ABCMdb

ABCB11 p.Gly855Arg

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Publications

PMID: 17264802 [PubMed] Lang C et al: "Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury."

No. Sentence Comment

5 Results Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Login to comment
7 The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional. Login to comment
63 The mutation G855R was introduced into the complete ABCB11 DNA sequence using the following primers: forward 50 -CCTCAGAAATAGCCCTAGAGCATT GACAACAAGAC-30 and reverse 50 -GTCTTGTTGTCA ATGCTCTAGGGCTATTTCTGAGG-30 . Login to comment
72 Transport assays ATP-dependent transport of labeled taurocholic acid was determined for reference ABCB11 and the A444V, M677 V, D676Y and G855R variants by a rapid filtration assay as described [26]. Login to comment
97 Chemical classification of all causative drugs revealed that the most prominent structures were the b-lactam ring of antibacterials in Fig. 2 Extracellular V284A V444A G855R R698H D676Y M677V Cytoplasm Secondary structure of bile salt export pump (BSEP) with nonsynonymous coding region variants. Login to comment
119 Two nonsynonymous changes were specific for the collective of patients with DC (exon 17: 2026G > T-D676Y and exon 21: 2563G > A-G855R). Login to comment
121 23) and the G855R mutation was observed in a heterozygous patient taking ethinylestradiol/gestagen for hormonal contraception (no. Login to comment
129 Sequencing of the grandmother revealed heterozygosity for the ABCB11 mutation at position G855R, which was also found in our index patient. Login to comment
158 Comparable protein amounts were detected for the alanine and valine containing constructs in position 444 (Fig. 5a), while expression levels of the M677V, D676Y and G855R variants amounted to 40, 60 and 20% of expression levels of reference BSEP (Fig. 6a), respectively. Login to comment
161 Furthermore, adjusted taurocholate transport activities for M677V and D676Y were similar to reference BSEP, whereas hardly any transport activity was seen with the G855R construct (Fig. 6c). Login to comment
174 The affected patients were heterozygous carriers of these mutations and developed cholestasis under intake of fluvastatin (D676Y) and ethinylestradiol/gestodene (G855R), respectively. Login to comment
175 No taurocholate transport activity could be detected for the G855R-containing construct and, very interestingly, the carrier of this mutant had a family history of hormonal cholestasis in two female family members. Login to comment
179 While the heterozygous state for the G855R mutation is probably sufficient to maintain bile salt secretion under normal conditions, our data readily explain the functional failure under certain circumstances, such as drug intake or hormonal challenges. Login to comment
194 Normalizedtransportactivity (in%ofref.BSEP) A 0 20 40 60 80 100 120 Ref. BSEP D676Y G855RM677V 140 Bile salt export pump (BSEP) expression and taurocholate transport in Sf9 membrane vesicles, expressing reference BSEP and the D676Y, M677V and the G855R constructs. Login to comment
195 (a) Expression levels of the D676Y, the M677V and the G855R constructs amounted to 60, 40 and 20% of reference BSEP, respectively. Login to comment
210 Third, the family history in the patient with the ABCB11 G855R mutation supports a common pathomechanism for certain forms of DC and intrahepatic cholestasis of pregnancy, which has already been observed for ABCB4-related forms of cholestasis [21]. Login to comment

PMID: 18987030 [PubMed] Dixon PH et al: "Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy."

No. Sentence Comment

2 Methods: ABCB11 variation in ICP was investigated by screening for five mutant alleles (E297G, D482G, N591S, D676Y and G855R) and the V444A polymorphism (c.1331T.C, rs2287622) in two ICP cohorts (n = 333 UK, n = 158 continental Europe), and controls (n = 261) for V444A. Login to comment
6 N591S was present in two patients; D676Y and G855R were not observed. Login to comment
19 This was initially proposed in the Finnish population following analysis of a two SNP (single nucleotide polymorphism) haplotype in 57 cases.30 However, a subsequent study in a larger cohort of 142 ICP cases failed to replicate the initial findings, leaving the role of BSEP open to question.31 A recent study of the entire coding region of the BSEP gene identified a single potential mutation (N591S) in a cohort of 21 women with ICP.32 In addition, a polymorphism (c.1331C.T, V444A, rs2287622) possibly affecting BSEP expression has been suggested to play a role in ICP32 33 and has recently been reported to be associated with drug-induced cholestasis (DIC).34 This association has been replicated recently in a slightly larger cohort.24 We sought to clarify the role of ABCB11 mutations in predisposition to ICP by screening a large cohort of patients for the two common mutant alleles, together with the N591S mutation found previously in a case of ICP32 and the two recently described mutations (D676Y and G855R) associated with DIC.34 We also genotyped the V444A polymorphism in the largest case/control study to date in ICP. Login to comment
48 RESULTS Sequencing DNA sequence was generated for the UK ICP cohort (333 patients) for exons 9 and 14 which contain the common European mutations E297G and D482G, together with exons 15, 17 and 21 containing the previously described ICP-linked mutation (N591S) and the two DIC-linked mutations (D676Y and G855R), respectively. Login to comment

PMID: 20422497 [PubMed] Pauli-Magnus C et al: "Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy."

No. Sentence Comment

84 Specifically, a heterozygous p.G855R mutation in BSEP leading to highly impaired taurocholate transport was associated with noninflammatory cholestasis and highly elevated serum bile acid levels in a young patient under the first use of an oral ethinylestradiol/gestodene combination for contraception.115 Interestingly, the mother and the maternal grandmother of the patient, who carried the same mutation had a history of ICP. Login to comment

PMID: 20103563 [PubMed] Klaassen CD et al: "Xenobiotic, bile acid, and cholesterol transporters: function and regulation."

No. Sentence Comment

6485 Three highly conserved mutants/variants (V444A, D676Y, G855R) strongly associate with susceptibility to drug-induced cholestasis (Table 14) (Lang et al., 2007). Login to comment
6508 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB11 BSEP N.D. G238V N.D. Intracellular A890G E297G 2 Intracellular N.D. C336S ↔ Normal G1296C R432T 2 Reduced T1331C V444A ↔ Normal/Reduced A1445G D482G 2 Normal/Reduced G2026T D676Y 2 Reduced G2563A G855R 2 Reduced G2944A G982R 2 Intracellular C3457T R1153C 2 Intracellular G3803A R1268Q 2 Intracellular searchers were able to identify functional roles for Mrp2 using rats lacking this transporter (Eisai hyperbilirubinemic rats on a Sprague-Dawley background and transport-deficient (TR-) on a Wistar background) (Paulusma et al., 1996; Ito et al., 1997). Login to comment

PMID: 22795478 [PubMed] Kubitz R et al: "The bile salt export pump (BSEP) in health and disease."

No. Sentence Comment

185 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