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; David D. Moore

doi:10.1038/ncomms10713

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. EngYaping Yang, Gabriel C. Washington, Matthew H. Porteus, William E. Berquist, Neeraja Kambham, Ravinder J. Singh, Fan Xia, Gregory M. Enns, David D. Moore

Laboratory Medicine and Pathology

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120 Scopus citations

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.

Original language	English (US)
Article number	10713
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10713
State	Published - Feb 18 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Gomez-Ospina, N., Potter, C. J., Xiao, R., Manickam, K., Kim, M. S., Kim, K. H., Shneider, B. L., Picarsic, J. L., Jacobson, T. A., Zhang, J., He, W., Liu, P., Knisely, A. S., Finegold, M. J., Muzny, D. M., Boerwinkle, E., Lupski, J. R., Plon, S. E., Gibbs, R. A., ... Moore, D. D. (2016). Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nature communications, 7, Article 10713. https://doi.org/10.1038/ncomms10713

Gomez-Ospina, N, Potter, CJ, Xiao, R, Manickam, K, Kim, MS, Kim, KH, 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 2016, 'Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis', Nature communications, vol. 7, 10713. https://doi.org/10.1038/ncomms10713

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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.",

author = "Natalia Gomez-Ospina and Potter, {Carol J.} and Rui Xiao and Kandamurugu Manickam and Kim, {Mi Sun} and Kim, {Kang Ho} and Shneider, {Benjamin L.} and Picarsic, {Jennifer L.} and Jacobson, {Theodora A.} and Jing Zhang and Weimin He and Pengfei Liu and Knisely, {A. S.} and Finegold, {Milton J.} and Muzny, {Donna M.} and Eric Boerwinkle and Lupski, {James R.} and Plon, {Sharon E.} and Gibbs, {Richard A.} and Eng, {Christine M.} and Yaping Yang and Washington, {Gabriel C.} and Porteus, {Matthew H.} and Berquist, {William E.} and Neeraja Kambham and Singh, {Ravinder J.} and Fan Xia and Enns, {Gregory M.} and Moore, {David D.}",

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AU - Gomez-Ospina, Natalia

AU - Potter, Carol J.

AU - Xiao, Rui

AU - Manickam, Kandamurugu

AU - Kim, Mi Sun

AU - Kim, Kang Ho

AU - Shneider, Benjamin L.

AU - Picarsic, Jennifer L.

AU - Jacobson, Theodora A.

AU - Zhang, Jing

AU - He, Weimin

AU - Liu, Pengfei

AU - Knisely, A. S.

AU - Finegold, Milton J.

AU - Muzny, Donna M.

AU - Boerwinkle, Eric

AU - Lupski, James R.

AU - Plon, Sharon E.

AU - Gibbs, Richard A.

AU - Eng, Christine M.

AU - Yang, Yaping

AU - Washington, Gabriel C.

AU - Porteus, Matthew H.

AU - Berquist, William E.

AU - Kambham, Neeraja

AU - Singh, Ravinder J.

AU - Xia, Fan

AU - Enns, Gregory M.

AU - Moore, David D.

PY - 2016/2/18

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N2 - 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.

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

Abstract

ASJC Scopus subject areas

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