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

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.

• Authors: Johannes Noe, Gerd A Kullak-Ublick, Wolfram Jochum, Bruno Stieger, Reinhold Kerb, Michael Haberl, Beat Müllhaupt, Peter J Meier, Christiane Pauli-Magnus
• Journal: Journal of hepatology (J Hepatol) Vol. 43 Issue 3 Pg. 536-43 (Sep 2005) ISSN: 0168-8278 [Print] Netherlands
• PMID: 16039748 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB11 protein, human
• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters
• Bile Acids and Salts
• DNA Primers
• Recombinant Proteins

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (chemistry, genetics, metabolism)
• Amino Acid Sequence
• Base Sequence
• Bile Acids and Salts (metabolism)
• Biological Transport
• Cholestasis, Intrahepatic (genetics)
• DNA Primers
• Female
• Gene Expression Regulation
• Humans
• Male
• Models, Molecular
• Molecular Sequence Data
• Mutagenesis, Site-Directed
• Mutation
• Pedigree
• Protein Conformation
• Recombinant Proteins (chemistry, metabolism)