ABCMdb

ABCB11 p.Tyr818Phe

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Publications

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

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
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: 19642168 [PubMed] Keitel V et al: "De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: a novel mechanism of cholestasis."

No. Sentence Comment

29 Compared to the reference sequence NM_003742 of BSEP (ABCB11), three homozygous missense changes were found: 1331T3C (V444A),17 2453A3T (Y818F), and 2944G3A (G982R)4 (start codon numbered as "1"). Login to comment
81 The patient`s mutations were introduced using the Quickchange-Multisite- mutagenesis kit (Stratagene) and the following primers: 2453A3T (Y818F): 5Ј-ccaatttctacagggatttgcctttgctaaatc- 3Ј; 2944G3A (G982R): 5Ј-cagaaagccaatatttacagattctgctt- tgcctttgc-3Ј. Login to comment
150 Introduction of the mutations V444A or Y818F separately or together into BSEP-YFP had no apparent effect on the localization of BSEPV444A, BSEPY818F, or BSEPV444A/Y818F as compared to wild-type BSEP-YFP (Fig. 2A, 4A). Login to comment
151 However, introduction of G982R alone or in combination with either V444A or Y818F (Fig. 4B) resulted in the retention of BSEPG982R, BSEPV444A/G982R, and BSEPY818F/G982R in the endoplasmic reticulum (ER) in colocalization with the ER marker protein disulfide isomerase. Login to comment
152 Combining all three mutations resulted in nondetectability of BSEPV444A/Y818F/G982R-YFP (Fig. 4C) independent of the cell type used (Supporting Fig. 3). Login to comment
154 Unexpectedly, K165 and K168 immunoreactivity, but no YFP fluorescence, was present in aggresomes of BSEPV444A/Y818F/ G982R-YFP-transfected cells after MG-132 treatment (Fig. 4G,J). Login to comment
165 Bars ϭ 10 ␮m. BSEPV444A/Y818F/G982R-YFP within the ER-associated degradation pathway. Login to comment
166 Furthermore, the apparent loss of YFP fluorescence is suggestive of an incomplete expression or a major folding defect of BSEPV444A/Y818F/G982R-YFP. Login to comment
175 It is of note, that in addition to the G982R and Y818F mutations, the common mutation/polymorphism V444A is necessary for the complete disappearance of BSEP. Login to comment
176 V444A has a high prevalence in the Caucasian population,17 has been linked to the development of drug-induced liver injury,30 and may aggravate cholestatic liver diseases such as intrahepatic cholestasis of pregnan- cy31 or benign recurrent intrahepatic cholestasis.32 Expression of BSEPV444A/Y818F/G982R in hepatic and nonhepatic cell lines was below detectability. Login to comment
184 The presence of G982R and Y818F caused the retention of mutated BSEPY818F/G982R-YFP within the endoplasmic reticulum. Login to comment
185 Combination of all three mutations of the patient (V444A,Y818F,G982R) induced complete absence of mutated BSEPV444A/Y818F/G982R-YFP. Login to comment
188 (G-L) Aggresomes, induced by MG132 in BSEPV444A/Y818F/G982R-YFP-expressing cells, contained immunoreactivity for the BSEP antibodies K165 (I) and K168 (L) but no green fluorescence, suggesting incomplete expression or misfolding of BSEPV444A/Y818F/G982R-YFP. 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

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

No. Sentence Comment

113 It was shown in vitro that the two BSEP mutations p.Y818F and p.G982R caused intracellular retention of BSEP. Login to 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

PMID: 25342496 [PubMed] Kubitz R et al: "Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis."

No. Sentence Comment

51 The three mutations/variants Y818F, G982R, and V444A have been found on the same allele in a PFIC-2 patient. Login to comment
52 BSEP with Y818F together with G982R is poorly expressed. Login to comment
87 Sex Age at LTX (years) Zygosity Nucleotide change Predicted (protein) effect BSEP expression (before LTX) BSEP autoantibodies detected Symptom recurrence- time after LTX (years) Triggering factors 1 [22, 63] F 3.5/3.5/4.9 hom hom c.2453A>T c.2944G>A p.Y818F p.G982R Absent (exp) Yes 1/0.4 Graft rejection after first LTX 2 [23] M 5.2 hom c.907A>G p.R303G Absent Yes 12 Unknown 3 [23] F 3.7 com het c.1741C>T IVS12+1G>T a p.L581F abb splic Absent Yes 3.5/5.2/8.1/12.1/13 EBV infection; ࢑ corticosteroids 4 [23] F 2.2 hom IVS17+1T>A a abb splic Absent Yes 2.1/4 Low CsA, switch from Tac to CsA 5 [62, 63] F 9 com het c.301delCA c.2944G>A p.Q101Dfs8X p.G982R Absent NA 3.3/17 ࢑ IS, pregnancy? Login to comment