ABCMdb

ABCB11 p.Val284Leu

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Publications

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

No. Sentence Comment

165 (*) The mutation V284L was found in a patient with PFIC2, whereas the SNP V284A occurs in healthy individuals trations are increased accordingly. Login to comment

PMID: 18692205 [PubMed] Chen HL et al: "Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography."

No. Sentence Comment

3 Results Seven mutations in 4 of 16 patients with PFIC from different families were detected by DHPLC, including M183V, V284L, R303K, R487H, W493X, G1004D, and 1145delC. Login to comment
46 Age of onset Bil T (␮mol/L) Bil D (␮mol/L) GGT (U/L) AST (U/L) ALT (U/L) Liver pathology Mutations found Exon Predicted effect Outcome 1 1 mo 169.3 121.4 56 518 244 IC, GCT c.850GϾC c.1145delC 9 11 p. Val284Leu p.Ala382AlafsX16 Death, 5 y 2 1 mo 100.9 51.3 30 88 66 IC, GCT, bridging fibrosis c.850GϾC c.1145delC 9 11 p. Val284Leu p.Ala382AlafsX16 Alive 5 y, chronic cholestasis, Failure to thrive 3 2 wk 119.7 58.1 36 500 341 IC, GCT c.547AϾG c.908GϾA 7 9 p.Met183Val p.Arg303Lys Death, 8 mo 4 1 mo 179.6 138.5 68 186 150 GCT, fibrosis c.1478GϾA c.3011GϾA 14 23 p.Trp493X p.Gly1004Asp Death, 2 yr 5 birth 237.7 155.6 47 1184 653 - c.1460GϾA 14 p.Arg487His Death, 1 y 6 2 mo 360.8 251.4 132 884 352 Lobular disarray NF Death, 9 mo 7 1 mo 119.7 109.4 25 54 49 IC, bridging fibrosis NF Alive, 7 y 8 2 mo 401.9 273.6 51 251 252 GCT, cell ballooning NF Death 1 y 6mo 9 3 mo 442.9 256.5 54 556 217 - NF Death, 7 mo 10 1 mo 157.3 90.6 20 606 828 GCT, hepatocyte ballooning, confluent necrosis NF Death, 9 mo 11 1 mo 193.2 136.8 52 523 345 GCT, focal necrosis NF Death 4 mo 12 2 mo 165.9 94.1 99 298 202 GCT, portal inflammation, ductal proliferation NF Death 8 mo 13 2 wk 277.0 194.9 64 1054 825 GCT, necrosis NF OLT, 6 mo 14 2 mo 413.8 229.1 51 625 665 GCT, biliary cirrhosis NF OLT, 9 mo 15 birth 371.1 271.9 68 584 400 GCT NF Alive, 10 mo 16 birth 176.1 145.4 57 352 249 GCT, bridging fibrosis NF Death, 9 mo 17 birth 136.8 46.2 47 29 117 GCT NF Alive, 5 y 18 32 y 143.6 63.3 24 105 91 Centrilobular canalicular cholestasis, hemosiderosis c.3011GϾA 23 p.Gly1004Asp Alive, 35 y, recurrent cholestasis IC, Intrahepatic cholestasis; GCT, giant-cell transformation; OLT, orthotopic liver transplantation; NF, mutations not found. Login to comment
80 RESULTS Mutations Detected in Patients with PFIC Of 17 patients with low-GGT PFIC, mutations in ABCB11 were found in 5 patients, including a sibling pair (patients 1 and 2) with compound heterozygous c.850GϾC (p.V284L) and c.1145delC (p.Ala382AlafsX16) mutations.12 Patient 3 had compound heterozygous c.547AϾG (p.M183V)/c.908GϾA (p.R303K) mutations. Login to comment
102 Analysis of Mutations in Normal Controls All the missense mutations detected above were tested in 80 normal control subjects (160 alleles), using DHPLC for M183V (exon 7), V284L (exons 9), R303K (exon 9), R487H (exon 14), L827I (exon 21), and G1004D (exon 23). Login to comment
109 The PolyPhen results indicated that V284L and G1004D are possibly damaging, and M183V, R303K, R487H, and L827I were predicted to be benign (Table IV). Login to comment
128 Prediction of functional consequences of nonsynonymous mutations and polymorphisms in ABCB11 found in Asian patients Amino acid change SIFT PolyPhen (PSIC score) EC/EU M183V 0.02 1.45 EC V284L 0.02 1.87 EC R303K 0.00 0.38 EC V444A 0.76 0.60 EC R487H 0.01 0.65 EC L827I 0.01 1.23 EC A865V 0.10 0.76 EC G1004D 0.00 1.97 EC SIFT, Sorting intolerant from tolerant (SIFT scores Ͻ0.05 indicate evolutionarily conserved amino acids, and mutation of these residues are predicted to be deleterious); PolyPhen, polymorphism phenotyping (a PSIC score Ͻ0.5 denotes benign variants, between 1.5 and 2 is possibly damaging, and Ͼ2 is probably damaging); EC, evolutionarily conserved; EU, evolutionarily unconserved. Login to comment
135 Although the PolyPhen analysis only predicted 2 missense mutations (V284L and G1004D) to be possibly deleterious, other mutations had borderline scores. Login to comment

PMID: 18853996 [PubMed] Chen ST et al: "Prenatal diagnosis of progressive familial intrahepatic cholestasis type 2."

No. Sentence Comment

6 Results: We report on two families of PFIC2 with inherited compound heterozygous mutations of ABCB11 (M183V and R303K in Family 1, V284L and 1145delC in Family 2) from the parents. Login to comment
8 A fetus with compound heterozygous missense mutation V284L and 1145delC was terminated in Family 2. Login to comment
73 In Family 2, compound heterozygous missense mutation V284L and a 1bp deletion at nucleotide 1145 at coding sequence were found in the first and second child.9 Both parents carried one mutation each (Fig. 2b). Login to comment
76 Genetic study of the fetus showed the same compound heterozygous missense mutation V284L and 1145delC mutation. Login to comment
97 (b) Cases 5, 6, 7, affected individuals with compound heterozygous V284L mutation and 1145delC. Login to comment
99 Case 9, an unaffected mother with the heterozygous V284L mutation. 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
144 No BSEP protein, mature or immature, was observed for the mutations V284L (c.850GϾC) and A588V (c.1763CϾT; Fig. 5A) and I541L (c.1621AϾC; Fig. 5B), indicating that these variants were rapidly degraded. Login to comment
212 With respect to L1242I, disruption of a Walker B motif is predicted to cause severe functional consequences.64 No detectable protein was observed for the predicted missense mutations V284L (c.850GϾC) and A588V (c.1763CϾT; Fig. 5A). Login to comment
213 V284A enhances, whereas V284L abolishes, BSEP protein levels. Login to comment

PMID: 19177487 [PubMed] Mullenbach R et al: "The transporter "variome": the missing link between gene variants and bile salt transporter function."

No. Sentence Comment

34 (2) Retention and degradation of the protein in the endoplasmatic reticulum (trafficking mutant, for example ABCB11 variants p.V284L and p.A588V). Login to comment

PMID: 19750581 [PubMed] Treepongkaruna S et al: "Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis."

No. Sentence Comment

90 Chen et al[13] have reported seven BSEP mutations (M183V, V284L, R303K, R487H, W493X, G1004D and 1145delC) in four PFIC patients of Chinese descent; none of these mutations has been described in Caucasian patients. Login to comment

PMID: 23022423 [PubMed] Anzivino C et al: "ABCB4 and ABCB11 mutations in intrahepatic cholestasis of pregnancy in an Italian population."

No. Sentence Comment

146 A further demonstration of the importance of the conservation of this valine in the evolution comes from previous evidence which identified other substitutions in the same position (p.V284L and p.V284A) [12,25,29] and analysed them by the mean of an in vitro minigene system reporting no protein formation for the variant p.V284L and an increased amount of protein for the SNP p.V284A [26]. Login to comment
147 The p.Q558H missense mutation is localised in the nucleotide binding domain1 at the level of the ABC signature motif; because this represents a functional domain, the mutation is likely to alter protein stability. Login to comment

PMID: 11815775 [PubMed] Chen HL et al: "FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low gamma-glutamyltranspeptidase levels."

No. Sentence Comment

52 onset/sex Symptoms follow-up Outcome features Genotype 1 1 mo/F Persistent JD, intractable 6 y Liver Hepatocellular FIC1: heterozygous pruritus, hepatomegaly, transplantation cholestasis, lobular deletion at mild diarrhea in infancy at 5.5 y disarray, Byler`s bile, nucleotide positions cirrhosis at 556~628; heterozygous hepatectomy nonsense mutation Q1131X 2 1 mo/F Persistent JD, rickets, 3.5 y Alive, growth Bland cholestasis, FIC1: homozygous pruritus, failure retardation fine granular bile missense mutation to thrive R296C 3 8 mo/M Mild JD, chronic 3 y Alive, progressive Cholestasis, FIC1: homozygous diarrhea in infancy JD, growth mild fibrosis missense mutation retardation I694N 4 1 mo/M JD, rickets 14 mo Alive Cholestasis, ND moderate fibrosis 5 1 mo/M Persistent JD 17 mo Biliary diversion Cholestasis, FIC1: heterozygous at 1 y, portal fibrosis, deletion at nucleotide moderate JD Byler`s bile position 185~282 6 Birth/F Progressive JD, 14 mo Death GCT, feathery FIC1 and BSEP: variceal bleeding degeneration no mutation 7 1 mo/F Persistent JD, 21 mo Alive, mild JD, GCT, pericellular BSEP: heterozygous severe pruritus, severe pruritus fibrosis 1 bp deletion at position chronic diarrhea 1145, and heterozygous V284L mutation 8 1 mo/F Progressive JD, 10 mo Alive, GCT, portal fibrosis BSEP: homozygous failure to thrive moderate JD G1004D mutation 9 1 mo/M Progressive JD, 4 mo Death GCT, fibrosis ND hepatic failure 10 Birth/F Progressive JD, 5 mo Death GCT, fibrosis ND hepatic failure 11 1.5 mo/M Progressive JD, 12 mo Death GCT ND hepatic failure 12 1 mo/M Progressive JD, 5 mo Death GCT, portal fibrosis ND hepatic failure 13 Birth/M Progressive JD, 15 mo Liver GCT, fibrosis ND failure to thrive, transplantation hepatic failure at 1 y All patients except 9 and 10 were of Chinese descent. Login to comment
78 A heterozygous 850G࢐C (V284L), and a heterozygous 1-bp deletion at position 1145 was found in 1 patient. Login to comment
80 The V284L missense mutation was in the intracellular loop between transmembrane spans 4 and 5. Login to comment
111 The BSEP (ABCB11) mutation V284L found in case 7 was in the vicinity of common European mutation E297G.7 No common mutations were shared among our patients, indicating that these mutations did not come from 123 Group 1 Group 2 P (n = 5) (n = 8) value Peak bilirubin (<17.1 &#b5;mol/L) 277 615 .059 (Range) (137-573) (180-1094) Peak AST (<60 U/L) 137 876 .002* (Range) (50-384) (504-1530) Peak ALT (<50 U/L) 74 471 .001* (Range) (24-174) (237-847) Serum GGT (<94 U/L) 24 55 .018* (Range) (14-41) (23-98) Serum bile acid (<10 &#b5;mol/L) 180 71 .001* (Range) (139-214) (16-127) Serum cholesterol (<200 U/L) 103 196 .207 (Range) (74-134) (47-438) Serum triglyceride (<200 U/L) 206 209 .966 (Range) (106-323) (38-448) AFP SD score 0.57 8.76 .007* (Range) (0-1.36) (2.4-16.2) Group 1, Patients with bland cholestasis in histology; Group 2, patients with giant cell transformation in histologic features. 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