ABCMdb

ABCB11 p.Asp676Tyr

Reviews:	p.Asp676Tyr !
Predicted by SNAP2:	A: N (66%), C: N (57%), E: N (87%), F: D (53%), G: N (61%), H: N (66%), I: N (66%), K: N (72%), L: N (61%), M: N (57%), N: N (72%), P: N (53%), Q: N (78%), R: N (57%), S: N (82%), T: N (82%), V: N (57%), W: D (75%), Y: N (53%),
Predicted by PROVEAN:	A: N, C: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N,

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[hide] Mutations and polymorphisms in the bile salt expor... Pharmacogenet Genomics. 2007 Jan;17(1):47-60. Lang C, Meier Y, Stieger B, Beuers U, Lang T, Kerb R, Kullak-Ublick GA, Meier PJ, Pauli-Magnus C
Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury.
Pharmacogenet Genomics. 2007 Jan;17(1):47-60., [PMID:17264802]

Abstract [show]
OBJECTIVES: Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms. METHODS: ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay. 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)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional. CONCLUSION: In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition.

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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
62 Amino acid exchanges were introduced by site-directed mutagenesis, using the Quickchange Site-Directed Mutagenesis Kit from Stratagene (La Jolla, California, USA) with the following mutagenesis primer pairs: (i) replacement of alanine to valine at position 444: forward 50 -CTAAAT GACCTCAACATGGTCATTAAACCAGGGG-30 and reverse 50 -CCCCTGGTTTAATGACCATGTTGAGGTCAT TTAG-30 ; (ii) replacement of aspartic acid to tyrosine at position 676: forward 50 -GGATGCAACTGAAGATTA CATGCTTGCGAGG-30 and reverse 50 -CCTCGCAAG CATGTAATCTTCAGTTGCATCC-30 ; (iii) replacement of methionine to valine at position 677: forward 50 -GCAACTGAAGATGACGTGCTTGCGAGGACC-30 and reverse 50 -GGTCCTCGCAAGCACGTCATCTTCAGT TGC-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
78 Furthermore, transport activity of taurocholic acid and its inhibition by fluvastatin was measured in reference BSEP and the D676Y construct in the presence and absence of ATP, allowing the estimation of IC50 values. Login to comment
82 All calculations Table 3 ABCB11 (BSEP) variant sites in drug-induced liver injury Amplicon DNA position cDNA position Nucleotide reference Nucleotide variant AA change AF DC (n = 46) AF DH (n = 26) AF controls (n = 190) Amplicon - 1 Intron - 1 - 2080 CTCT delCTCT 0.02 0.00 0.10 Amplicon - 1 Intron - 1 - 1952 T C 0.43 0.54 0.48 Amplicon - 1 Intron - 1 - 1820 G A 0.09 0.04 0.10 Amplicon - 1 Intron - 1 - 1746 G A 0.09 0.04 0.10 Amplicon - 1 Intron - 1 - 1275 G A 0.07 0.04 0.03 Amplicon - 1 Intron - 1 - 1239 G A 0.24 0.35 0.30 Amplicon - 1 Intron - 1 - 1155 T C 0.57 0.65 0.62 Amplicon - 1 Intron - 1 - 1009 T C 0.09 0.04 0.02 Amplicon - 1 Intron - 1 - 837 A G 0.02 0.00 0.02 Amplicon 2 Intron 1 - 50 G A 0.09 0.04 0.02 Amplicon 4 Intron 3 - 20 T C 0.09 0.08 0.07 Amplicon 5 Exon 5 270 T C syn 0.09 0.04 0.03 Amplicon 5 Intron 5 8 G A 0.00 0.13 0.05 Amplicon 9 Exon 9 851 T C V284A_c 0.02 0.00 0.01 Amplicon 10 Intron 9 - 69 C T 0.00 0.04 0.05 Amplicon 10 Intron 9 - 31 C T 0.00 0.04 0.05 Amplicon 10 Intron 9 - 17 G A 0.00 0.04 0.05 Amplicon 10 Intron 9 - 15 A G 0.77 0.65 0.70 Amplicon 10 Exon 10 957 A G syn 0.00 0.04 0.05 Amplicon 13 Exon 13 1331 T C V444A_c 0.76 0.50 0.59 Amplicon 13 Intron 13 70 C T 0.76 0.50 0.59 Amplicon 14 Intron 14 32 T C 0.75 0.54 0.60 Amplicon 17 Exon 17 2026 G T D676Y 0.02 0.00 0.00 Amplicon 17 Exon 17 2029 A G M677V 0.00 0.04 0.04 Amplicon 18 Exon 18 2093 G A R698H_c 0.02 0.00 0.01 Amplicon 18 Exon 18 2134 T C syn 0.02 0.00 0.01 Amplicon 19 Intron 18 - 17 C A 0.52 0.62 0.43 Amplicon 20 Intron 19 - 17 T C 0.66 0.75 0.69 Amplicon 21 Exon 21 2563 G A G855R_c 0.02 0.00 0.00 Amplicon 24 Exon 24 3084 G A syn 0.50 0.62 0.46 Amplicon 28 Intron 27 - 34 G A 0.48 0.62 0.45 cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number NM_003742.2. 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
120 The D676Y mutation was observed in a heterozygous patient taking fluvastatin (no. 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
162 In addition, fluvastatin could be shown to inhibit transport activity of reference BSEP and of the D676Y construct. Login to comment
166 56 Pharmacogenetics and Genomics 2007, Vol 17 No 1 and D676Y, respectively (log IC50 1.70 and 1.78 for reference BSEP and D676Y, respectively) (Fig. 7). 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
187 BSEP and MDR3 mutations in drug-induced liver injury Lang et al. 57 In contrast, functional characterization of taurocholate transport activity showed unaltered transport for the D676Y construct, which could be inhibited by fluvastatin in a concentration-dependent manner. Login to comment
189 As taurocholate transport activity and BSEP inhibition characteristics of the D676Y mutation were similar to those of reference BSEP, however, the occurrence of cholestasis in this patient is not explained by our findings. Login to comment
191 Fig. 6 150 kDa Ref. BSEP M 677V D676Y G 855R M ock transf. Login to comment
192 0 10 20 30 40 50 60(b) (a) (c) Taurocholateuptake (pmol/mgprotein×min) Ref. BSEP D676Y G855RM677V Mock transf. 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

[hide] Contribution of variant alleles of ABCB11 to susce... Gut. 2009 Apr;58(4):537-44. Epub 2008 Nov 5. Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C
Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy.
Gut. 2009 Apr;58(4):537-44. Epub 2008 Nov 5., [PMID:18987030]

Abstract [show]
BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) has a complex aetiology with a significant genetic component. ABCB11 encodes the bile salt export pump (BSEP); mutations cause a spectrum of cholestatic disease, and are implicated in the aetiology of ICP. 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. PCR primers were used to amplify and sequence patient and control DNA. The molecular basis for the observed phenotypes was investigated in silico by analysing the equivalent residues in the structure of the homologous bacterial transporter Sav1866. RESULTS: E297G was observed four times and D482G once. N591S was present in two patients; D676Y and G855R were not observed. The V444A polymorphism was associated with ICP (allelic analysis for C vs T: OR 1.7 (95% CI 1.4 to 2.1, p<0.001)). In addition, CC homozygotes were more likely to have ICP than TT homozygotes: OR 2.8 (95% CI 1.7 to 4.4 p<0.0001). Structural analyses suggest that E297G and D482G destabilize the protein fold of BSEP. The molecular basis of V444A and N591S was not apparent from the Sav1866 structure. CONCLUSIONS: Heterozygosity for the common ABCB11 mutations accounts for 1% of European ICP cases; these two mutants probably reduce the folding efficiency of BSEP. N591S is a recurrent mutation; however, the mechanism may be independent of protein stability or function. The V444A polymorphism is a significant risk factor for ICP in this population.

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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

[hide] Genetic determinants of drug-induced cholestasis a... Semin Liver Dis. 2010 May;30(2):147-59. Epub 2010 Apr 26. Pauli-Magnus C, Meier PJ, Stieger B
Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy.
Semin Liver Dis. 2010 May;30(2):147-59. Epub 2010 Apr 26., [PMID:20422497]

Abstract [show]
Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 ( ABCB4) and BSEP ( ABCB11) have been associated with intrahepatic cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired cholestasis, as well as pathogenetic mechanisms leading to intrahepatic cholestasis of pregnancy or drug-induced cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of cholestasis.

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125 Specifically, full-length sequencing of ABCB11 and ABCB4 revealed a heterozygous p.D676Y mutation in BSEP observed in a patient taking fluvas- tatin and a heterozygous p.I764L mutation in MDR3 observed in a patient taking risperidone:115 both suffered from hepatocellular cholestasis. Login to comment

[hide] Xenobiotic, bile acid, and cholesterol transporter... Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26. Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26., [PMID:20103563]

Abstract [show]
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

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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

[hide] The bile salt export pump (BSEP) in health and dis... Clin Res Hepatol Gastroenterol. 2012 Dec;36(6):536-53. doi: 10.1016/j.clinre.2012.06.006. Epub 2012 Jul 12. 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., [PMID:22795478]

Abstract [show]
The bile salt export pump (BSEP) is the major transporter for the secretion of bile acids from hepatocytes into bile in humans. Mutations of BSEP are associated with cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 2 (PFIC-2), benign recurrent intrahepatic cholestasis type 2 (BRIC-2) and genetic polymorphisms are linked to intrahepatic cholestasis of pregnancy (ICP) and drug-induced liver injury (DILI). Detailed analysis of these diseases has considerably increased our knowledge about physiology and pathophysiology of bile secretion in humans. This review focuses on expression, localization, and function, short- and long-term regulation of BSEP as well as diseases association and treatment options for BSEP-associated diseases.

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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