title: Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.
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.
authors.affiliation: Lucile Packard Children's Hospital, Divisions of Medical Genetics, Stanford University Medical Center, Stanford, California 94305, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gomez-Ospina
authors.affiliation: Section of Human and Molecular Genetics, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Potter
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Section of Human and Molecular Genetics, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
authors.forename: Kandamurugu
authors.initials: K
authors.lastname: Manickam
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Kang Ho
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Picarsic
authors.affiliation: Section of Human and Molecular Genetics, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
authors.forename: Theodora A
authors.initials: TA
authors.lastname: Jacobson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Institute of Liver Studies, King's College Hospital, London SE5 9R5, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Boerwinkle
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Pediatric Stem Cell Transplantation, Stanford University Medical Center, Stanford, California 94305, USA.
authors.forename: Gabriel C
authors.initials: GC
authors.lastname: Washington
authors.affiliation: Pediatric Stem Cell Transplantation, Stanford University Medical Center, Stanford, California 94305, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Porteus
authors.affiliation: Pediatric Gastroenterology, Stanford University Medical Center, Stanford, California 94305, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Berquist
authors.affiliation: Anatomic and Clinical Pathology, Stanford University Medical Center, Stanford, California 94305, USA.
authors.forename: Neeraja
authors.initials: N
authors.lastname: Kambham
authors.affiliation: Immunochemistry Core Laboratory, College of Medicine, Mayo Clinic, Rochester, Minnesota 55902, USA.
authors.forename: Ravinder J
authors.initials: RJ
authors.lastname: Singh
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Lucile Packard Children's Hospital, Divisions of Medical Genetics, Stanford University Medical Center, Stanford, California 94305, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D001647:Bile Acids and Salts / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human