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Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

Author

Listed:
  • Natalia Gomez-Ospina

    (Lucile Packard Children’s Hospital, Stanford University Medical Center)

  • Carol J. Potter

    (Section of Human and Molecular Genetics, Nationwide Children's Hospital)

  • Rui Xiao

    (Baylor College of Medicine
    Baylor College of Medicine)

  • Kandamurugu Manickam

    (Section of Human and Molecular Genetics, Nationwide Children's Hospital)

  • Mi-Sun Kim

    (Baylor College of Medicine)

  • Kang Ho Kim

    (Baylor College of Medicine)

  • Benjamin L. Shneider

    (Baylor College of Medicine)

  • Jennifer L. Picarsic

    (University of Pittsburgh School of Medicine)

  • Theodora A. Jacobson

    (Section of Human and Molecular Genetics, Nationwide Children's Hospital)

  • Jing Zhang

    (Baylor College of Medicine)

  • Weimin He

    (Baylor College of Medicine)

  • Pengfei Liu

    (Baylor College of Medicine)

  • A. S. Knisely

    (Institute of Liver Studies, King’s College Hospital
    Present address: Institut fur Pathologie, Medizinishce Universitat Graz, A-803 Graz, Austria.)

  • Milton J. Finegold

    (Baylor College of Medicine)

  • Donna M. Muzny

    (Human Genome Sequencing Center, Baylor College of Medicine)

  • Eric Boerwinkle

    (Human Genome Sequencing Center, Baylor College of Medicine)

  • James R. Lupski

    (Baylor College of Medicine)

  • Sharon E. Plon

    (Baylor College of Medicine)

  • Richard A. Gibbs

    (Baylor College of Medicine
    Human Genome Sequencing Center, Baylor College of Medicine)

  • Christine M. Eng

    (Baylor College of Medicine)

  • Yaping Yang

    (Baylor College of Medicine)

  • Gabriel C. Washington

    (Pediatric Stem Cell Transplantation, Stanford University Medical Center)

  • Matthew H. Porteus

    (Pediatric Stem Cell Transplantation, Stanford University Medical Center)

  • William E. Berquist

    (Pediatric Gastroenterology, Stanford University Medical Center)

  • Neeraja Kambham

    (Anatomic and Clinical Pathology, Stanford University Medical Center)

  • Ravinder J. Singh

    (Immunochemistry Core Laboratory, College of Medicine, Mayo Clinic)

  • Fan Xia

    (Baylor College of Medicine)

  • Gregory M. Enns

    (Lucile Packard Children’s Hospital, Stanford University Medical Center)

  • David D. Moore

    (Baylor College of Medicine
    Baylor College of Medicine)

Abstract

Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our findings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection.

Suggested Citation

  • Natalia Gomez-Ospina & Carol J. Potter & Rui Xiao & Kandamurugu Manickam & Mi-Sun Kim & Kang Ho Kim & Benjamin L. Shneider & Jennifer L. Picarsic & Theodora A. Jacobson & Jing Zhang & Weimin He & Peng, 2016. "Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis," Nature Communications, Nature, vol. 7(1), pages 1-8, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10713
    DOI: 10.1038/ncomms10713
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