ABCMdb

ABCB11 p.Arg432Thr

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PMID: 16763017 [PubMed] Lang T et al: "Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11)."

No. Sentence Comment

286 A splicing mutation (ϩ3)AϾC (intron 4) combined with a frameshift mutation in exon 22 (p.K930X), resulting in a PFIC2 phenotype and two nonsynonymous variants in exon 9 (p. E297G) and in exon 12 (p.R432T), were encountered in the patient exhibiting a BRIC (benign recurrent intrahepatic cholestasis) phenotype. Login to comment

PMID: 17051391 [PubMed] Stieger B et al: "The bile salt export pump."

No. Sentence Comment

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

PMID: 17181454 [PubMed] Sakurai A et al: "Prediction of drug-induced intrahepatic cholestasis: in vitro screening and QSAR analysis of drugs inhibiting the human bile salt export pump."

No. Sentence Comment

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
121 Nonsynonymous polymorphisms and mutations in the ABCB11 gene NCBI No. Exon Nucleotide Amino acid alteration Phenotype Ref. Position Alteration rs11568361 5 167 C→T Ser56Leu - [102] - 5 341 G→C Ser114Arg PFIC2 [47]* - 6 557 A→G Glu186Gly BRIC2 [45,48] - 6 580 T→C Ser194Pro - [44] rs11568358 7 616 A→G Ile206Val - [102] - 7 695 T→del Frame shift at position 232 PFIC2 [47] - 7 713 G→T Gly238Val PFIC2 [47] - 8 779 G→A Gly260Asp - [44] - 8 851 T→C Val284Ala - [44] rs11568372 8 890 A→G Glu297Gly PFIC2/BRIC2 [35,43,45,47,102] rs2287617 8 896 G→A Arg299Lys - [102] - 8 908 G→del Frame shift at position 303 PFIC2 [35] - 9 1007 G→C Cys336Ser PFIC2 [47] - 9 1015 C→G Leu339Val - [46] - 11 1244 G→A Arg415Gln - [39] - 11 1294 G→C Arg432Thr BRIC2 [43] rs2287622 12 1331 T→C Val444Ala ICP/PFIC2? Login to comment

PMID: 19101985 [PubMed] Byrne JA et al: "Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing."

No. Sentence Comment

67 ABCB11 Missense Mutations and SNPs Functionally Analyzed in This Study Exon Nucleotide Change Predicted Protein Effect Location in Protein Associated Phenotype Prevalence or Frequency* Any Defect(s) Identified Reference 4 c.149TϾC L50S NH2 term PFIC 1 family (het) Immature protein 31 5 c.270TϾC F90F EC1 SNP 2.7%-7.7% 43, 45 6 c.403GϾA E135K EC1 BRIC 1 family (het) Reduced levels of mature protein † 6 c.409GϾA E137K EC1 BRIC / ICP 1 family (het) Immature protein ‡ 7 c.500CϾT A167V TM2 PFIC 1 family (hom) Mild exon skipping beta 7 c.557AϾG E186G IC1 BRIC 2 families (both het) Moderate exon skipping; greatly reduced levels of mature protein 8, 37 7 c.580TϾC S194P IC1 SNP-PSC 1.1% 43 7 c.593TϾC L198P IC1 BRIC / ICP / DC 1 family (het) Greatly reduced levels of mature protein # 8 c.713GϾT G238V EC2 PFIC 1 family (hom) 29 8 c.725CϾT T242I TM4 PFIC 1 family (het) 31 8 c.779GϾA G260D TM4 SNP-PBC 0.8% 43 9 c.850GϾC V284L IC2 PFIC 1 family (het) No protein 28 9 c.851TϾC V284A IC2 SNP 0.5% Increased levels of mature protein 43, 45† 9 c.889GϾA E297K IC2 Prolonged NNH 1 family (het) Moderate differential splicing; immature protein ‡ 9 c. 890AϾG E297G IC2 PFIC, BRIC PFIC, 45 families (14 hom, 31 het) BRIC, 4 families (2 hom, 2 het) Greatly reduced levels of mature protein 7, 8, 12, 29-32, 35 10 c.936GϾT Q312H IC2 PFIC 1 family (het) ‡ 10 c.937CϾA R313S IC2 PFIC 1 family (het) 31 10 c.957AϾG G319G TM5 SNP 1.5 - 7.5% Mild exon skipping 42, 43, 45 10 c.980GϾA G327E TM5 PFIC 1 family (het) 31 10 c.1007GϾC C336S TM5 PFIC 1 family (het) 29 11 c.1168GϾC A390P NBF PFIC, BRIC 2 families (both het) Immature protein 31; # 12 c.1129GϾA G410D NBF PFIC 1 family (het) 31 12 c.1238TϾG L413W NBF PFIC 1 family (het) Greatly reduced levels of mature protein 31 12 c.1244GϾA R415Q NBF SNP-ICP 1.3% 42 12 c.1295GϾC R432T NBF BRIC 1 family (het) Reduced levels of mature protein 12 13 c.1331CϾT A444V NBF SNP, ICP, CC, DC, BRIC 43-60% Increased levels of mature protein 8, 28, 37, 39-45 13 c.1381AϾG K461E WA PFIC 1 family (hom) Immature protein 7 13 c.1388CϾT T463I WA PFIC 1 family (het) Mild exon skipping 31 13 c.1396CϾA Q466K Adj WA PFIC 1 family (het) 31 13 c.1409GϾA R470Q Adj WA PFIC 2 families (1 het, 1 consanguineous) Immature protein 31 14 c.1442TϾA V481E NBF1 PFIC 1 family (het) 31 14 c.1445AϾG D482G NBF1 PFIC 22 families (16 het, 6 hom) Severe differential splicing; immature protein 7, 30-32 14 c.1468AϾG N490D NBF1 PFIC 1 family (het) Greatly reduced levels of mature protein; reduction in bile salt transport 31 14 c.1493TϾC I498T NBF1 PFIC / BRIC 1 family (het) 38 14 c.1530CϾA T510T NBF1 SNP-PBC 0.7% 43 14 c.1535TϾC I512T NBF1 PFIC 1 family (het) 31 14 c.1544AϾC N515T NBF1 PFIC 1 family (het) 31, 32 14 c.1440GϾA R517H NBF1 PFIC 1 family (het) No protein 31, 32 14 c.1605CϾT A535A NBF1 SNP 0.3% Slightly reduced levels mature protein 39, 45 14 c.1621AϾC I541L NBF1 PFIC 3 families (1 het, 2 consanguineous) No protein 31-33 15 c.1643TϾA F548Y Adj ABCm PFIC 1 family (het) 31, 32 15 c.1685GϾA G562D ABCm PFIC 1 family (het) 31 15 c.1708GϾA A570T Adj ABCm/WB PFIC, BRIC PFIC, 1 family Greatly reduced levels of mature protein; reduction in bile salt transport 8, 31 Table 1. Login to comment
141 Mature BSEP, but at somewhat reduced levels, was detected for E135K (c.403GϾA; Fig. 5B), T655I (c.1964CϾT; Fig. 5C), R432T (c.1295GϾC; Fig. 5.e), the PFIC-associated SNP Y818F (c.2453AϾT; Fig. 5E), and the SNP A535A (c.1605CϾT; Fig. 5F). Login to comment

PMID: 20028269 [PubMed] Stieger B et al: "Role of the bile salt export pump, BSEP, in acquired forms of cholestasis."

No. Sentence Comment

78 For example, in a patient with benign recurrent intrahepatic cholestasis type 2, the two compound heterozygous mutations, E297G and R432T, were identified. Login to comment

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

No. Sentence 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: 16890614 [PubMed] Keitel V et al: "Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy."

No. Sentence Comment

79 In addition to changes in protein localization, V444A may alter transport activity as described recently for 2 BRIC-associated BSEP mutations (R432T and E297G).19 Another possibility of reduced transporter activity includes an increased susceptibility of V444A toward the inhibitory effect of estrogens.20 Homozygous V444A can be expected in 25% of the population, but homozygous V444A alone cannot explain the severity of ICP in our patient. Login to comment

PMID: 14699511 [PubMed] Kullak-Ublick GA et al: "Enterohepatic bile salt transporters in normal physiology and liver disease."

No. Sentence Comment

119 A clinical syndrome with recurrent intrahepatic cholestasis but normal liver architecture in an adolescent patient has been associated with compound heterozygosity for the E297G and a novel R432T mutation,176 suggesting that certain adult forms of cholestasis may also be caused by BSEP mutations and reduced transport function. Login to comment
141 Role of Bile Salt Transporters in the Pathogenesis of Liver Disease Species Transport protein Gene symbol Physiologic function Alterations in liver disease References Basolateral transport proteins Rat Ntcp Slc10a1 Naϩ-dependent hepatocellular bile salt uptake Decreased expression in rat models of cholestasis Decreased mRNA and protein levels during pregnancy, associated with decreased nuclear binding of HNF1␣ and RAR␣:RXR␣ 201,211,231 232 Human NTCP SLC10A1 Naϩ-dependent hepatocellular bile salt uptake Decreased mRNA and protein levels in human cholestatic liver disease 30,187 Decreased expression in HCC 72 Rat Oatp1 Slc21a1 Multispecific uptake of organic anions and amphipathic compounds Decreased expression in bile duct ligation and in ethinyl estradiol induced cholestasis 211,233 Oatp2 Slc21a5 Multispecific uptake of organic anions and of cardiac glycosides (digoxin) Decreased mRNA but not protein levels in carbon tetrachloride induced liver injury Decreased mRNA and protein levels in ethinylestradiol-induced cholestasis 234 126 Oatp4 Slc21a10 Multispecific uptake of organic anions and amphipathic compounds Decreased expression in bile duct ligation and sepsis 235 Human OATP-C SLC21A6 Hepatocellular uptake of bile salts and other organic anions Reduced mRNA in PSC and inflammatory cholestasis Decreased expression in HCC 29,30 217 OATP8 SLC21A8 Hepatocellular uptake of organic anions, peptides, and xenobiotics Decreased expression in HCC because of increased expression of the transcriptional repressor HNF3beta 218 Rat/human Mrp1/MRP1 ABCC1 Efflux of cytotoxic cations and non-bile salt organic anions Increased expression in hepatoma cells and sepsis 199,236 Rat/human Mrp3/MRP3 ABCC3 Efflux of organic anions, bile salts, and anticancer agents Increased expression in Eisai Hyperbilirubinemic Rats and in bile duct ligation Increased expression in Dubin-Johnson syndrome and primary biliary cirrhosis 237 61 Hepatocyte canalicular transport proteins Mouse/rat/ human Bsep/Bsep/ BSEP ABCB11 Canalicular efflux of bile salts Gene mutations and absence of the protein in patients with PFIC2, characterized by low GGT levels and reduced biliary bile acid excretion 174,238 Compound heterozygosity for the E297G/R432T mutations in a patient with recurrent intrahepatic cholestasis 176 Reduced mRNA and canalicular BSEP staining in human inflammatory cholestasis 30 Cisinhibition by cholestatic drugs such as cyclosporine A 190 Transinhibition by the cholestatic estrogen metabolite estradiol-17beta-D-glucuronide 190,239 Increased expression in C57L/J gallstone-susceptible mice, despite reduced bile salt excretory capacity 220,240 Mouse/rat/ human Mdr2/Mdr2/ MDR3 ABCB4 Biliary excretion of phospholipids Mdr2 -/- knockout mice exhibit an absence of phospholipids in bile and develop progressive liver disease with portal inflammation, bile duct proliferation and fibrosis 241 PFIC3, characterized by high GGT levels and absent lipoprotein X in serum, is caused by mutations in the MDR3 gene (chromosome 7q21) 177 MDR3 mutations in PFIC3 are associated with intrahepatic cholestasis of pregnancy 242 Rat/human Mrp2/MRP2 ABCC2 Canalicular excretion of organic anions Decreased mRNA and protein levels in bile duct ligation and endotoxinemia 200,243 Decreased canalicular density of Mrp2 transporter molecules in endotoxinemia, taurolithocholate cholestasis, and bile duct ligation 145,200,243 Mutations in the rat Mrp2 gene cause hereditary conjugated hyperbilirubinemia 244 Mutations in the human MRP2 gene cause the Dubin-Johnson syndrome with absent protein expression 181,183 MRP2 function is inhibited by anabolic 17␣-alkylated steroids 245,246 Decreased canalicular MRP2 staining in PBC and inflammatory cholestasis 30,31 Decreased mRNA levels in PSC 29 Human FIC1 ATP8B1 Putative aminophospholipid translocator P-type ATPase, positional candidate in genetic linkage analysis of PFIC1 (Byler`s disease) and BRIC 171 PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis. Login to comment

PMID: 18698235 [PubMed] Kobayashi K et al: "Functional analysis of nonsynonymous single nucleotide polymorphism type ATP-binding cassette transmembrane transporter subfamily C member 3."

No. Sentence Comment

173 For example, E297G ABCB11 is mislocalized to ER when heterologously expressed in MDCK cells [39,40], although the patient with compound heterozygosity for E297G and R432T ABCB11 showed normal canalicular localization, and the primary cause of dysfunction of ABCB11 was attributed to the reduced transport function [41]. Login to comment

PMID: 16039748 [PubMed] Noe J et al: "Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis."

No. Sentence Comment

4 Results: The PFIC2 patient was compound heterozygous for a splicing mutation in intron 4 ((C3)AOC) combined with an early stop codon at position 930 (R930X), while the BRIC2 patient was compound heterozygous for two nonsynonymous mutations in exon 9 (E297G) and exon 12 (R432T), respectively. Login to comment
6 In BRIC2, taurocholate transport was decreased to 13% and 20% of reference levels for R432T and E297G, respectively. Login to comment
7 Conclusions: The intron 4 (C3)AOC, R930X and R432T represent previously undescribed mutations of the ABCB11 gene that confer a PFIC2 and a BRIC2 phenotype, respectively. Login to comment
61 The single nucleotide polymorphisms 890AOG (codon GAGOGGG) and 1294GOC (codon AGAOACA), which result in the nonsynonymous mutations E297G and R432T, respectively, were introduced into the reference h ABCB11 cDNA. Login to comment
68 Functional transport studies ATP-dependent transport of labeled bile salts was determined for the E297G and the R432T mutations by a rapid filtration assay as described [16]. Login to comment
100 The parents of the patient had normal liver enzyme levels in the absence of clinical signs of hepatopathy. 3.2.1. Sequencing Sequence analysis indicated a nonsynonymous mutation in exon 9 (891GOA) predicting the substitution of a glutamate by a glycine in position 297 (E297G) combined with a nonsynonymous mutation in exon 12 (1296GOC), predicting a substitution of an arginine by a threonine in position 432 (R432T). Login to comment
101 Analysis of the patient`s parents indicated that the E297G mutation was inherited from the mother, whereas the R432T mutation was inherited from the father (Fig. 1). Login to comment
110 Transport studies Western blot analysis detected comparable protein amounts for R432T, E297G and reference BSEP in SF-9 cell vesicles (Fig. 3). Login to comment
111 Transport capacity of the mutated constructs amounted to about 13 and 20% of reference activity for the R432T and the E297G construct, respectively (Fig. 3). Login to comment
112 Initial taurocholate transport by reference BSEP as well as by R432T and E297G mutants exhibited saturability with increasing substrate concentrations (Fig. 4). Login to comment
114 The Km values for R432T and the E297G mutant were 5.6 mmol/L and 22 mmol/L, respectively, which is comparable to the Km value of reference BSEP. Login to comment
115 In contrast, the maximum taurocholate transport velocity for the BSEP mutants was greatly reduced, with Vmax values of 53 pmol/L mg proteinK1 minK1 , and 111 pmol/ L mg proteinK1 minK1 for R432T and E297G, respectively, compared to 686 pmol/L mg proteinK1 minK1 for reference BSEP (Fig. 4). Login to comment
127 Compound heterozygosity for two nonsynonymous variants in exon 9 (E297G) and in exon 12 (R432T) was encountered in the patient exhibiting a BRIC phenotype. Login to comment
128 While the E297G site had already been associated with inherited intrahepatic cholestasis, the R432T mutation was previously undescribed in cholestatic disease. Login to comment
133 However, it cannot completely be excluded that in our patient the R432T allele is compensating for defective BSEP expression associated with the E297G mutation. Login to comment
146 Kinetics of ATP-dependent transport of taurocholate by reference BSEP, R432T BSEP mutant and E297G BSEP mutant in membrane vesicles isolated from Sf9 cells. Login to comment
147 Initial uptake rates for taurocholate by reference BSEP, E297G mutant (60 s) and R432T mutant (90 s) were determined in the presence and absence of ATP (5 mmol/L). Login to comment

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

No. Sentence Comment

182 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 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

PMID: 24711118 [PubMed] Guyot C et al: "Differential effects of membrane cholesterol content on the transport activity of multidrug resistance-associated protein 2 (ABCC2) and of the bile salt export pump (ABCB11)."

No. Sentence Comment

11 The transport activity of the BSEP mutants p.E297G and p.R432T increased at high cholesterol content but did not reach the capacity of normal BSEP. Login to comment
177 Finally, we studied the effect of cholesterol on two mutant forms of BSEP, p.E297G and p.R432T, found in patients with BSEP deficiency syndromes. Login to comment
262 (A, D, and G) Western blot analysis of p.444A variant (A), p.E297G (D), and p.R432T (G) mutant BSEP-expressing vesicles with and without cholesterol loading (30 mg protein per lane). Login to comment

PMID: 25027376 [PubMed] Kubitz R et al: "Genetic variations of bile salt transporters."

No. Sentence Comment

137 BSEP/Bsep NTCP ASBT Exon skipping E186G G1116R G319G R1128C T463I R1128H A926P E1186K A1028Aa R1231W A1110E Aberrant splicing E297K R1153H R832C S1154P S1144R No splice product T586I R1231Q Reduced plasma membrane expression E135K A570T I223T E297Gb N591Sb V444A R1050C Intracellular retention Y818F G982R Reduced or absent bile salt transport A570T R432T A64T K314E V98Ic M264V I206V Q558H I223T C144Y P290S E297Gb N591Sb S267F L243P G374S E1186K I279T T262M a A1028A induces significant exon skipping in vitro but probably not in vivo (unpublished data; Dro &#a8;ge, Ha &#a8;ussinger, Kubitz). Login to comment