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

TitleMutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis.
Publication TypeJournal Article
Year of Publication2016
AuthorsGomez-Ospina, N, Potter, CJ, Xiao, R, Manickam, K, Kim, M-S, Kim, KHo, Shneider, BL, Picarsic, JL, Jacobson, TA, Zhang, J, He, W, Liu, P, Knisely, AS, Finegold, MJ, Muzny, DM, Boerwinkle, E, Lupski, JR, Plon, SE, Gibbs, RA, Eng, CM, Yang, Y, Washington, GC, Porteus, MH, Berquist, WE, Kambham, N, Singh, RJ, Xia, F, Enns, GM, Moore, DD
JournalNat Commun
Volume7
Pagination10713
Date Published2016 Feb 18
ISSN2041-1723
KeywordsATP Binding Cassette Subfamily B Member 11, ATP-Binding Cassette Transporters, Bile Acids and Salts, Cholestasis, Intrahepatic, Female, Humans, Male, Mutation, Receptors, Cytoplasmic and Nuclear, Young Adult
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.

DOI10.1038/ncomms10713
Alternate JournalNat Commun
PubMed ID26888176
PubMed Central IDPMC4759630
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States