ABCMdb

PMID: 23685087

Soroka CJ, Boyer JL
Biosynthesis and trafficking of the bile salt export pump, BSEP: therapeutic implications of BSEP mutations.
Mol Aspects Med. 2014 Jun;37:3-14. doi: 10.1016/j.mam.2013.05.001. Epub 2013 May 15., [PubMed]

Sentences

No. Mutations Sentence Comment

136 ABCB11 p.Glu297Gly ABCB11 p.Arg1268Gln ABCB11 p.Gly238Val ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg When seven PFIC2 missense mutations were expressed in MDCK cells, five of these common mutations (G238V, E297G, G982R, R1153C and R1268Q) were unable to traffic to the apical membrane (Wang et al., 2002). Login to comment 138 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Two common mutations in human BSEP, E297G and D482G, have been reported to have both reduced (Noe et al., 2005; Wang et al., 2002) and normal (Hayashi et al., 2005; Lam et al., 2007) transport activity. Login to comment 139 ABCB11 p.Asp482Gly The D482G mutation has also been found to have enhanced aberrant mRNA splicing, perhaps providing an explanation for the variable expression, function and severity of disease (Byrne et al., 2009). Login to comment 140 ABCB11 p.Asp482Gly This mutation (D482G) is the most common PFIC missense mutation in the European population and 16% of BSEP deficiency patients who develop malignancy have this mutation (Knisely et al., 2006; Strautnieks et al., 2008). Login to comment 142 ABCB11 p.Asp482Gly In addition, Bryne et al. have reported that the D482G-containing mRNA is unstable (Byrne et al., 2009). Login to comment 143 ABCB11 p.Glu297Gly The variability in the clinical phenotype of the E297G mutation, on the other hand, may be due to the ability of the mRNA to be stabilized by splicing factors present in the hepatocyte (Byrne et al., 2009). Login to comment 145 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Arg1050Cys ABCB11 p.Ala570Thr We examined differences in protein maturation, plasma membrane localization and transport activity in mutants of rat Bsep representing two PFIC2 (D482G and E297G), two BRIC2 (A570T and R1050C) and one ICP (N591) mutation (Lam et al., 2007). Login to comment 146 ABCB11 p.Glu297Gly It was found that all but the PFIC2 mutation, E297G, retained the ability to transport taurocholate. Login to comment 168 ABCB11 p.Val444Ala ABCB11 p.Met677Val The BSEP variants, V444A and M677V, have been reported to consistently occur with frequencies of greater that 50% (Lang et al., 2006; Saito et al., 2002). Login to comment 169 ABCB11 p.Val444Ala The V444A variant has been found in patients with DILI (Lang et al., 2007) and intrahepatic cholestasis of pregnancy (Dixon et al., 2009; Meier et al., 2008) with greater frequency than controls. Login to comment 170 ABCB11 p.Val444Ala In contrast, preliminary study from Japan reported a lower frequency of the V444A variant in DILI (Kagawa et al., 2012). Login to comment 177 ABCB11 p.Asp482Gly HEK293 cells were transfected with WT Bsep-GFP (A and B) or D482G- GFP (C and D) and confocal microscopy was used to monitor the plasma membrane expression of the constructs after treatment with sodium butyrate (NaB) for 24 h. (A) DMSO control treated cells express WT Bsep-GFP primarily on the plasma membrane. Login to comment 179 ABCB11 p.Asp482Gly (C) Cells transfected with mutant D482G Bsep-GFP show little GFP fluorescence due to degradation of the protein (see details in Lam et al. (2007)). Login to comment 180 ABCB11 p.Asp482Gly (D) Treatment with NaB resulted in stabilization of the protein and cells show increased plasma membrane expression of the D482G mutant of Bsep-GFP. Login to comment 182 ABCB11 p.Asp482Gly For example, the very low plasma membrane expression of the PFIC2 mutant, D482G, could be increased by treatment with low temperature, sodium butyrate (Fig. 2) and sodium 4-phenylbutyrate (4-PB) in MDCK II, HEK293, or HepG2 cells (Hayashi and Sugiyama, 2007; Lam et al., 2007; Plass et al., 2004). Login to comment 185 ABCB11 p.Asp482Gly ABCB11 p.Arg1268Gln ABCB11 p.Gly238Val ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg In vitro studies using rat Bsep mutants of the human mutations G238V, D482G, G982R, R1153C, and R1268Q all resulted in retention of Bsep in the ER to different extents (Wang et al., 2008). Login to comment 186 ABCB11 p.Asp482Gly Ubiquitinylation with over expression of E3 ubiquitin ligases shortened the half life of both the wild type protein and the already short half life of the PFIC2 mutant, D482G, however small amounts of the mutant protein were still able Fig. 3. Login to comment 197 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly This and other studies also suggest that the residence time on the cell surface of the common D482G and E297G mutant proteins is greatly reduced due to accelerated internalization, reduced recycling or targeting of the endocytosed protein for degradation. Login to comment 200 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Indeed, in vitro studies demonstrate that 4-phenylbutyrate (4-PBA) can increase the cell surface expression of PFIC2 mutant proteins D482G and E297G in MDCK cells and stimulate bile salt secretion and Bsep expression in vivo in rats (Hayashi and Sugiyama, 2007). Login to comment 207 ABCB11 p.Gly982Arg ABCB11 p.Thr1210Pro ABCB11 p.Ala257Val A preliminary report from the same group finds that 4-PBA decreases pruritus and serum bile acid concentrations, and improves liver function within 3 months of treatment in 3 PFIC2 children harboring a least one missense mutation (A257V, G982R and T1210P) (Gonzales et al., 2012b). 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