Two common PFIC2 mutations are associated with the impaired membrane trafficking of BSEP/ABCB11

Hepatology. 2005 Apr;41(4):916-24. doi: 10.1002/hep.20627.


Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by a mutation in the bile salt export pump (BSEP/ABCB11) gene. However, the mechanisms for the deficiency in the function of two mutations (E297G and D482G), which are frequently found in European patients, have not yet been identified. In the present study, we examined the transport activity and cellular localization of these two mutants in human embryonic kidney 293 and Madin-Darby canine kidney II cells, respectively. Introduction of E297G and D482G mutations into the human BSEP gene by site-directed mutagenesis resulted in a significant reduction in the BSEP expression level, which was associated with impaired membrane trafficking. Most of the D482G BSEP and some of the E297G BSEP underwent only core glycosylation and appeared to be predominantly located in the endoplasmic reticulum. The inhibition of proteasome function by MG132 resulted in the cellular accumulation of the core glycosylation form of the two mutants. In contrast, transport studies for taurocholate and glycocholate with membrane vesicles isolated from complementary DNA-transfected cells indicated that both mutations did not significantly affect the transport function of BSEP per se. In conclusion, E297G and D482G mutations result in impaired membrane trafficking, whereas the transport functions of these mutants remain largely unchanged.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Aspartic Acid
  • Biological Transport
  • Cell Line
  • Cholestasis, Intrahepatic / genetics*
  • Dogs
  • Endoplasmic Reticulum / metabolism
  • Glutamic Acid
  • Glycine
  • Glycosylation
  • Humans
  • Membranes / metabolism
  • Mutation*
  • Proteasome Endopeptidase Complex / metabolism
  • Tissue Distribution


  • ABCB11 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Aspartic Acid
  • Glutamic Acid
  • Proteasome Endopeptidase Complex
  • Glycine