Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis
ABSTRACT Inherited dysfunction of the bile salt export pump BSEP (ABCB11) causes a progressive and a benign form of familial intrahepatic cholestasis, denominated as PFIC2 and BRIC2, respectively. We functionally characterized novel ABCB11 mutations encountered in two patients with a PFIC2 and a BRIC2 phenotype, respectively.
BSEP expression was determined in liver biopsies by immunohistochemistry. ABCB11 mutations were functionally characterized by taurocholate transport in SF9 cells transfected with human ABCB11.
The PFIC2 patient was compound heterozygous for a splicing mutation in intron 4 ((+3)A > C) combined with an early stop codon at position 930 (R930X), while the BRIC2 patient was compound heterozygous for two nonsynonymous mutations in exon 9 (E297G) and exon 12 (R432T), respectively. Hepatic BSEP expression was absent in PFIC2 and preserved in BRIC2. In BRIC2, taurocholate transport was decreased to 13% and 20% of reference levels for R432T and E297G, respectively.
The intron 4 (+3)A > C, R930X and R432T represent previously undescribed mutations of the ABCB11 gene that confer a PFIC2 and a BRIC2 phenotype, respectively. By combining functional in-vitro characterization with immunohistochemical detection of variant BSEP we provide direct evidence for the role of ABCB11 mutations in the pathogenesis of different forms of intrahepatic cholestasis.
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- "Drug transporter genes of the ABC transporter superfamily are biologically plausible candidates for a role in DILI susceptibility, especially because some ABC transporter family gene products transport bile acids in addition to drugs . Also, some inherited forms of cholestasis have been demonstrated to result from specific mutations in the ABCB4 (MDR3) and ABCB11 (BSEP) genes . Some evidence for an association between cholestatic liver injury due to a range of drugs and a polymorphism in exon 13 of ABCB11 that had previously been reported to be associated with cholestasis of pregnancy was reported . "
ABSTRACT: Considerable progress has been made in identifying genetic risk factors for idiosyncratic adverse drug reactions in the past 30 years. These reactions can affect various tissues and organs, including liver, skin, muscle and heart, in a drug-dependent manner. Using both candidate gene and genome-wide association studies, various genes that make contributions of varying extents to each of these forms of reactions have been identified. Many of the associations identified for reactions affecting the liver and skin involve human leukocyte antigen (HLA) genes and for reactions relating to the drugs abacavir and carbamazepine, HLA genotyping is now in routine use prior to drug prescription. Other HLA associations are not sufficiently specific for translation but are still of interest in relation to underlying mechanisms for the reactions. Progress on non-HLA genes affecting adverse drug reactions has been less, but some important associations, such as those of SLCO1B1 and statin myopathy, KCNE1 and drug-induced QT prolongation and NAT2 and isoniazid-induced liver injury, are considered. Future prospects for identification of additional genetic risk factors for the various adverse drug reactions are discussed.Genome Medicine 01/2013; 5(1):5. DOI:10.1186/gm409 · 5.34 Impact Factor
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- "Kosters and Karpen Page 29 Table Transporter Tissue/Cell type Cellular location Major role Regulation in human disease Human SNPs, polymorphisms & mutations Bsep Hepatocyte Canalicular membrane ATP- dependent bile acid efflux Suppressed in sepsis and cholestasis Strautnieks et al. 1998 Jansen et al. 1999 Saito et al 2002 Wang et al 2002 Pauli-Magnus et al 2004 Plass et al 2004 Van Mil et al 2004 Hayashi et al 2005 Noe et al 2005 Lang et al 2006 Meier et al 2006 Kagawa et al 2007 Lam et al 2007 Lang et al 2007 Stieger et al 2007 Ntcp Hepatocyte Sinusoidal membrane Na + dependent bile acid uptake Suppressed in sepsis & cholestasis Ho et al 2004 Geyer et al 2007 Asbt Enterocyte, cholangiocyte, kidney Apical membrane Na + dependent bile acid uptake Unknown Oelkers et al 1997 Geyer et al 2007 Ostα/β Hepatocyte, enterocyte, cholangiocyte, kidney Sinusoidal membrane bile acid efflux by facilitated diffusion Upregulated in liver in late stage PBC None described Xenobiotica. Author manuscript; available in PMC 2010 February 17. "
ABSTRACT: In recent years the discovery of a number of major transporter proteins expressed in the liver and intestine specifically involved in bile acid transport has led to improved understanding of bile acid homeostasis and the enterohepatic circulation. Sodium (Na(+))-dependent bile acid uptake from portal blood into the liver is mediated primarily by the Na(+) taurocholate co-transporting polypeptide (NTCP), while secretion across the canalicular membrane into the bile is carried out by the bile salt export pump (BSEP). In the ileum, absorption of bile acids from the lumen into epithelial cells is mediated by the apical Na(+) bile salt transporter (ASBT), whereas exit into portal blood across the basolateral membrane is mediated by the organic solute transporter alpha/beta (OSTalpha/beta) heterodimer. Regulation of transporter gene expression and function occurs at several different levels: in the nucleus, members of the nuclear receptor superfamily, regulated by bile acids and other ligands are primarily involved in controlling gene expression, while cell signalling events directly affect transporter function, and subcellular localization. Polymorphisms, dysfunction, and impaired adaptive responses of several of the bile acid transporters, e.g. BSEP and ASBT, results in liver and intestinal disease. Bile acid transporters are now understood to play central roles in driving bile flow, as well as adaptation to various pathological conditions, with complex regulation of activity and function in the nucleus, cytoplasm, and membrane.Xenobiotica 08/2008; 38(7-8):1043-71. DOI:10.1080/00498250802040584 · 2.20 Impact Factor
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- "The bile salt export pump mediates uphill canalicular bile acid secretion . Inherited dysfunction of the bile salt export pump causes a progressive and a benign form of familial intrahepatic cholestasis, denominated as PFIC2 and BRIC2, respectively . Inborn defects in its function cause intrahepatic cholestasis in infants; inhibition of its function by drugs causes hepatotoxicity . "
ABSTRACT: The bile salt export pump mediates uphill canalicular bile acid secretion. Inherited dysfunction of the bile salt export pump causes a progressive and a benign form of familial intrahepatic cholestasis. Mutations within the bile salt export pump gene are reported. Presently, prediction of protein nanostructure and function is a great challenge in the proteomics and structural genomics era. Identification of the point vulnerable to mutation is a new trend to expand knowledge on disorders at the genomic and proteomic level of diseases. A bioinformatic analysis was performed to study the positions that determine peptide motifs in the amino acid sequence of the bile salt export pump. To identify the weak linkage in bile salt export pump, a new bioinformatic tool named GlobPlot was used. The positions 16-34, 119-127, 451-459, 550-561, 1084-1099, 1108-1118, 1135-1140, 1211-1217, and 1314-1321 were identified as the positions prone to mutation. Based on this study, the weak linkages in the bile salt export pump can be identified and can provide good information for expectation of possible new mutations that can lead to cross species jumping. In addition, the results from this study provide useful information for further research on the bile salt export pump.HPB 02/2007; 9(6):444-6. DOI:10.1080/13651820701660421 · 2.68 Impact Factor