ABCMdb

PMID: 22795478

Kubitz R, Droge C, Stindt J, Weissenberger K, Haussinger D
The bile salt export pump (BSEP) in health and disease.
Clin Res Hepatol Gastroenterol. 2012 Dec;36(6):536-53. doi: 10.1016/j.clinre.2012.06.006. Epub 2012 Jul 12., [PubMed]

Sentences

No. Mutations Sentence Comment

165 ABCB11 p.Val444Ala A role of BSEP for the development of CC was also suggested on the basis of an association to the BSEP polymorphism p.V444A in a study of 172 CC-patients [127]. Login to comment 173 ABCB11 p.Asp482Gly ABCB11 p.Arg1231Gln ABCB11 p.Thr586Ile ABCB11 p.Ser1154Pro ABCB11 p.Arg1153His ABCB11 p.Ser1144Arg By the use of an in vitro minigene approach, interference with splicing was shown for c.1445A > G (p.D482G), c.1757C > T (p.T586I), c.3432C > A (p.S1144R), c.3458G > A (p.R1153H), c.3460T > C (p.S1154P), c.3691C > T (p.R1231 W) and c.3692G > A (p.R1231Q) [132]. Login to comment 176 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Val444Ala Interestingly, the very common polymorphism p.V444A of BSEP (allele frequency > 50%), which may occur isoallelic to mutations, strongly increases ERAD, as shown in expression studies of cloned BSEP [23]; thirdly, a decrease in half-life may shorten residency of BSEP at the canalicular membrane as shown for the two common PFIC-2 mutations p.E297G and p.D482G in Madin-Darby canine kidney (MDCK) cells [134]. Login to comment 182 ABCB11 p.Glu297Gly ABCB11 p.Glu186Gly ABCB11 p.Arg432Thr ABCB11 p.Arg1050Cys ABCB11 p.Arg1128His ABCB11 p.Ala926Pro ABCB11 p.Gly1004Asp ABCB11 p.Thr923Pro ABCB11 p.Ala570Thr Mutations such as p.E186G, p.E297G, p.R432T, p.A570T, p.T923P, p.A926P, p.G1004D, p.R1050C and p.R1128H have been described in BRIC-2 patients [137,140-142] (Table 1). Login to comment 185 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Glu297Gly ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Val444Ala ABCB11 p.Arg1268Gln ABCB11 p.Gly238Val ABCB11 p.Arg1153Cys ABCB11 p.Gly982Arg ABCB11 p.Cys336Ser ABCB11 p.Arg575* ABCB11 p.Glu636Gly ABCB11 p.Arg487His ABCB11 p.Ala865Val ABCB11 p.Trp330* ABCB11 p.Met677Val ABCB11 p.Ser194Pro ABCB11 p.Arg698His ABCB11 p.Val284Ala ABCB11 p.Gly260Asp ABCB11 p.Asn591Ser ABCB11 p.Arg415Gln ABCB11 p.Glu186Gly ABCB11 p.Arg1090* ABCB11 p.Thr619Ala ABCB11 p.Arg616Gly ABCB11 p.Arg299Lys ABCB11 p.Ile206Val ABCB11 p.Arg958Gln ABCB11 p.Arg432Thr ABCB11 p.Ile541Leu ABCB11 p.Tyr472* ABCB11 p.Tyr772* ABCB11 p.Arg1050Cys ABCB11 p.Arg1128His ABCB11 p.Ala926Pro ABCB11 p.Ser593Arg ABCB11 p.Gly1004Asp ABCB11 p.Gly1004Asp ABCB11 p.Thr923Pro ABCB11 p.Ile498Thr ABCB11 p.Ile498Thr ABCB11 p.Lys461Glu ABCB11 p.Val284Leu ABCB11 p.Ser56Leu ABCB11 p.Glu592Gln ABCB11 p.Gln558His ABCB11 p.Leu339Val ABCB11 p.Arg1057* ABCB11 p.Ala570Thr ABCB11 p.Ala570Thr ABCB11 p.Glu1186Lys ABCB11 p.Gly855Arg ABCB11 p.Asp676Tyr ABCB11 p.Phe540Leu ABCB11 p.Met183Val ABCB11 p.Trp493* ABCB11 p.Arg303Lys ABCB11 p.Arg303Lys ABCB11 p.Leu827Ile ABCB11 p.Arg487Pro ABCB11 p.Asn490Asp ABCB11 p.Glu297Lys ABCB11 p.Val481Glu ABCB11 p.Gly562Asp ABCB11 p.Arg517His ABCB11 p.Thr463Ile ABCB11 p.Arg470Gln ABCB11 p.Gly410Asp ABCB11 p.Ala390Pro ABCB11 p.Ala390Pro ABCB11 p.Asn515Thr ABCB11 p.Gln466Lys ABCB11 p.Glu135Lys ABCB11 p.Phe548Tyr ABCB11 p.Glu137Lys ABCB11 p.Glu137Lys ABCB11 p.Ile512Thr ABCB11 p.Gly327Glu ABCB11 p.Gln312His ABCB11 p.Thr242Ile ABCB11 p.Ala167Val ABCB11 p.Leu198Pro ABCB11 p.Leu198Pro ABCB11 p.Leu198Pro ABCB11 p.Leu50Ser ABCB11 p.Arg313Ser ABCB11 p.Thr586Ile ABCB11 p.Glu709Lys ABCB11 p.Arg1128Cys ABCB11 p.Thr1210Pro ABCB11 p.Thr859Arg ABCB11 p.Ile627Thr ABCB11 p.Leu1242Ile ABCB11 p.Ser1154Pro ABCB11 p.Ala588Val ABCB11 p.Arg1153His ABCB11 p.Ser1144Arg ABCB11 p.Gly1116Arg ABCB11 p.Gly1116Arg ABCB11 p.Asn1211Asp ABCB11 p.Tyr818Phe ABCB11 p.Ala1110Glu ABCB11 p.Thr655Ile ABCB11 p.Thr655Ile ABCB11 p.Thr655Ile ABCB11 p.Leu1197Gly ABCB11 p.Arg948Cys ABCB11 p.Arg948Cys ABCB11 p.Asn979Asp ABCB11 p.Gln121Lys ABCB11 p.Arg487Leu ABCB11 p.Arg223Cys ABCB11 p.Arg303Gly ABCB11 p.Leu581Phe ABCB11 p.Gln869Pro ABCB11 p.Gly499Glu ABCB11 p.Ala167Thr ABCB11 p.Cys107Arg ABCB11 p.Gly1292Val ABCB11 p.Arg415* ABCB11 p.Gly188Trp ABCB11 p.Gln1058* ABCB11 p.Gln702* ABCB11 p.Tyr354* ABCB11 p.Ser226Leu ABCB11 p.Ile420Thr ABCB11 p.Met62Lys ABCB11 p.Ile528* ABCB11 p.Ile112Thr ABCB11 p.Asp549Val ABCB11 p.Ile182Lys ABCB11 p.Met183Thr ABCB11 p.Gly455Glu ABCB11 p.Trp114Arg ABCB11 p.Arg470* ABCB11 p.Tyr1041* ABCB11 p.Arg387His ABCB11 p.Ser699Pro ABCB11 p.Gly1116Phe ABCB11 p.Gly19Arg ABCB11 p.Gly877Arg ABCB11 p.Cys68Tyr ABCB11 p.Ile541Thr ABCB11 p.Arg928* ABCB11 p.Asp1243Gly ABCB11 p.Ser901Arg ABCB11 p.Cys1083Tyr ABCB11 p.Leu1055Pro ABCB11 p.Gly1116Glu ABCB11 p.Gly766Arg ABCB11 p.Val1212Phe ABCB11 p.Val43Ile ABCB11 p.Tyr157Cys ABCB11 p.Thr1029Lys ABCB11 p.Tyr472Cys ABCB11 p.Gly1298Arg ABCB11 p.Arg520* ABCB11 p.Glu1302* ABCB11 p.Ala382Gly ABCB11 p.Met217Arg ABCB11 p.Ser874Pro ABCB11 p.Gln546Lys ABCB11 p.Arg696Gln ABCB11 p.Ile1183Thr ABCB11 p.Leu1006Phe ABCB11 p.Asp440Glu ABCB11 p.Ser701Pro ABCB11 p.Ala1044Pro ABCB11 p.Ser1114Arg ABCB11 p.Asn1009His ABCB11 p.Glu96* ABCB11 p.Met677Leu ABCB11 p.Gly374Ser ABCB11 p.His423Arg ABCB11 p.Gly1032Arg ABCB11 p.Trp342Gly ABCB11 p.Gly648Val ABCB11 p.Thr965Ser ABCB11 p.Val444Gly ABCB11 p.Arg698Cys ABCB11 p.Arg1235* ABCB11 p.Gly295Cys ABCB11 p.Met123Thr ABCB11 p.Val444Asp ABCB11 p.Gly295Arg ABCB11 p.Gly295Ser ABCB11 p.Gln791* ABCB11 p.Ala459Val ABCB11 p.Ala1283Val ABCB11 p.Thr87Arg ABCB11 p.Arg128His ABCB11 p.Asn1173Asp ABCB11 p.Val597Met ABCB11 p.Gln1215* ABCB11 p.Trp330Arg ABCB11 p.Lys1145Asn ABCB11 p.Val1147* ABCB11 p.Ser1120Asn ABCB11 p.Ile939Met ABCB11 p.Ala865Asp ABCB11 p.Ala865Gly PFIC BRIC/NFC ICP Other liver diseases Genetic variants without disease association Missense mutations M1V C336S D549V L1055P E135K E137K T87R V43I S701P G19R W342G G556R C1083Y E137K L198P M123T S56L L712L L50S A382G G562D A1110E E186G E297G S194P Q121K A865D M62K R387H A570T S1114R L198P R415Q L198P R128H A865G C68Y A390P L581F G1116E E297G V444A G260D I206V S874P C107R G410D A588V G1116F G374S D482G E297K V284A I939M I112T L413W S593R G1116R A390P N591S V444A G295C R958Q W114R I420T I627T S1120N R432T T655I T510T G295R F959C Y157C D440E E636G R1128C V444A T655I G295S F959V A167T G455E R698C S1144R I498T D676Y R299K T965S A167V K461E S699P R1153C A570T P710P R303K F971L I182K T463I E709K R1153H T586I L827I L339V F971Y M183T Q466K G758R S1154P G648V G855R H423R L1006F M183V R470Q G766R N1173D T655I E1186K V444A N1009H G188W Y472C Y818F T1210P T923P V444D K1145N M217R V481E R832C N1211D A926P V444G I1183T R223C D482G R832H V1212F R948C A459V S226L R487H T859R R1231Q G1004D I468I G238V R487P A865V R1231W R1050C R487L T242I N490D Q869P L1242I G1116R Q546K A257G I498T G877R D1243G R1128H Q558H V284L G499E S901R R1268Q L1197G E592Q E297G I512T R948C A1283V R1231Q V597M R303G N515T N979D G1292V R616G R303K R517H G982R G1298R T619A Q312H F540L G1004D M677L R313S I541L T1029K M677V G327E I541T G1032R R696Q W330R F548Y A1044P R698H Nonsense mutations (premature stop-codons) S25X Y472X Y772X R1090X E96X W493X Q791X V1147X W330X R520X R928X Q1215X Y354X I528X Y1041X R1235X R415X R575X R1057X E1302X R470X Q702X Q1058X Table 1 (Continued) PFIC BRIC/NFC ICP Other liver diseases Genetic variants without disease association Splice site mutations 76 + 3G > T 908 + 1delG 2178 + 1G > T 3057-2A > G Q159Q 77-1G > C 908 + 1G > T 2179-2A > G 3213 + 1delG Q361Q 99-1G > T 908 + 1G > A 2343 + 1G > T 3213 + 4A > G 150 + 3A > C 1435-13 -8del 2343 + 2T > C 3213 + 5G > A 390-1G > A 2012-8T > G 2611-2A > T 611 + 1G > A 2178 + 1G > A R1001R Deletions/insertions/frame shifts Q101Dfs8X L380Wfs18X G648Vfs5X Q1058Hfs38X F959Hfs1X T127Hfs6X A382 A388del K700Sfs12X I1061Vfs34X F959Gfs48X N199Ifs14X P456Pfs24X T919del L1165del L232Cfs9X H484Rfs5X K930Efs92X A1192Efs50X R303Sfs17X I528Sfs21X K930Efs79X T1256Tfs40X V368Rfs27X I610Qfs45X K969 K972del Synonymous variants without disease association R33R F90F L232L I416I G557G I876I A1028A K1145K D36D I134I Y269Y G418G V597V G937G K1070K R52R S136S Q312Q F427F A804A Y981Y T1086T D58D V195V G319G E395E A535A G817G G1004G A1110A The overview shows ࣈ 290 known variants of BSEP on the protein level, except splice site mutations, which are shown on cDNA level. Login to comment 192 ABCB11 p.Gly374Ser Figure 4 Membrane expression of wildtype bile salt export pump (BSEP) and BSEP-G374S in HEK293 cells. Login to comment 193 ABCB11 p.Gly374Ser (A) Wildtype BSEP-EYFP (BSEP-wt) and (B) BSEP-G374S-EYFP (green) were transfected in HEK293 cells. Login to comment 195 ABCB11 p.Gly374Ser While expression of Na+ -K+ -ATPase was not significantly different (C), total (D) and plasma membrane expression (E) of BSEP was significantly higher (*) in cells transfected with mutant BSEP-G374S as compared to wildtype BSEP. Login to comment 196 ABCB11 p.Gly374Ser Although G374S is associated with a severe cholestatic phenotype, there is no obvious trafficking defect. Login to comment 197 ABCB11 p.Ile498Thr ABCB11 p.Gly374Ser be a transition between BRIC-2 and PFIC-2 as shown for a patient compound heterozygous for p.I498T and c.2098delA [143] or siblings with the homozygous mutation p.G374S. Login to comment 200 ABCB11 p.Gly374Ser While an inverse correlation between the amount of BSEP at the plasma membrane and the severity of phenotypes has been described for other mutations [144] p.G374S showed an increased membrane expression of BSEP (as compared to wildtype BSEP) despite the severity of the phenotype (Weissenberger, H&#e4;ussinger, Kubitz, unpublished) (Fig. 4). Login to comment 208 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Asn591Ser A few ''common`` BSEP mutations (including p.E297G, p.D482G and p.N591S) have been detected in ICP-patients in heterozygous form and account for about 1.4% (7/491) of ICP-patients [150]. Login to comment 209 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly ABCB11 p.Asn591Ser Canalicular expression of BSEP with the ''typical`` ICP mutation p.N591S was higher than that of the BRIC-2 (p.A570 T, p.R1050 C) or PFIC-2 mutations (p.D482G, p.E297G) [144]. Login to comment 210 ABCB11 p.Asn591Ser Recently, a neonate has been described with homozygousity for p.N591S and, in addition, a homozygous mutation (p.H338Y) in the SLC27A5 gene. Login to comment 212 ABCB11 p.Asn591Ser ABCB11 p.Asn591Ser This child presented with liver fibrosis within the first year of life, while a sibling was free of symptoms although it had the same homozygous SLC27A5 mutation, while it was heterozygous for p.N591S [151], demonstrating a ''dose effect`` of N591S. Login to comment 213 ABCB11 p.Val444Ala Apart from rare mutations, the common BSEP polymorphism p.V444A (c.1331T > C, rs2287622, valine to alanine at position 444) has been linked to ICP. Login to comment 215 ABCB11 p.Val444Ala Contraceptive-induced cholestasis (CIC) is similar to ICP and presents with pruritus, and may be more strongly associated with p.V444A [153]. Login to comment 227 ABCB11 p.Val444Ala Drug-induced liver injury The common BSEP polymorphism p.V444A (c.1331T > C) is not only associated to ICP (see above), but predisposes for the development of drug-induced liver injury (DILI). Login to comment 229 ABCB11 p.Val444Ala The common explanation for the relation between p.V444A and ICP or DILI is a decreased expression of BSEP in the presence of the polymorphism as shown in a small cohort [132,163], whereas no differences in the transport kinetics of the two variants (valine or alanine at position 444 of BSEP) were observed [162]. Login to comment 235 ABCB11 p.Val444Ala However, BSEP expression may be severely reduced in MDR3- dependent ICP when p.V444A is present [167]. Login to comment 236 ABCB11 p.Val444Ala Furthermore, p.V444A may influence development of liver fibrosis in patients with chronic hepatitis C infection. Login to comment 239 ABCB11 p.Val444Ala The polymorphism p.V444A has a less stringent impact on HCV treatment as compared to IL-28B polymorphisms [170-173] and further studies are needed [174] to more precisely define the role of BSEP in interferon-based therapy regimens of HCV. Login to comment 241 ABCB11 p.Val444Ala In a recent study a higher prevalence of p.V444A was observed in CC-patients [127]. Login to comment 242 ABCB11 p.Val444Ala Restricted BSEP expression due to the genetic polymorphism p.V444A or due to BSEP mutations may result in altered biliary bile salt concentrations, which in turn may have an impact of cholangiocyte proliferation or apoptosis [175]. Login to comment