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

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, Pengfei Liu, A. S. Knisely, Milton J. Finegold, Donna M. Muzny, Eric Boerwinkle, James R. Lupski, Sharon E. Plon, Richard A. Gibbs, Christine M. Eng, Yaping Yang, Gabriel C. Washington, Matthew H. Porteus, William E. Berquist, Neeraja Kambham, Ravinder J. Singh, Fan Xia, Gregory M. Enns and David D. Moore ()
Additional contact information
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
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
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10713

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