2. Academic Validation
  3. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis

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

  • Nat Commun. 2016 Feb 18;7:10713. doi: 10.1038/ncomms10713.
Natalia Gomez-Ospina 1,  Carol J Potter 2,  Rui Xiao 3 4,  Kandamurugu Manickam 2,  Mi-Sun Kim 3,  Kang Ho Kim 3,  Benjamin L Shneider 5,  Jennifer L Picarsic 6,  Theodora A Jacobson 2,  Jing Zhang 4,  Weimin He 4,  Pengfei Liu 4,  A S Knisely 7,  Milton J Finegold 8,  Donna M Muzny 9,  Eric Boerwinkle 9,  James R Lupski 4,  Sharon E Plon 4,  Richard A Gibbs 4 9,  Christine M Eng 4,  Yaping Yang 4,  Gabriel C Washington 10,  Matthew H Porteus 10,  William E Berquist 11,  Neeraja Kambham 12,  Ravinder J Singh 13,  Fan Xia 4,  Gregory M Enns 1,  David D Moore 3 4
Affiliations

Affiliations

  • 1 Lucile Packard Children's Hospital, Divisions of Medical Genetics, Stanford University Medical Center, Stanford, California 94305, USA.
  • 2 Section of Human and Molecular Genetics, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
  • 3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 5 Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 6 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
  • 7 Institute of Liver Studies, King's College Hospital, London SE5 9R5, UK.
  • 8 Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 9 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 10 Pediatric Stem Cell Transplantation, Stanford University Medical Center, Stanford, California 94305, USA.
  • 11 Pediatric Gastroenterology, Stanford University Medical Center, Stanford, California 94305, USA.
  • 12 Anatomic and Clinical Pathology, Stanford University Medical Center, Stanford, California 94305, USA.
  • 13 Immunochemistry Core Laboratory, College of Medicine, Mayo Clinic, Rochester, Minnesota 55902, USA.
PMID: 26888176 DOI: 10.1038/ncomms10713
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.

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