A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump

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

“…8 In the study using rat Bsep gene, the pathogenic mechanism for the D482G mutation was not identified because D482G rat Bsep is localized in the apical membrane as well as the cytoplasm of MDCK cells, and this mutation did not significantly affect taurocholate transport examined using membrane vesicles isolated from Sf9 cells. 7 In contrast, in the study with mouse Bsep gene, it was found that D482G mutation resulted in impaired canalicular trafficking in HepG2 cells, although this mutation did not affect the transport of taurocholate examined using membrane vesicles isolated from Sf21 cells.…”

“…7,8 Rat and mouse Bsep genes were used for the analysis because of the difficulties in obtaining human BSEP-expressing cells. It was shown that the introduction of some mutations in the consensus region (such as E297G) into the rat and mouse Bsep genes resulted in altered cellular distribution of the Bsep.…”

The bile salt export pump

“…Therefore, studies using heterologous expression systems of mutated forms of BSEP were used to subsidize for this lack of in vivo data. Expression of various BSEP mutations affecting conserved amino acids in a rat or mouse background in polarized cells such as MDCK or HepG2 cells has resulted in defects of apical trafficking and/or functional impairment of BSEP as well as in temperature-sensitive, unstable forms of BSEP [81,97]. It should, however, be noted that such studies on the functional impact of the human mutations based on heterologous expression systems may lead to conflicting results suggesting species-specific effects on transport function [81,97].…”

“…Expression of various BSEP mutations affecting conserved amino acids in a rat or mouse background in polarized cells such as MDCK or HepG2 cells has resulted in defects of apical trafficking and/or functional impairment of BSEP as well as in temperature-sensitive, unstable forms of BSEP [81,97]. It should, however, be noted that such studies on the functional impact of the human mutations based on heterologous expression systems may lead to conflicting results suggesting species-specific effects on transport function [81,97]. Therefore, directly testing the human mutated forms of BSEP in vivo seems to be an important prerequisite to obtain insights into the functional consequences of BSEP mutations [37,70].…”

Recent insights into the function and regulation of the bile salt export pump (ABCB11)

“…Interestingly, the D482G mutation was found to exhibit decreased transport activity in this study, but after being cloned into mouse Bsep displayed normal function (48). This …”