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

Noe, Johannes and Kullak-Ublick, Gerd A. and Jochum, Wolfram and Stieger, Bruno and Kerb, Reinhold and Haberl, Michael and Müllhaupt, Beat and Meier, Peter J. and Pauli-Magnus, Christiane. (2005) Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. Journal of hepatology, Vol. 43, H. 3. S. 536-543.

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Official URL: http://edoc.unibas.ch/dok/A5261584

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Abstract

BACKGROUND/AIMS: 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. METHODS: BSEP expression was determined in liver biopsies by immunohistochemistry. ABCB11 mutations were functionally characterized by taurocholate transport in SF9 cells transfected with human ABCB11. RESULTS: 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. CONCLUSIONS: 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.
Faculties and Departments:11 Rektorat und Verwaltung > Vizerektorat Forschung
UniBasel Contributors:Meier-Abt, Peter J.
Item Type:Article, refereed
Bibsysno:Link to catalogue
Publisher:Elsevier
ISSN:0168-8278
Note:Publication type according to Uni Basel Research Database: Journal item
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Last Modified:22 Mar 2012 14:24
Deposited On:22 Mar 2012 13:41

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