Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis

Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zurich, Rämistrasse 100, E RAE 09, 8091 Zürich, Switzerland.
Journal of Hepatology (Impact Factor: 11.34). 09/2005; 43(3):536-43. DOI: 10.1016/j.jhep.2005.05.020
Source: PubMed


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 [58]. Also, some inherited forms of cholestasis have been demonstrated to result from specific mutations in the ABCB4 (MDR3) and ABCB11 (BSEP) genes [59]. 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 [60]. "
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    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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    • "In patients with PFIC2, mutations or single nucleotide polymorphisms (SNPs) in the BSEP gene result in either reduced levels of mRNA transcription or translation or reduced protein stability or activity (Strautnieks et al., 2008; Byrne et al., 2009; Ho et al., 2010), and liver injury is considered to be caused by intracellular accumulation of cytotoxic bile constituents (Perez and Briz, 2009). Less functionally severe ABCB11 gene mutations have been shown to result in benign recurrent intrahepatic cholestasis type 2, which is characterized by nonprogressive cholestasis (Noe et al., 2005). Defective expression of additional biliary transporters has been implicated in other forms of genetically inherited cholestatic liver injury. "
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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. "
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