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

被引：238

作者：

Gomez-Ospina, Natalia ^{[1
]}

Potter, Carol J. ^{[2
]}

Xiao, Rui ^{[3
,4
]}

Manickam, Kandamurugu ^{[2
]}

Kim, Mi-Sun ^{[3
]}

Kim, Kang Ho ^{[3
]}

Shneider, Benjamin L. ^{[5
]}

Picarsic, Jennifer L. ^{[6
]}

Jacobson, Theodora A. ^{[2
]}

Zhang, Jing ^{[4
]}

He, Weimin ^{[4
]}

Liu, Pengfei ^{[4
]}

Knisely, A. S. ^{[7
,14
]}

Finegold, Milton J. ^{[8
]}

Muzny, Donna M. ^{[9
]}

Boerwinkle, Eric ^{[9
]}

Lupski, James R. ^{[4
]}

Plon, Sharon E. ^{[4
]}

Gibbs, Richard A. ^{[4
,9
]}

Eng, Christine M. ^{[4
]}

Yang, Yaping ^{[4
]}

Washington, Gabriel C. ^{[10
]}

Porteus, Matthew H. ^{[10
]}

Berquist, William E. ^{[11
]}

Kambham, Neeraja ^{[12
]}

Singh, Ravinder J. ^{[13
]}

Xia, Fan ^{[4
]}

Enns, Gregory M. ^{[1
]}

Moore, David D. ^{[3
,4
]}

机构：

[1] Stanford Univ, Med Ctr, Div Med Genet, Lucile Packard Childrens Hosp, Stanford, CA 94305 USA

[2] Nationwide Childrens Hosp, Sect Human & Mol Genet, Columbus, OH 43205 USA

[3] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA

[4] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[5] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[6] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15261 USA

[7] Kings Coll Hosp London, Inst Liver Studies, London SE5 9R5, England

[8] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA

[9] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[10] Stanford Univ, Med Ctr, Pediat Stem Cell Transplantat, Stanford, CA 94305 USA

[11] Stanford Univ, Med Ctr, Pediat Gastroenterol, Stanford, CA 94305 USA

[12] Stanford Univ, Med Ctr, Anat & Clin Pathol, Stanford, CA 94305 USA

[13] Mayo Clin, Coll Med, Immunochemistry Core Lab, Rochester, MN 55902 USA

[14] Med Univ Graz, Inst Pathol, A-803 Graz, Austria

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

FARNESOID-X-RECEPTOR; OBETICHOLIC ACID; LIVER-DISEASE; SERUM; 7-ALPHA-HYDROXY-4-CHOLESTEN-3-ONE; URSODEOXYCHOLIC ACID; CHILDREN; STEATOHEPATITIS; MALABSORPTION; HOMEOSTASIS; PREGNANCY;

D O I：

10.1038/ncomms10713

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：8

共 43 条

[1]

Association between Serum Atypical Fibroblast Growth Factors 21 and 19 and Pediatric Nonalcoholic Fatty Liver Disease [J].