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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; Kullak-Ublick, Gerd A; Jochum, Wolfram; Stieger, Bruno; Kerb, Reinhold; Haberl, Michael; Müllhaupt, Beat; Meier, Peter J; 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, 43(3):536-543.

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.

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Hepatology
Language:English
Date:September 2005
Deposited On:21 Jul 2015 10:58
Last Modified:13 Jul 2025 01:36
Publisher:Elsevier
ISSN:0168-8278
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.jhep.2005.05.020
PubMed ID:16039748

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