Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency.
Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency.
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胆汁酸偶联的遗传缺陷会导致脂溶性维生素缺乏症。
DOI：
10.1053/j.gastro.2013.02.004
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发表时间：
2013-05
期刊：
影响因子：
29.4
通讯作者：
Bull LN
中科院分区：
文献类型：
--
作者：
Setchell KD;Heubi JE;Shah S;Lavine JE;Suskind D;Al-Edreesi M;Potter C;Russell DW;O'Connell NC;Wolfe B;Jha P;Zhang W;Bove KE;Knisely AS;Hofmann AF;Rosenthal P;Bull LN
胆汁酸合成的最后一步涉及与甘氨酸和牛磺酸的结合，其促进高的管腔内胶束浓度以促进脂质吸收。我们调查了10例脂溶性维生素缺乏症患儿胆汁酸结合遗传缺陷的临床、生化、分子和形态学特征，其中一些患儿伴有生长障碍或短暂性新生儿胆汁淤积性肝炎。我们通过对尿液、胆汁和血清样本进行质谱分析，并对编码胆汁酸-CoA：氨基酸N-酰基转移酶（BAAT）和胆汁酸-CoA连接酶（SLC 27 A5）的基因进行序列分析，确定了导致这种疾病的遗传缺陷。尿胆汁酸水平升高（432±248 μmol/L），主要以非结合形式（79.4%±3.9%）以及硫酸盐和葡萄糖醛酸排泄。尿液、胆汁和血清中不存在甘氨酸或牛磺酸结合物。十二指肠胆汁中非结合胆汁酸占胆汁酸的95.7%±5.8%，其中胆酸占总胆汁酸的82.4%±5.5%。十二指肠胆汁酸浓度为12.1±5.9 mmol/L-a浓度过低，无法有效吸收脂质。生化特征与胆汁酸酰胺化缺陷一致。BAAT的分子分析证实了8例受试患者中4种不同的纯合突变。基于对10名儿科患者的研究，破坏胆汁酸酰胺化的遗传缺陷导致脂溶性维生素缺乏和生长障碍，表明胆汁酸结合在脂质吸收中的重要性。一些患者发生了具有胆管病特征的肝病。这些发现表明，患有特发性新生儿胆汁淤积症或不明原因的脂溶性维生素缺乏症的患者应筛查胆汁酸结合缺陷。
The final step in bile acid synthesis involves conjugation with glycine and taurine, which promotes a high intraluminal micellar concentration to facilitate lipid absorption. We investigated the clinical, biochemical, molecular, and morphologic features of a genetic defect in bile acid conjugation in 10 pediatric patients with fat-soluble vitamin deficiency, some with growth failure or transient neonatal cholestatic hepatitis. We identified the genetic defect that causes this disorder using mass spectrometry analysis of urine, bile, and serum samples, and sequence analysis of the genes encoding bile acid-CoA:amino acid N-acyltransferase (BAAT) and bile acid-Co A ligase (SLC27A5). Levels of urinary bile acids were increased (432±248 μmol/L) and predominantly excreted in unconjugated forms (79.4%±3.9%), and as sulfates and glucuronides. Glycine or taurine conjugates were absent in the urine, bile and serum. Unconjugated bile acids accounted for 95.7%±5.8% of the bile acids in duodenal bile, with cholic acid accounting for 82.4%±5.5% of total. Duodenal bile acid concentrations were 12.1±5.9 mmol/L—a concentration too low for efficient lipid absorption. The biochemical profile was consistent with defective bile acid amidation. Molecular analysis of BAAT confirmed 4 different homozygous mutations in 8 patients tested. Based on a study of 10 pediatric patients, genetic defects that disrupt bile acid amidation cause fat-soluble vitamin deficiency and growth failure, indicating the importance of bile acid conjugation in lipid absorption. Some patients developed liver disease with features of a cholangiopathy. These findings indicate that patients with idiopathic neonatal cholestasis or later onset of unexplained fat-soluble vitamin deficiency should be screened for defects in bile acid conjugation.
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影响因子：
13.5
作者：
DAUGHERTY, CC;SETCHELL, KDR;BALISTRERI, WF
通讯作者：
BALISTRERI, WF
影响因子：
64.8
作者：
Frazer, Kelly A.;Ballinger, Dennis G.;Cox, David R.;Hinds, David A.;Stuve, Laura L.;Gibbs, Richard A.;Belmont, John W.;Boudreau, Andrew;Hardenbol, Paul;Leal, Suzanne M.;Pasternak, Shiran;Wheeler, David A.;Willis, Thomas D.;Yu, Fuli;Yang, Huanming;Zeng, Changqing;Gao, Yang;Hu, Haoran;Hu, Weitao;Li, Chaohua;Lin, Wei;Liu, Siqi;Pan, Hao;Tang, Xiaoli;Wang, Jian;Wang, Wei;Yu, Jun;Zhang, Bo;Zhang, Qingrun;Zhao, Hongbin;Zhao, Hui;Zhou, Jun;Gabriel, Stacey B.;Barry, Rachel;Blumenstiel, Brendan;Camargo, Amy;Defelice, Matthew;Faggart, Maura;Goyette, Mary;Gupta, Supriya;Moore, Jamie;Nguyen, Huy;Onofrio, Robert C.;Parkin, Melissa;Roy, Jessica;Stahl, Erich;Winchester, Ellen;Ziaugra, Liuda;Altshuler, David;Shen, Yan;Yao, Zhijian;Huang, Wei;Chu, Xun;He, Yungang;Jin, Li;Liu, Yangfan;Shen, Yayun;Sun, Weiwei;Wang, Haifeng;Wang, Yi;Wang, Ying;Xiong, Xiaoyan;Xu, Liang;Waye, Mary M. Y.;Tsui, Stephen K. W.;Wong, J. Tze-Fei;Galver, Luana M.;Fan, Jian-Bing;Gunderson, Kevin;Murray, Sarah S.;Oliphant, Arnold R.;Chee, Mark S.;Montpetit, Alexandre;Chagnon, Fanny;Ferretti, Vincent;Leboeuf, Martin;Olivier, Jean-Franccois;Phillips, Michael S.;Roumy, Stephanie;Sallee, Clementine;Verner, Andrei;Hudson, Thomas J.;Kwok, Pui-Yan;Cai, Dongmei;Koboldt, Daniel C.;Miller, Raymond D.;Pawlikowska, Ludmila;Taillon-Miller, Patricia;Xiao, Ming;Tsui, Lap-Chee;Mak, William;Song, You Qiang;Tam, Paul K. H.;Nakamura, Yusuke;Kawaguchi, Takahisa;Kitamoto, Takuya;Morizono, Takashi;Nagashima, Atsushi;Ohnishi, Yozo;Sekine, Akihiro;Tanaka, Toshihiro;Tsunoda, Tatsuhiko;Deloukas, Panos;Bird, Christine P.;Delgado, Marcos;Dermitzakis, Emmanouil T.;Gwilliam, Rhian;Hunt, Sarah;Morrison, Jonathan;Powell, Don;Stranger, Barbara E.;Whittaker, Pamela;Bentley, David R.;Daly, Mark J.;de Bakker, Paul I. W.;Barrett, Jeff;Chretien, Yves R.;Maller, Julian;McCarroll, Steve;Patterson, Nick;Pe'er, Itsik;Price, Alkes;Purcell, Shaun;Richter, Daniel J.;Sabeti, Pardis;Saxena, Richa;Schaffner, Stephen F.;Sham, Pak C.;Varilly, Patrick;Altshuler, David;Stein, Lincoln D.;Krishnan, Lalitha;Smith, Albert Vernon;Tello-Ruiz, Marcela K.;Thorisson, Gudmundur A.;Chakravarti, Aravinda;Chen, Peter E.;Cutler, David J.;Kashuk, Carl S.;Lin, Shin;Abecasis, Goncalo R.;Guan, Weihua;Li, Yun;Munro, Heather M.;Qin, Zhaohui Steve;Thomas, Daryl J.;McVean, Gilean;Auton, Adam;Bottolo, Leonardo;Cardin, Niall;Eyheramendy, Susana;Freeman, Colin;Marchini, Jonathan;Myers, Simon;Spencer, Chris;Stephens, Matthew;Donnelly, Peter;Cardon, Lon R.;Clarke, Geraldine;Evans, David M.;Morris, Andrew P.;Weir, Bruce S.;Tsunoda, Tatsuhiko;Johnson, Todd A.;Mullikin, James C.;Sherry, Stephen T.;Feolo, Michael;Skol, Andrew
通讯作者：
Skol, Andrew
DOI：
10.1023/b135931_10
发表时间：
2010-01-01
期刊：
STEROID ANALYSIS: SECOND EDITION
影响因子：
--
作者：
Sjovall, Jan;Griffiths, William J.;Goto, Junichi
通讯作者：
Goto, Junichi
影响因子：
30.8
作者：
Carlton, VEH;Harris, BZ;Bull, LN
通讯作者：
Bull, LN
影响因子：
4.1
作者：
VESSEY, DA;ZAKIM, D
通讯作者：
ZAKIM, D