ABCMdb

ABCB11 p.Arg698His

ClinVar:	c.2093G>A , p.Arg698His N , Benign
Reviews:	p.Arg698Cys D p.Arg698His N
Predicted by SNAP2:	A: N (53%), C: D (85%), D: D (63%), E: D (85%), F: D (75%), G: D (63%), H: D (80%), I: D (53%), K: D (75%), L: D (59%), M: D (63%), N: N (57%), P: D (59%), Q: N (66%), S: N (78%), T: D (80%), V: D (59%), W: D (85%), Y: D (66%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: N, P: D, Q: N, S: N, T: N, V: D, W: D, Y: D,

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Publications
[hide] BSEP and MDR3 haplotype structure in healthy Cauca... Hepatology. 2004 Mar;39(3):779-91. Pauli-Magnus C, Kerb R, Fattinger K, Lang T, Anwald B, Kullak-Ublick GA, Beuers U, Meier PJ
BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis.
Hepatology. 2004 Mar;39(3):779-91., [PMID:14999697]

Abstract [show]
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are characterized by a cholestatic pattern of liver damage, also observed in hereditary or acquired dysfunction of the canalicular membrane transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein type 3 (MDR3, ABCB4). Controversy exists whether a genetically determined dysfunction of BSEP and MDR3 plays a pathogenic role in PBC and PSC. Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3. Sequencing spanned approximately 10,000 bp including promoter and coding regions as well as 50-350 bp of flanking intronic regions. In all, 46 and 45 variants were identified in BSEP and MDR3, respectively. No differences between the groups were detected either in the total number of variants (BSEP: control group: 37, PBC: 37, PSC: 31; and MDR3: control group: 35; PBC: 32, PSC: 30), or in the allele frequency of the common variable sites. Furthermore, there were no significant differences in haplotype distribution and linkage disequilibrium. In conclusion, this study provides an analysis of BSEP and MDR3 variant segregation and haplotype structure in a Caucasian population. Although an impact of rare variants on BSEP and MDR3 function cannot be ruled out, our data do not support a strong role of BSEP and MDR3 genetic variations in the pathogenesis of PBC and PSC.

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68 Nonsynonymous changes observed as singletons or doubletons encoded the following amino acid changes: S194P, G260D, V284A, R698H, Table 1. Login to comment
73 Alignment of all mammalian BSEP sequences indicated that 5 of the 6 nonsynonymous coding variants were in codons for an evolutionarily conserved amino acid (S194P, V284A, V444A, R698H, and A1228V) (Table 2). Login to comment

[hide] Genetic variability, haplotype structures, and eth... Drug Metab Dispos. 2006 Sep;34(9):1582-99. Epub 2006 Jun 8. Lang T, Haberl M, Jung D, Drescher A, Schlagenhaufer R, Keil A, Mornhinweg E, Stieger B, Kullak-Ublick GA, Kerb R
Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11).
Drug Metab Dispos. 2006 Sep;34(9):1582-99. Epub 2006 Jun 8., [PMID:16763017]

Abstract [show]
Biliary excretion of bile salts and other bile constituents from hepatocytes is mediated by the apical (canalicular) transporters P-glycoprotein 3 (MDR3, ABCB4) and the bile salt export pump (ABCB11). Mutations in ABCB4 and ABCB11 contribute to cholestatic diseases [e.g., progressive familial intrahepatic cholestasis 2 (PFIC2), PFIC3, and intrahepatic cholestasis of pregnancy], and our objective was to establish genetic variability and haplotype structures of ABCB4 and ABCB11 in healthy populations of different ethnic backgrounds. All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin. In total, 76 and 86 polymorphisms were identified in ABCB4 and ABCB11, respectively; among them, 14 and 28 exonic polymorphisms, and 8 and 10 protein-altering variants, of which 4 were predicted to have functional consequences. Both genes showed substantial ethnic differences with respect to allele number, frequency of common and population-specific sites, and patterns of linkage disequilibrium. Population genetic analysis suggested some selective pressure against changes in the protein, supporting the important endogenous role of these transporters. Haplotype variability was greater in ABCB11 than in ABCB4. An ABCB11 promoter haplotype was associated with significant decrease of activity compared with wild type. Our results contribute to a better understanding of the molecular basis and of ethnic differences in drug response, and provide a valuable tool for future research on the heredity of cholestatic liver injury.

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67 The numbers 1 to 53 in the variant ID column indicate all variants included in haplotype analysis and linkage disequilibrium estimation. Variant ID 5Ј Sequence Genetic Variation 3Ј Sequence Region Amino Acid Change CA AA JA Total n % n % n % n % 54 GTAGTCACA g.-15595CϾT TTTCAGAGC Promoter 186 0.5 92 0.0 88 0.0 366 0.3 1 ACACTCTCT g.-15281_-15278 delCTCT CACACAGCA Promoter 186 10.2 92 4.3 86 26.7 364 12.6 2 CCCCCTCCC g.-15150TϾC GCCCCCAGA Promoter 148 48.0 76 39.5 92 25.0 316 58.9 3 TGACTGTAG g.-15018GϾA GACCACAAC Promoter 158 10.1 78 0.0 92 29.3 328 13.1 4 ATTAAGCAC g.-14944GϾA ATCAACTCA Promoter 198 10.1 72 0.0 96 28.1 366 12.8 5 CTATTGGGA g.-14589AϾT TCTTTTCCC Promoter 198 0.0 90 2.2 88 0.0 376 0.5 55 TGAAGCAAA g.-14524AϾT TTTTTTTCC Promoter 198 0.0 90 1.1 88 0.0 376 0.3 6 TACATTTGC g.-14473GϾA TCAACTCAG Promoter 198 2.5 90 18.9 88 0.0 376 8.8 7 TTGCATAGA g.-14437GϾA GAAACATCT Promoter 198 29.8 94 22.3 96 14.6 388 24.2 8 ATTATATGT g.-14353TϾC ATAATTTTG Promoter 190 61.6 80 92.5 88 75.0 358 71.8 56 ATAAACCAT g.-14316CϾA TTATACATA Promoter 192 0.5 80 0.0 88 0.0 360 0.3 9 ACCATCTTA g.-14312TϾC ACATAAATT Promoter 192 0.0 80 0.0 88 3.4 360 0.8 57 ATAAATTCC g.-14300AϾT ATAGAGAAA Promoter 192 0.0 80 1.3 88 0.0 360 0.3 10 TTTAATTTC g.-14207TϾC GCAAATTAA Promoter 190 2.1 80 17.5 88 10.2 358 7.5 11 TTGTTACAC g.-14104CϾT TTAGGAGGA Promoter 196 2.6 92 0.0 96 0.0 384 1.3 12 CATGATAGC g.-14035AϾG CCCAACTCC Promoter 194 1.5 92 1.1 96 0.0 382 1.0 58 AAGGCTGGA g.-13910GϾA TGAGAGGCA Promoter 202 0.0 94 1.1 96 0.0 392 0.3 13 AGAGGAAGA g.-13814GϾA GCAGCACAA Promoter 194 0.0 94 6.4 88 0.0 376 1.6 14 GCACAAATA g.-13801TϾC ATTGGAGCT Promoter 194 1.5 94 0.0 88 0.0 376 0.8 15 CTCAGACTT g.-13662TϾC TGAGCAAGG Promoter 192 0.0 94 7.4 86 0.0 372 1.9 83 TTAAAGGTA g.-13523͓T͔9 GTCTTGTTA Promoter 200 10.0 90 11.1 96 28.1 386 14.8 84 TTAAAGGTA g.-13523͓T͔10 GTCTTGTTA Promoter 200 9.0 90 18.9 96 6.3 386 10.6 85 TTAAAGGTA g.-13523͓T͔11 GTCTTGTTA Promoter 200 65.0 90 53.3 96 45.8 386 57.5 86 TTAAAGGTA g.-13523͓T͔12 GTCTTGTTA Promoter 200 16.0 90 16.7 96 19.8 386 17.1 59 CTGGGCCAG g.-13595GϾA AGCATCTGG Promoter 198 0.0 94 1.1 96 0.0 388 0.3 16 CAAGCACAC g.-13333TϾC CTGTGTTTG Promoter 196 0.0 76 0.0 96 3.9 368 0.9 17 ATGTTTCTC g.-13297GϾA TATGTCACT Promoter 196 0.0 76 3.9 96 0.0 368 0.8 60 TCCACAGTG g.-13142GϾA AGTCCATTA Exon 1 194 0.0 76 0.0 92 1.1 362 0.3 18 TTGATTAAA g.-77GϾA AAGAAAGAA Intron 1 202 2.5 88 11.4 90 12.2 380 6.8 19 ATTTTTTTT g.1319delT CTGACAGAT Intron 2 198 0.0 88 3.4 92 0.0 378 0.8 20 TTTAAATCC g.3754TϾC TATGTTTTT Intron 3 198 7.1 62 32.3 88 12.5 348 12.9 21 GTTACAAGA g.3781TϾC GAGAAGAAA Exon 4 D36D 198 0.0 62 0.0 88 26.1 348 6.6 22 GAATCTAGT g.4542AϾT ACTAAATTA Intron 4 184 0.0 90 0.0 92 2.2 366 0.5 61 CAAGTTTCG g.4621GϾA TTTTCTTCA Exon 5 R52R 184 0.0 90 1.1 92 0.0 366 0.3 23 AGATGTTTT g.4735TϾC ATTGACTAC Exon 5 F90F 184 2.7 90 13.3 92 12.0 366 7.7 24 GGGTAGGTT g.4862GϾA TTTTTGTTT Intron 5 182 4.9 90 2.2 94 0.0 366 3.0 25 GCTGAACAT g.21416CϾT GAGAGCGAA Exon 6 I134I 192 0.0 86 18.6 88 0.0 366 4.4 26 AGCTCCTCC g.21507GϾA TATAATTTA Intron 6 196 0.0 92 18.5 92 0.0 380 4.5 27 ACAATGAGA g.21554TϾG GCAATGTGT Intron 6 196 0.0 92 0.0 92 4.3 380 1.1 62 TGTATTGAA g.22567AϾT GTACTTTCT Intron 6 198 0.5 94 0.0 94 0.0 386 0.3 63 TTTGAATGA g.24203TϾC CAAATTCAG Intron 7 192 0.5 90 0.0 94 0.0 376 0.3 64 TCTAGTGAT g.24248AϾG TTAATAAAA Exon 8 I206V 194 0.0 90 1.1 96 0.0 380 0.3 28 TACGGACTA g.27224TϾC GAGCTGAAG Exon 9 Y269Y 200 0.0 80 0.0 96 27.1 376 6.9 65 CTGATGAAG g.27268TϾC CATTTCATC Exon 9 V284A 200 0.5 80 0.0 96 0.0 376 0.3 66 GTGAGAAAA g.27313GϾA AGAGGTTGA Exon 9 R299K 200 0.0 80 0.0 96 1.0 376 0.3 29 ACTGCATCA g.31773CϾT GGCCTGTTT Intron 9 178 5.1 70 1.4 48 0.0 296 3.4 30 TGTTTCTGC g.31811CϾT GAAATTGAC Intron 9 196 4.6 72 4.2 86 0.0 354 3.4 31 TTGACTCAA g.31825GϾA CATTTTGTC Intron 9 196 4.6 72 26.4 86 0.0 354 7.9 32 GACTCAAGC g.31827AϾG TTTTGTCTT Intron 9 196 70.4 72 84.7 86 90.7 354 78.2 33 TAGAAAAGG g.31890AϾG ATAGTGATG Exon 10 G319G 196 4.6 72 26.4 86 0.0 354 7.9 34 GACTTATTG g.32034AϾT CCGAGACAT Intron 10 196 0.0 66 4.5 82 0.0 344 0.9 67 CCTCAGTGT g.38161CϾT ATAGTAGGA Exon 11 V366V 196 0.0 88 1.1 94 0.0 378 0.3 35 CATTTTTGA g.38248GϾA ACAATAGAC Exon 11 E395E 196 0.0 88 8.0 96 0.0 380 1.8 36 GCAGAGATA g.41348CϾT GCCAAAGAT Intron 11 198 0.0 72 2.8 80 0.0 350 0.6 37 CCACAAATT g.41622GϾT CTCATTTTC Intron 12 196 1.0 72 0.0 74 0.0 342 0.6 38 CAGTGACAA g.44255delT CTGAACTTT Intron 12 190 0.0 94 2.1 92 0.0 376 0.5 39 TCAACATGG g.44308TϾC CATTAAACC Exon 13 V444A 190 59.5 90 65.6 92 80.4 372 66.1 40 TTGATCAAA g.44481CϾT AGAAAGGTG Intron 13 188 59.0 90 65.6 92 80.4 370 65.9 68 CAAGGAGGC g.46246CϾT AATGCCTAC Exon 14 A535A 184 0.0 86 0.0 96 1.0 366 0.3 41 GGGAGAAAC g.46311TϾC AAGAGGTCG Intron 14 182 60.4 86 66.3 94 79.8 362 66.9 42 GTTGCTCAT g.48611CϾG GCTTGTCTA Exon 16 R616G 194 0.0 90 2.2 96 0.0 380 0.5 69 CGCTTGTCT g.48620AϾG CGGTCAGAG Exon 16 T619A 194 0.0 90 1.1 96 0.0 380 0.3 70 CAGAGCTGC g.48634AϾG GATACCATC Exon 16 A623A 194 0.0 90 1.1 96 0.0 380 0.3 43 GAAGATGAC g.49653AϾG TGCTTGCGA Exon 17 M677V 190 4.2 86 14.0 88 0.0 364 5.5 71 CCGGCAAC g.53835GϾA CTCCAAGTC Exon 18 R698H 196 0.5 82 0.0 94 0.0 372 0.3 72 GAACCTCCA g.53876TϾC TAGCTGTTG Exon 18 L712L 196 0.5 82 0.0 94 0.0 372 0.3 44 TTAATATAA g.59981CϾA CCTCTCTCT Intron 18 192 43.2 84 21.4 90 27.8 366 34.4 45 AATAGATTT g.73116_73119delATTT TTCTATTTA Intron 19 192 0.0 66 6.1 96 0.0 354 1.1 46 ATTTATAAT g.73132_73133insCAA AAAGTTACT Intron 19 194 0.0 66 6.1 96 0.0 356 1.1 47 ACTTTCTTG g.73148TϾC TTACTATCT Intron 19 196 69.4 66 93.9 96 0.0 358 82.1 qanal/courses/predoc97/blosum62.cmp), and Grantham values (Grantham, 1974). 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117 Six singletons were detected in exon 8 (c.616AϾG 3 p.I206V), exon 9 (c.851TϾC 3 p.V284 and c.A896GϾA 3 p.R299K), exon 16 (1855AϾG 3 p.T619A), exon 18 (c.2093GϾA 3 p.R698H), and exon 23 (c.2873GϾA 3 p.R958Q). Login to comment
177 Amino Acid Change Scoring Systems for Nonsynonymous Variants Grantham SIFT PolyPhen Blosum62 EC/EU MDR3 D87E 45 1.00 0.48 2 EC P95S 74 0.48 0.87 -1 EC T175A 58 0.01 0.72 -1 EC I367V 29 0.23 0.96 3 EC E450G 98 0.01 0.13 -2 EC R590Q 43 0.01 2.51 1 EC R652G 125 0.36 1.47 -2 EU E1099G 98 0.04 1.58 -2 EC BSEP I206V 29 1.00 0.23 3 EU V284A 64 0.13 0.43 -2 EC R299K 26 1.00 0.38 2 EU V444A 64 0.63 0.78 -2 EC R616G 125 0.01 3.16 -2 EC T619A 58 0.00 1.78 -1 EC M677V 21 0.29 0.82 1 EU R698H 29 0.30 0.57 0 EC A865V 64 0.02 1.12 0 EC R958Q 43 0.04 0.24 1 EU neutral mutation model (Tajima, 1989). Login to comment

[hide] The bile salt export pump. Pflugers Arch. 2007 Feb;453(5):611-20. Epub 2006 Oct 19. Stieger B, Meier Y, Meier PJ
The bile salt export pump.
Pflugers Arch. 2007 Feb;453(5):611-20. Epub 2006 Oct 19., [PMID:17051391]

Abstract [show]
Canalicular secretion of bile salts mediated by the bile salt export pump Bsep constitutes the major driving force for the generation of bile flow. Bsep is a member of the B-family of the super family of ATP-binding cassette transporters and is classified as ABCB11. Bsep has a narrow substrate specificity, which is largely restricted to bile salts. Bsep is extensively regulated at the transcriptional and posttranscriptional level, which directly modulates canalicular bile formation. Pathophysiological alterations of Bsep by either inherited mutations or acquired processes such as inhibition by drugs or disease-related down regulation may lead to a wide spectrum of mild to severe forms of liver disease. Furthermore, many genetic variants of Bsep are known, some of which potentially render individuals susceptible to acquired forms of liver disease.

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160 Their bile flow rate is slightly but not significantly lower in comparison to controls, but the total bile salt output into bile is massively reduced and their liver bile salt concen- S114R G238V V284L* C336S D482G R487H S593R E636G G982R G1004D R1153CD R1268Q E186G E297G R432T I498T I498T T923P A926P R1050C R1128H S194P G260D N519S A1228V V444A K461E M677V R698H PFIC2 BRIC2 acquired cholestasis SNP Fig. 2 Putative secondary structure of Bsep (NT-005403) generated with the TOPO program (http://www.sacs.ucsf.edu/TOPO-run/wtopo.pl). Login to comment

[hide] Prediction of drug-induced intrahepatic cholestasi... Expert Opin Drug Saf. 2007 Jan;6(1):71-86. Sakurai A, Kurata A, Onishi Y, Hirano H, Ishikawa T
Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump.
Expert Opin Drug Saf. 2007 Jan;6(1):71-86., [PMID:17181454]

Abstract [show]
Drug-induced intrahepatic cholestasis is one of the major causes of hepatotoxicity, which often occur during the drug discovery and development process. Human ATP-binding cassette transporter ABCB11 (sister of P-glycoprotein/bile salt export pump) mediates the elimination of cytotoxic bile salts from liver cells to bile, and, therefore, plays a critical role in the generation of bile flow. The authors have recently developed in vitro high-speed screening and quantitative structure-activity relationship analysis methods to investigate the interaction of ABCB11 with a variety of compounds. Based on the extent of inhibition of the bile salt export pump, the authors analysed the quantitative structure-activity relationship to identify chemical groups closely associated with the inhibition of ABCB11. This approach provides a new tool to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.

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120 H2N COOH S56L G238V G260D C336S L339V V444A K461E D482G T923P K930X G982R R1090X R1153C Outside Inside R1268Q A1228VE1186K R1128H R1057X R1050C A926P A865V R698H E636G M677V S593R E592Q N591S R575XA570T Q558H I498T R432T R415Q R299K E297G V284A I206V S194P E186G cholestasis Expert Opin. Drug Saf. (2007) 6(1) Table 1. Login to comment
124 [47] - 15 1907 A→G Glu636Gly PFIC2 [46] rs11568364 16 2029 A→G Met677Val - [39,41,44,102] - 16 2093 G→A Arg698His - [44] - 16 2098 A→del Frame shift at position 700 PFIC2? Login to comment

[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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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

[hide] Missense mutations and single nucleotide polymorph... Hepatology. 2009 Feb;49(2):553-67. Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ
Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing.
Hepatology. 2009 Feb;49(2):553-67., [PMID:19101985]

Abstract [show]
The gene encoding the human bile salt export pump (BSEP), ABCB11, is mutated in several forms of intrahepatic cholestasis. Here we classified the majority (63) of known ABCB11 missense mutations and 21 single-nucleotide polymorphisms (SNPs) to determine whether they caused abnormal ABCB11 pre-messenger RNA splicing, abnormal processing of BSEP protein, or alterations in BSEP protein function. Using an in vitro minigene system to analyze splicing events, we found reduced wild-type splicing for 20 mutations/SNPs, with normal mRNA levels reduced to 5% or less in eight cases. The common ABCB11 missense mutation encoding D482G enhanced aberrant splicing, whereas the common SNP A1028A promoted exon skipping. Addition of exogenous splicing factors modulated several splicing defects. Of the mutants expressed in vitro in CHO-K1 cells, most appeared to be retained in the endoplasmic reticulum and degraded. A minority had BSEP levels similar to wild-type. The SNP variant A444 had reduced levels of protein compared with V444. Treatment with glycerol and incubation at reduced temperature overcame processing defects for several mutants, including E297G. Taurocholate transport by two assessed mutants, N490D and A570T, was reduced compared with wild-type. Conclusion: This work is a comprehensive analysis of 80% of ABCB11 missense mutations and single-nucleotide polymorphisms at pre-mRNA splicing and protein processing/functional levels. We show that aberrant pre-mRNA splicing occurs in a considerable number of cases, leading to reduced levels of normal mRNA. Thus, primary defects at either the protein or the mRNA level (or both) contribute significantly to BSEP deficiency. These results will help to develop mutation-specific therapies for children and adults suffering from intrahepatic cholestasis due to BSEP deficiency.

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68 Continued Exon Nucleotide Change Predicted Protein Effect Location in Protein Associated Phenotype Prevalence or frequency* Any Defect(s) Identified Reference BRIC, 1 family (both hom) 15 c.1757CϾT T586I Adj WB BRIC 1 family (het) No splicing † 15 c.1763CϾT A588V Adj WB PFIC 2 families (both het) No protein 31, 32 15 c.1772AϾG N591S Adj WB SNP-ICP 2.6% 42 15 c.1779TϾA S593R NBF1 PFIC 1 family (het) 29 15 c.1791GϾT V597V NBF1 SNP 2.6% 42 16 c.1880TϾC I627T IC3 PFIC 1 family (het) ‡ 16 c.1964CϾT T655I IC3 BRIC / ICP / DC 1 family (het) Reduced levels of mature protein ‡ 17 c.2029AϾG M677V IC3 SNP 1.6-5.6% 39, 42-45 18 c.2093GϾA R698H IC3 SNP 0.3 - 0.8% 43, 45 18 c.2125GϾA E709K IC3 SNP-PFIC 1 family (het) ‡ 18 c.2130TϾC P710P IC3 SNP-PBC 0.5 - 3.1% 43 20-21 c.2412AϾC A804A TM8 SNP 1.1% 45 20-21 c.2453AϾT Y818F IC4 SNP-PFIC 2 families (hom) Reduced levels of mature protein ‡ 20-21 c.2494CϾT R832C IC4 PFIC 2 families (1 het, 1 consanguineous) Moderate differential splicing 31, 32 20-21 c.2576CϾG T859R IC4 PFIC 1 family (het) 31 22 c.2767AϾC T923P IC5 BRIC 1 family (het) 8 22 c.2776GϾC A926P IC5 BRIC 1 family (het) Mild exon skipping 8 23 c.2842CϾT R948C IC5 PFIC 2 families (both het) Immature protein 31 23 c.2935AϾG N979D TM11 PFIC 1 family (consanguineous) 31 23 c.2944GϾA G982R TM11 PFIC 4 families (1 hom, 1 consanguineous, 2 het) Immature protein 7, 29, 31 23 c.3011GϾA G1004D EC6 PFIC 1 family (hom) 28 24 c.3084AϾG A1028A TM12 SNP-PBC 39.86 - 56.3% Severe exon skipping 8, 43, 45 24 c.3148CϾT R1050C C term BRIC 2 familes (1 hom, 1 het) Immature protein 8 25 c.3329CϾA A1110E Adj WA PFIC 2 familes (both het) Mild exon skipping; immature protein 31 25 c.3346GϾC G1116R WA PFIC / BRIC 1 family (consanguineous) Mild exon skipping ‡ 25 c.3382CϾT R1128C NBF2 PFIC 1 family (consanguineous) Mild exon skipping; immature protein 31 25 c.3383GϾA R1128H NBF2 BRIC 1 family (hom) Mild exon skipping; greatly reduced levels of mature protein 8 26 c.3432CϾA S1144R NBF2 PFIC 1 family (het) Severe differential splicing 29 26 c.3457CϾT R1153C NBF2 PFIC 4 families (2 consanguineous, 2 het) Immature protein 7, 31, 36 26 c.3458GϾA R1153H NBF2 PFIC 4 families (2 consanguineous, 2 het) Severe differential splicing; immature protein 31 26 c.3460TϾC S1154P NBF2 PFIC 1 family (het) Severe differential splicing 31 26 c.3556GϾA E1186K NBF2 SNP 1%-10% Mild exon skipping ‡ 26 c.3589_3590 delCTinsGG L1197G NBF2 BRIC 1 family (het) † 27 c.3628AϾC T1210P Adj ABCm PFIC 1 family (hom) Immature protein 31 27 c.3631AϾG N1211D Adj ABCm SNP-PFIC 1 family (het) ‡ 27 c.3669GϾC E1223D ABCm Prolonged NNH 1 family (het) ‡ 27 c.3683CϾT A1228V Adj ABCm/WB SNP-PBC 0.8% 43 27 c.3691CϾT R1231W Adj ABCm/WB PFIC 1 family (het) Severe exon skipping; immature protein 30, 31 27 c.3692GϾA R1231Q Adj ABCm/WB PFIC 2 families (1 consanguineous, 1 het) No splicing; immature protein 31, 34 27 c.3724CϾA L1242I WB PFIC 1 family (het) 31 28 c.3892GϾA R1268Q¶ NBF2 PFIC 1 family (hom) Immature protein 7 *Prevalence or frequency is quoted depending on how data were presented in the original publication(s). Login to comment

[hide] Genetic variations of the ABC transporter gene ABC... Drug Metab Pharmacokinet. 2009;24(3):277-81. Kim SR, Saito Y, Itoda M, Maekawa K, Kawamoto M, Kamatani N, Ozawa S, Sawada J
Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population.
Drug Metab Pharmacokinet. 2009;24(3):277-81., [PMID:19571440]

Abstract [show]
The bile salt export pump (BSEP) encoded by ABCB11 is located in the canalicular membrane of hepatocytes and mediates the secretion of numerous conjugated bile salts into the bile canaliculus. In this study, 28 ABCB11 exons (including non-coding exon 1) and their flanking introns were comprehensively screened for genetic variations in 120 Japanese subjects. Fifty-nine genetic variations, including 19 novel ones, were found: 14 in the coding exons (6 nonsynonymous and 8 synonymous variations), 4 in the 3'-UTR, and 41 in the introns. Three novel nonsynonymous variations, 361C>A (Gln121Lys), 667C>T (Arg223Cys), and 1460G>T (Arg487Leu), were found as heterozygotes and at 0.004 allele frequencies. These data provide fundamental and useful information for genotyping ABCB11 in the Japanese and probably other Asian populations.

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53 Six variations previously reported in other ethnic groups were not detected: 616AÀG (Ile206Val; found with 0.011 frequency in African-Americans), 851TÀC (Val284Ala; 0.005 in Caucasians), 1846CÀG (Arg616Gly; 0.022 in African-Americans), 1855AÀG (Thr619Ala; 0.011 in African-Americans), 2029AÀG (Met677Val; 0.042 in Caucasians and 0.14 in African-Americans), and 2093GÀA (Arg698His; 0.005 in Caucasians).7) These variations might be ethnic-specific. Login to comment

[hide] ATP8B1 and ABCB11 analysis in 62 children with nor... Hepatology. 2010 May;51(5):1645-55. Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, Bernard O, Jacquemin E
ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history.
Hepatology. 2010 May;51(5):1645-55., [PMID:20232290]

Abstract [show]
Progressive familial intrahepatic cholestasis (PFIC) types 1 and 2 are characterized by normal serum gamma-glutamyl transferase (GGT) activity and are due to mutations in ATP8B1 (encoding FIC1) and ABCB11 (encoding bile salt export pump [BSEP]), respectively. Our goal was to evaluate the features that may distinguish PFIC1 from PFIC2 and ease their diagnosis. We retrospectively reviewed charts of 62 children with normal-GGT PFIC in whom a search for ATP8B1 and/or ABCB11 mutation, liver BSEP immunostaining, and/or bile analysis were performed. Based on genetic testing, 13 patients were PFIC1 and 39 PFIC2. The PFIC origin remained unknown in 10 cases. PFIC2 patients had a higher tendency to develop neonatal cholestasis. High serum alanine aminotransferase and alphafetoprotein levels, severe lobular lesions with giant hepatocytes, early liver failure, cholelithiasis, hepatocellular carcinoma, very low biliary bile acid concentration, and negative BSEP canalicular staining suggest PFIC2, whereas an absence of these signs and/or presence of extrahepatic manifestations suggest PFIC1. The PFIC1 and PFIC2 phenotypes were not clearly correlated with mutation types, but we found tendencies for a better prognosis and response to ursodeoxycholic acid (UDCA) or biliary diversion (BD) in a few children with missense mutations. Combination of UDCA, BD, and liver transplantation allowed 87% of normal-GGT PFIC patients to be alive at a median age of 10.5 years (1-36), half of them without liver transplantation. CONCLUSION: PFIC1 and PFIC2 differ clinically, biochemically, and histologically at presentation and/or during the disease course. A small proportion of normal-GGT PFIC is likely not due to ATP8B1 or ABCB11 mutations.

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90 The p.R698H mutation previously reported as a possible rare SNP was identified in three children.11,12 However, BSEP canalicular staining was negative or focal negative in these three patients, and biliary BA concentration was low in one of them; two were heterozygous for p.R698H and one was heterozygous compound. Login to comment
101 11† p.R1128C p.R1128C na na PFIC2 no. Login to comment
104 14b† p.I420T p.I1061VfsX34 na na PFIC2 no. 15*,‡ p.A167T p.G1058HfsX38 0.5 BSEP À PFIC2 no. 16* p.R1231W p.I528X na na PFIC2 no. 17 p.M62K p.I112T þ p.R698H 0.10 BSEP À PFIC2 no. 18* p.E297G p.H484RfsX5 0.16 BSEP À PFIC2 no. 19* p.E297G p.I610GfsX45 0.23 BSEP À PFIC2 no. Login to comment
105 20† p.A257G p.G982R na na PFIC2 no. 21* p.I182K c.3213 15 G>A na BSEP À PFIC2 no. 22 p.D549V c.76 13 G>T na na PFIC2 no. Login to comment
106 23†,§ p.M183T p.G455E na na PFIC2 no. Login to comment
108 30† p.Y1041X nf 0.22 BSEP À PFIC2 no. 31* p.R470X nf na na PFIC2 no. 32* p.R698H nf na BSEP 6 PFIC2 no. Login to comment
109 33†,‡ p.R698H nf na BSEP 6 PFIC2 no. 34 p.M1V p.R387H na na PFIC2 no. Login to comment
89 The p.R698H mutation previously reported as a possible rare SNP was identified in three children.11,12 However, BSEP canalicular staining was negative or focal negative in these three patients, and biliary BA concentration was low in one of them; two were heterozygous for p.R698H and one was heterozygous compound. Login to comment

[hide] ABCB4 and ABCB11 mutations in intrahepatic cholest... Dig Liver Dis. 2013 Mar;45(3):226-32. doi: 10.1016/j.dld.2012.08.011. Epub 2012 Sep 27. Anzivino C, Odoardi MR, Meschiari E, Baldelli E, Facchinetti F, Neri I, Ruggiero G, Zampino R, Bertolotti M, Loria P, Carulli L
ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population.
Dig Liver Dis. 2013 Mar;45(3):226-32. doi: 10.1016/j.dld.2012.08.011. Epub 2012 Sep 27., [PMID:23022423]

Abstract [show]
BACKGROUND: Genetic alterations in the ATP-binding cassette subfamily B member 4 (ABCB4) and ATP-binding cassette subfamily B member 11 (ABCB11) have been associated to the onset of intrahepatic cholestasis of pregnancy (ICP) in predisposed women. AIMS: To identify new and/or frequent ABCB4 and ABCB11 genes variants in a cohort of Italian patients with ICP and to evaluate the possible pathogenetic role for the novel mutations identified. METHODS: DNA of 33 unrelated Italian women with obstetric cholestasis were screened for mutations in the entire coding sequence of ABCB4 and ABCB11 genes. Polymerase chain reaction and automated sequencing was performed on the 27 coding exons of both genes. RESULTS: Genotyping revealed 11 mutations, 5 of whom were novel variants: 2 localized on ABCB4 (p.I587DfsX603, p.I738LfsX744) and 3 on ABCB11 (p.V284D, p.Q558H, p.P731S). The most severe phenotypes were associated with the variants p.I587DfsX603, p.I738LfsX744 and p.V284D. Moreover, the already described mutation p.N510S found in ABCB4 seems to be strictly involved in the onset of ICP in that particular patient. CONCLUSIONS: Our data support the hypothesis of a significant involvement of ABCB4 mutations in the onset of ICP, but also confirm an important role for ABCB11 mutations in increasing the susceptibility to cholestasis of pregnancy.

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92 Variants p.E135K, p.D482G and p.R698H were reported in previous studies [12,25-28]. Login to comment
101 Nucleotide change and effect on protein Location PSIC scores by PolyPhen-2 analysis Reference 1 c.217 C > G (p. L73V) Exon 4 0.489 [12] 2 c.523 A > G (p.T175A) Exon 6 0.774 [12] 3 c.1529 A > G (p.N510S) Exon 13 2.075 [24] 4 c.1758 1759 ins G (p.I587DfsX603) Exon 15 X This study 5 c.2211(+1) G > T (p.I738LfsX744) 5 Intron 17 X This study ABCB11 mutations 6 c.403 G > A (p.E135K) Exon 6 0.502 [26] 7 c.852 T > A (p.V284D) Exon 9 2.175 This study 8 c.1445 A > G (p.D482G) Exon 14 1.364 [26-28] 9 c.1674 G > C (p.Q558H) Exon 15 1.383 This study 10 c.2093 G > A (p.R698H) Exon 18 0.821 [12,25] 11 c.2191 C > T (p. P731S) Exon 19 0.851 This study New mutations are shown in bold. Login to comment
112 Finally, the variant p.R698H is referred as a polymorphism [12,25], however it was not detected in any of the 100 control subjects screened in our study. Login to comment
129 Table 4 Clinical details of patients with ABCB11 mutations. Parameters Patient 6 E135K Patient7 V284D Patient 8 D482G Patient 9 Q558H Patient 10 R698H Patient 11 P731S Onset of pruritus 3rd trimester 2nd trimester 3rd trimester 2nd trimester 2nd trimester 3rd trimester Parity 2 1 2 2 2 2 Previous ICP Yes Yes Yes No Yes Yes Peak of AST (U/L) 24 92 29 125 244 105 Peak of ALT (U/L) 26 215 37 315 514 198 Peak of Bilirubin (mg/dL) 0.53 0.49 Nd 0.36 0.3 0.46 Peak of GGT (U/L) 7 25 Nd 23 14 16 Total bile acids (òe;mol/L) 93.6 112.4 28 Nd 20.4 23.4 Delivery Induction of labour (36w+4 )a Caesarean section (38w)a Induction of labour (38w+4 )a Caesarean section (36w)a Caesarean section (38w)a Induction of labour (38w) Cholelithiasis No No No No No No UDCA therapy Yes Yes No Yes Yes Yes AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: ॹ-glutamyl transpeptidase; Nd: not determined. a Caesarean section or induction of labour due to pregnancy complications related to ICP (foetal distress and/or intolerable pruritus and/or persistent elevation of AST and ALT). Login to comment
93 Variants p.E135K, p.D482G and p.R698H were reported in previous studies [12,25-28]. Login to comment
102 Nucleotide change and effect on protein Location PSIC scores by PolyPhen-2 analysis Reference 1 c.217 C > G (p. L73V) Exon 4 0.489 [12] 2 c.523 A > G (p.T175A) Exon 6 0.774 [12] 3 c.1529 A > G (p.N510S) Exon 13 2.075 [24] 4 c.1758 1759 ins G (p.I587DfsX603) Exon 15 X This study 5 c.2211(+1) G > T (p.I738LfsX744) 5 Intron 17 X This study ABCB11 mutations 6 c.403 G > A (p.E135K) Exon 6 0.502 [26] 7 c.852 T > A (p.V284D) Exon 9 2.175 This study 8 c.1445 A > G (p.D482G) Exon 14 1.364 [26-28] 9 c.1674 G > C (p.Q558H) Exon 15 1.383 This study 10 c.2093 G > A (p.R698H) Exon 18 0.821 [12,25] 11 c.2191 C > T (p. P731S) Exon 19 0.851 This study New mutations are shown in bold. Login to comment
113 Finally, the variant p.R698H is referred as a polymorphism [12,25], however it was not detected in any of the 100 control subjects screened in our study. Login to comment
130 Table 4 Clinical details of patients with ABCB11 mutations. Parameters Patient 6 E135K Patient7 V284D Patient 8 D482G Patient 9 Q558H Patient 10 R698H Patient 11 P731S Onset of pruritus 3rd trimester 2nd trimester 3rd trimester 2nd trimester 2nd trimester 3rd trimester Parity 2 1 2 2 2 2 Previous ICP Yes Yes Yes No Yes Yes Peak of AST (U/L) 24 92 29 125 244 105 Peak of ALT (U/L) 26 215 37 315 514 198 Peak of Bilirubin (mg/dL) 0.53 0.49 Nd 0.36 0.3 0.46 Peak of GGT (U/L) 7 25 Nd 23 14 16 Total bile acids (òe;mol/L) 93.6 112.4 28 Nd 20.4 23.4 Delivery Induction of labour (36w+4 )a Caesarean section (38w)a Induction of labour (38w+4 )a Caesarean section (36w)a Caesarean section (38w)a Induction of labour (38w) Cholelithiasis No No No No No No UDCA therapy Yes Yes No Yes Yes Yes AST: aspartate aminotransferase; ALT: alanine aminotransferase; GGT: ॹ-glutamyl transpeptidase; Nd: not determined. a Caesarean section or induction of labour due to pregnancy complications related to ICP (foetal distress and/or intolerable pruritus and/or persistent elevation of AST and ALT). 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