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A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis

Nature Genetics volume 20, pages 233–238 (1998)Cite this article

Abstract

The progressive familial intrahepatic cholestases (PFIC) are a group of inherited disorders with severe cholestatic liver disease from early infancy. A subgroup characterized by normal serum cholesterol and γ-glutamyltranspeptidase (γGT) levels is genetically heterogeneous with loci on chromosomes 2q (PFIC2) and 18q. The phenotype of the PFIC2-linked group is consistent with defective bile acid transport at the hepatocyte canalicular membrane. The PFIC2 gene has now been identified by mutations in a positional candidate, BSEP, which encodes a liver-specific ATP-binding cassette (ABC) transporter, sister of p-glycoprotein (SPGP). The product of the orthologous rat gene has been shown to be an effective bile acid transporter in vitro. These data provide evidence that SPGP is the human bile salt export pump (BSEP).

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Figure 1: Physical mapping of BSEP. a, A composite map of the PFIC2 region based on current genetic and physical maps35 (Whitehead integrated map at http://www-genome.wi.mit.edu; Stanford Human Genome Center, whole-genome radiation hybrid G3 maps at http://www-shgc.stanford.edu).
Figure 2: SPGP amino acid sequence.
Figure 3: Northern-blot analysis of BSEP expression.
Figure 4: Predicted topology and mutations of SPGP.
Figure 5: The amino acid sequence in the immediate vicinity of the E297G mutation.

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Acknowledgements

This study was made possible by the cooperation of patients, their families and referring physicians, in particular: A. Dhawan, D. Herzog, R. Houwen, M. Ishitani, D. Kemmler, S. McDiarmid, P. McKeirnan, H. Mandel, M. Martin, B. Portmann, W. Rebhandl, C. Riely, H. Soriano, A. Urbania & P. Whitington. The authors are very grateful to many members of the Department of Paediatrics, UCL Medical School, for expert advice and assistance, in particular: J. Barclay, P. Munroe, M. Williamson, K. Parker and H. Mitchison. R.J.T. was a Wellcome Trust Medical Graduate Research Training Fellow. S.S.S. is funded by a Medical Research Council (UK) project grant. Additional funding was provided by the Children's Liver Disease Foundation. This work was also supported by a National Institutes of Health R01 grant (DK50697) to N.F. L.B. was supported by a postdoctoral National Research Service Award from the National Institutes of Mental Health and by a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression.

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Authors and Affiliations

  1. Department of Paediatrics, University College London Medical School, London, UK

    Sandra S. Strautnieks, R. Mark Gardiner & Richard J. Thompson

  2. Department of Psychiatry, Neurogenetics Laboratory, Center for Neurobiology and Psychiatry, and Liver Center, UCSF, San Francisco, California, USA

    Laura N. Bull & Nelson B. Freimer

  3. Division of Surgical Pathology, University of Texas Medical Branch, Galveston, Texas, USA

    Alexander S. Knisely

  4. Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Samuel A. Kocoshis

  5. Department of Genetics and Pathology, University of Uppsala, Uppsala, Sweden

    Niklas Dahl & Henrik Arnell

  6. Department of Pediatrics, Université Catholique Louvain, Louvain, Belgium

    Etienne Sokal

  7. Department of Medical Genetics, Université Catholique Louvain, Louvain, Belgium

    Karine Dahan

  8. BC Cancer Research Centre, Vancouver, British Columbia, Canada

    Sarah Childs & Victor Ling

  9. Sheffield Children's Hospital, Sheffield, UK

    M. Stuart Tanner

  10. Naperville, Illinois, USA

    Amir F. Kagalwalla

  11. Department of Pediatrics, Huddinge University Hospital, Huddinge, Sweden

    Antal Németh

  12. Children's Memorial Health Institute, Warsaw, Poland

    Joanna Pawlowska

  13. Department of Child Health, King's College Hospital and King's College School of Medicine and Dentistry, London, UK

    Alastair Baker & Giorgina Mieli-Vergani

  14. Programs in Biomedical Sciences and Genetics, UCSF, California, USA

    Nelson B. Freimer

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Correspondence to Richard J. Thompson.

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Strautnieks, S., Bull, L., Knisely, A. et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nat Genet 20, 233–238 (1998). https://doi.org/10.1038/3034

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