Indiana University Medical Center, Indianapolis, 46202, Indiana, USA

    Robert Bacallao

  4. Azabu University, Sagamihara, Japan

    Masahiko Ishibashi

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Correspondence to Peter C. Harris.

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Ward, C., Hogan, M., Rossetti, S. et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 30, 259–269 (2002). https://doi.org/10.1038/ng833

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